Do I Lose Cognitive Function as Fast as my Twin Partner? Analyses Based on Classes of MMSE Trajectories of Twins Aged 80 and older

Do I Lose Cognitive Function as Fast as my Twin Partner? Analyses Based on Classes of MMSE Trajectories of Twins Aged 80 and older | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Do I Lose Cognitive Function as Fast as my Twin Partner? Analyses Based on Classes of MMSE Trajectories of Twins Aged 80 and older Graciela Muniz-Terrera, Annie Robitaille, Jantje Goerdten, Fernando Massa, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.2.22580/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 31 Oct, 2020 Read the published version in Age and Ageing → Version 1 posted You are reading this latest preprint version Abstract Background: Aging is associated with an increasing risk of decline in cognitive abilities. The decline is, however, not a homogeneous process. There are substantial differences across individuals although previous investigations have identified individuals with distinct cognitive trajectories. Evidence is accumulating that lifestyle contributes significantly to the classification of individuals into various clusters. How and whether genetically related individuals, like twins, change in a more similar manner is yet not fully understood. Methods: In this study, we fitted growth mixture models to Mini Mental State Exam scores (MMSE) from participants of the Swedish OCTO Twin study of oldest old monozygotic (MZ) and same-sex dizygotic (DZ) twins with the purpose of investigating whether twin pairs can be assigned to the same class of cognitive change. Results: We identified 4 distinct groups (latent classes) whose MMSE trajectories followed various patterns of change over time: a class of stable and high performing individuals, two groups of high performers who declined at different annual rates, and a small group of impaired individuals who declined more rapidly. Notably, our analyses show that few individuals in fact could be assigned to the same class as their co-twin. Conclusions: Our study provides evidence for more substantial impact of environmental, rather than genetic, influences on cognitive change trajectories in later life. Geriatrics & Gerontology Twins Growth Mixture Models Cognitive trajectories Figures Figure 1 Figure 2 Introduction Twins provide a unique and valuable source of information to better estimate the relative importance of genetic and environmental influences on various traits and functions. However, it is becoming increasingly apparent that the genetic setup can account only for a portion of the observed variance in most processes related to development, function, and disease. Monozygotic twin pairs (MZ), despite sharing identical DNA sequences, are often discordant, indicating that the same genotype in fact can produce distinct phenotypes. This points towards the involvement of environmental influences and gene-environmental (GxE) interactions. It is therefore quite unlikely that the unique sequence of our genomes provides the full blueprint for observed traits and functioning. Cognitive health and functioning are domains shown to be influenced by genetics as well as modifiable environmental risk factors. Twin studies converge on the conclusion that cognitive abilities are quite heritable also in later life (e.g. McGue and Christensen (1); McClearn et al. (2) using baseline data from the sample in the present). There are, however, differences related to specific ability under study. Analyses of subgroups defined by their actual cognitive level can present a more differential picture. For example, analyses by Petrill et al. (3), using baseline data from the sample used in the present study, showed high heritability for the high end of the distribution, but very low heritability at the low performance continuum. Longitudinal studies have shown that the E4 variant of the Apolipoprotein E allele is associated with greater cognitive decline among individuals without dementia (4). There is also a substantially increased risk among E4 variant carriers, especially in those with two ε4 alleles, to develop dementia (5). Although the E4 allele is known as the single most influential genetic risk factor for late-onset sporadic Alzheimer's disease (AD), it cannot be considered as the determinant of the disease. Many studies have shown that healthy lifestyle behaviors have a protective role. Individuals who engage in these behaviors typically perform better on cognitive tests and decline at a slower rate than those with a less healthy lifestyle. For instance, nonsmokers have been shown to decline at a slower rate in specific and global cognitive functions compared with smokers (6, 7). Similarly, it has been shown that individuals who engage in cognitively stimulating activities decline at a slower rate than individuals who do not stimulate their brains (8-10). They also have a lower risk of subsequent cognitive impairment and dementia (10-13). Furthermore, individuals with a physically active lifestyle decline at a slower rate than more sedentary individuals (14, 15). Existing evidence has examined the role of many modifiable risk factors on cognitive trajectories in older adults. But, these studies have often neglected the heterogeneity which is likely to produce subgroups of individuals with distinct cognitive trajectories (classes). The question is whether a classification of individuals into different subgroups, defined by their exposures to potential risk factors, can inform us about the relative contribution of environmental and underlying genetic influences. A first step toward an improved understanding of the observed heterogeneity of cognitive change is to cluster individuals according to their trajectories over time and then to identify distinguishing factors that contribute to the classification of individuals into clusters. Growth mixture models, GMM (16), offer analytical models specifically developed to identify groups of individuals (latent classes) who change in a similar manner. A multinomial logistic model with covariates can also produce a probabilistic classification of individuals into each of the classes identified. Several studies have employed this methodology to improve knowledge about aging related cognitive decline. For example, Muniz Terrera, Matthews , and Brayne (17) fitted GMM to Mini Mental State Exam scores (18) from a British sample aged 75 years and older at study entry. They identified a group of individuals whose Mini-Mental-State-Examination (MMSE) scores remained stable over time, another group that declined at fast rate and a third group of medium rate decliners. Olaya, Bobak, Haro, and Demakakos (19) analysed episodic memory scores from participants of the English Longitudinal Study of Ageing and identified 4 groups of individuals (low/decline, low/stable, average/stable and good/stable group) in the sample of individuals who entered the study aged 59-64 years old; whilst in the group of older adults (65-79 years at study entry), they identified 4 groups characterized as very low/rapid decline, low/decline, average/stable and good/stable. Hayden et al. (20), in an analysis of a global composite cognitive score, derived from a battery of 19 neuropsychological tests administered in the Religious Order Study, identified 3 groups; individuals whose trajectories over time were characterized with slow decline from a slightly above average baseline score, a group of moderate decliners, and a third group of individuals whose baseline score were low followed by a fast decline. The literature provides increasing evidence demonstrating a great heterogeneity of cognitive trajectories in older adults. However, research efforts focusing specifically on heterogeneity in the segment of the oldest old is limited. In addition, we lack knowledge about whether pairs of twins in this segment of the population show similar trajectories. In this paper, we used data from the OCTO Twin Study, a longitudinal study of Swedish twins aged 80 and older, to examine whether: (i) we can identify distinct classes or clusters of individuals with similar cognitive trajectories, defined by their scores on the Mini Mental State Exam (MMSE), (ii) pairs of monozygotic twins (MZ) are more likely than pairs of same-sex dizygotic twins (DZ) to be assigned to the same class, and ( iii ) a list of a set of previously identified and modifiable risk factors are relevant for the assignment of individuals into various classes. Analytical Methods OCTO Twin Study The sample used in these analyses was drawn from the comprehensive longitudinal Origins of Variance in the Old-Old: Octogenarian Twins (known as the OCTO-Twin Study) based on the oldest cohort of the Swedish Twin Registry (21). The sample includes 702 participants, with 351 complete twin pairs (149 identical (monozygotic) and 202 same-sex fraternal (dizygotic pairs)), born in 1913 and earlier, who were, or became, 80 years of age during the first wave of data collection (1991-1993). Participants were re-assessed biannually (over an 8 year period) at their homes or place of residency by medical research nurses specially trained for the study. The average rate of attrition from one wave of examination to the next was 20% (10% per year), primarily due to death. Full details of the study population characteristics have been published previously (2, 21, 22), including findings on cognitive performances relative to survival (see Johansson et al. (23)). Global cognitive function was assessed using the Mini-Mental State Examination MMSE screening device (18), which has become a frequently used screening device for overall cognitive function in clinical and research samples. The MMSE measures various domains including orientation, registration (immediate memory), short-term memory (but not long-term memory), attention, the ability to follow verbal and written commands, writing and copying. Scores range from 0–30 and high values indicate better cognitive status. The observed trajectories and scores in our sample, plotted against years past from baseline, are depicted in Figure 1. In addition to socio demographic information about participants such as age, sex and years of education, whether or not they ever received a dementia diagnosis, lifestyle information was also collected. Specifically, smoking habits were assessed by asking whether participants ever smoked, they smoked “now and then”, they had been smokers but quitted or whether they were current smokers. Participants were also asked about whether they had or presently stimulated their brains to some or a large extent in cognitively demanding activities. They were also asked whether they trained and stimulated their bodies to some or a large extent. Table 1 presents the descriptive characteristics of the sample. Ethics The OCTO-Twin Study received approval from the Ethics Committee at the Karolinska Institute in Stockholm and from the Swedish Data Inspection Authority. Informed written consent was obtained from all participants or their relative or caregiver where capacity to consent was questionable, for example, due to severe cognitive impairment or dementia. Statistical Analysis We fitted a series of growth mixture models (GMM) to MMSE scores aligned as a function of number of years past from study entry to identify subgroups (classes) of individuals with similar MMSE trajectories. The number of available time points (i.e. 5 waves) allowed us to examine linear as well as accelerating patterns of change. Class specific intercepts and slopes were adjusted for sociodemographic factors (age, sex and education) and a dementia indicator variable. To learn about the role of these sociodemographic factors and of lifestyle factors on class assignment, we adjusted the multinomial logistic model for class probability for baseline age, education, sex, smoking status, physical activity and engagement in cognitively stimulating activities. Baseline age and education (measured in years) were modelled as continuous variables centered at the sample median values, 83 years of age and 7 years of education respectively. A dementia indicator was coded as 1 if an individual ever received a diagnosis of dementia and 0 if the individual never was diagnosed with dementia during the study period. Sex was coded as 0 for a male participant and 1 for a female participant. Binary indicators were derived to describe lifestyle factors and coded as follows: individuals who ever smoked were coded as 1 and those who never smoked were coded as 0; individuals who never trained their brains were coded as 1 and those who said they did were coded as 0. Similarly, individuals who did not engage in any physical training were coded as 0 and those who did were coded as 1. We followed recommended practice to select the optimal model, including the identification of the number of classes. We fitted a series of models with an increasing number of classes and selected the best fitting model by comparing model fit indices, evaluating of entropy values and considering interpretability of each class (24). Specifically, we inspected the Bayesian Information Criterion (BIC), the sample-size adjusted BIC (SSABIC), entropy values and the Lo-Mendel-Rubin likelihood ratio test (LMR-LRT). Lower BIC and SSABIC values indicate a more parsimonious and better fitting model, whereas higher entropy values signal better class separation. Once the best fitting model was identified, an a posteriori analysis of the distribution of twins across classes and the distribution of pairs of twins and their zygosity by class was conducted to investigate if monozygotic pairs were more likely to be assigned to the same class than dizygotic pairs. Models were estimated in Mplus v8.0 by full maximum likelihood (FML) and robust standard errors (MLR) to non-normality and non-independence of observations (25). Missing data are assumed to be missing at random. To avoid local maxima for the EM (expectation-maximization) algorithm, we estimated the models with up to 1000 random starting values. The MMSE is known to produce ceiling and floor effects. To investigate whether our results were sensitive to these effects, we fitted Tobit Growth Mixture models and compared results to the ones generated by the traditional GMM formulation. Results Our analytical sample comprised of 628 individuals, of whom 220 (35%) were men and 408 (64%) women. Women were older than men (women: 83.61 (SD=3.17) yrs. old vs men: 82.95 (SD=2.76) yrs. old, t-test, p-value=0.007) and had fewer years of education than men (women: 6.96 (SD=1.89), men: 7.51 (SD=2.90), t-test, p-value=0.01). More than 73% of the sample (n=463) remained free of dementia over the study follow-up period. See Table 1 for descriptive sample characteristics. The sample included 272 (43%) monozygotic and 356 (57%) dizygotic individuals. Sixty-three individuals (10% of total sample, 24 monozygotic and 39 dizygotic twins) were excluded due to missing data for their co-twin. Monozygotic twins were slightly more educated than dizygotic twins (7.50 (SE=0.16) years of education vs 6.89 (SE=0.10) years of education respectively, t-test, p-value=0.0009) and a larger proportion of monozygotic twins were sedentary compared to dizygotic twins (63% vs 53% respectively, chi square test, p-value=0.02). Sixty per cent (60%) of monozygotic and 68% of dizygotic individuals were women. Inspection of BIC, SSABIC, and the Lo-Mendel-Rubin likelihood ratio test values resulted in the identification of a 4-class model as the best fitting model. The entropy for this model was 0.74, a value that suggests a good discrimination of individuals into these 4 classes. Table 1 Descriptive statistics of the OCTO-Twin sample Variables N Mean (SD) Baseline characteristics N (%) MMSE 1 628 26.3 (3.9) Monozygotic 272 (43.0) MMSE 2 524 24.9 (6.2) Female 408 (65.0) MMSE 3 404 24.4 (7.1) Smoker 248 (39.5) MMSE 4 298 23.7 (7.5) Stimulates the body 266 (42.4) MMSE 5 217 22.3 (7.8) Stimulates brain 416 (66.3) Education (years) 7.5 (2.3) Diagnosed with dementia 165 (26.3) MMSE 1-5 are the MMSE scores at every follow-up. SD standard deviation MMSE trajectory classes and characteristics First, we examine the characteristics revealed in the 4 class model (see Table 2). In Figure 1 we show a graphical illustration of the observed and estimated MMSE trajectories in our analytical sample. Table 2 Results from the 4- class growth mixture model that best fitted the OCTO-Twin sample High performers and stable N=198 High performers with slow decline N=194 High performers with fast decline N=181 Impaired very fast decline N=55 β (SE) p β (SE) p β (SE) p β (SE) p Fixed effects MMSE Level 28.9 (0.14) 0.00 27.62 (0.32) 0.00 26.34 (0.59) 0.00 19.30 (2.18) 0.00 Baseline age -0.08 (0.03) 0.00 -0.16 (0.07) 0.02 -0.18 (0.12) 0.12 0.28 (0.23) 0.24 Education 0.04 (0.02) 0.04 0.09 (0.08) 0.26 0.30 (0.17) 0.09 0.73 (0.62) 0.23 Women 0.26 (0.13) 0.06 0.24 (0.37) 0.51 -0.15 (0.72) 0.83 2.71 (2.26) 0.23 Dementia -0.50 (0.09) 0.02 0.13 (0.42) 0.75 -1.18 (0.74) 0.11 -4.29 (1.28) 0.00 Linear Slope -0.04 (0.04) 0.30 -0.31 (0.09) 0.00 -0.96 (0.14) 0.00 -2.95 (0.86) 0.00 Baseline age 0.00 (0.00) 0.60 -0.04 (0.08) 0.82 -0.02 (0.03) 0.47 -0.02 (0.09) 0.77 Education 0.00 (0.00) 0.42 -0.01 (0.02) 0.51 -0.08 (0.05) 0.11 -0.84 (0.53) 0.10 Women 0.02 (0.04) 0.61 0.03 (0.10) 0.72 0.10 (0.18) 0.57 -0.06 (1.03) 0.95 Dementia -0.11 (0.09) 0.23 -0.76 (0.14) 0.00 -1.40 (0.18) 0.00 -0.76 (0.52) 0.15 Random effects Level 0.06 (0.08) 0.42 0.06 (0.08) 0.42 0.06 (0.08) 0.42 0.06 (0.08) 0.42 Linear Slope 0.02 (0.00) 0.00 0.02 (0.00) 0.00 0.02 (0.00) 0.00 0.02 (0.00) 0.00 Error 0.66 (0.06) 0.00 5.30 (0.48) 0.00 22.24 (2.43) 0.00 27.11 (3.72) 0.00 High Performers and Stable class The largest class was comprised of 32% of the sample (n=198). A reference individual in this class is a man aged 83 years at study entry with 7 years of education with an average MMSE score at study entry of 28.9 (SE=0.1), and who remained free of dementia over the study period. The annual rate of MMSE change was only -0.04 (SE=0.04), an estimate that did not reach conventional significance thresholds. In this class, older baseline age was associated with a lower baseline MMSE performance (ß=-0.08 (SE=0.03), while education was associated with higher baseline MMSE score (ß=0.04 (SE=0.02)). Individuals who later received a diagnosis of dementia had poorer MMSE performance at study entry than individuals who remained free of dementia (ß=-0.48, SE=0.10)) High Performers with Slow Decline class Thirty-one per cent (31%, n=194) of the sample were assigned to a class with an average MMSE score of 27.6 (SE=0.3) at study entry. Their annual decline was -0.3(0.09) MMSE points. Age was associated with poorer baseline MMSE performance, and those who ever received a diagnosis of dementia declined at a faster rate than those who remained free from dementia. High Performers with Fast Decline class Twenty-nine per cent (29%, n=181) of the sample was assigned to a class with a slightly lower baseline MMSE score than the other class of high performing individuals, but they declined at a faster rate. Specifically, in this class, the reference individual had an average MMSE score at study entry of 26.3 (SE=0.6) with an annual decline of -0.9 (SE=0.1) MMSE points. Individuals who received a diagnosis of dementia declined 1.4 MMSE points faster per year than those who remained non-demented. None of the risk factors emerged as significantly associated with MMSE baseline performance, nor with rate of change. Impaired Very Fast Decline class Finally, 8 % (n=55) of the sample was assigned to a class characterized by low baseline scores and more substantial decline. Their average MMSE score at study entry was 19.3 (SE=2.2), followed by an annual decline of -2.9 (SE=0.8). Individuals who received a diagnosis of dementia had even poorer baseline MMSE performance, compared with those who remained free from dementia. None of the other risk factors reached significance levels. Risk factors and class assignment probability Next, we examine the effect of risk factors in relation to the above classification (see Table 3). Compared with the high performing and stable class and as expected, older age at study entry, was associated with higher odds of being in the class of impaired performers with very fast decline. This was also the case in the two classes of high performing individuals. Women and more educated individuals had lower odds of being in the class of High Performers with Fast decline individuals , than in the High Performers and Stable class of individuals. Individuals who did not engage in physical activity were more likely to be in the High Performing with Fast Decline class, compared to the High Performing and Stable class of individuals , a finding that suggests a partial protective effect of education and physical activity. Table 3 Odds ratio results from multinomial model for class assignment with reference to the High Performers and Stable class High performers with slow decline High performers with fast decline Impaired very fast decline OR (SE) p OR (SE) p OR (SE) p Baseline age 1.12 (0.06) 0.05 1.17 (0.07) 0.01 1.22 (0.09) 0.00 Education 0.92 (0.05) 0.11 0.75 (0.08) 0.00 0.75 (0.11) 0.03 Women 0.88 (0.28) 0.67 0.51 (0.18) 0.00 1.04 (0.62) 0.93 Smoking 1.18 (0.34) 0.60 0.96(0.32) 0.92 1.08 (0.57) 0.88 Stimulates the body 1.12 (0.33) 0.71 2.28 (0.60) 0.03 5.20 (2.36) 0.07 Stimulates the brain 1.31 (0.36) 0.38 1.89 (0.54) 0.10 6.73 (4.84) 0.23 OR odds ratio; SE standard error Distribution of twins across classes In the next step, we examine the distribution of twins and partners across the four classes. In the high performing and stable class there were 47 twin pairs (i.e., 94 individuals out of 198). In the classes of High Performers with Slow Decline and High Performers with Fast Decline, there were 27 twin pairs (54 individuals out of 194) and 23 pairs (46 individuals out of 181), respectively. In the class of Impaired individuals with Very Fast Decline , there were 4 pairs of twins (8 individuals out of 55). These numbers indicate that 47.5 % of the individuals in the High Performers and Stable Class in fact had a twin partner in the same class. The corresponding proportion of having a twin in the same class was 23.7% among the High Performers with Slow Decline, and 29.8% in the class of High Performers with Fast Decline. Lastly, in the Impaired and Fast Declining class 14.4 % of individuals had a co-twin in the same class. In the final step we conducted posteriori analyses, to test whether zygosity was associated with the likelihood of being assigned to a certain class (see Figure 2). Our analyses, however, failed to find evidence in support of an association ( X 2 (3 p=0.46), which means that the likelihood for being in a certain class was similar for MZ and same-sex DZ twins. Discussion In the present study we investigated the heterogeneity change trajectories in the Mini-Mental-State Examination Screening Test (MMSE, (18)) in a sample of oldest-old monozygotic and same-sex dizogtic Swedish twins. More specifically, we evaluated whether a sub-classification of individuals into various change trajectories (classes) also could provide information about the likelihood for genetic resemblance and risk factor exposures. We first identified 4 distinct subgroups of individuals with similar change trajectories. The majority of individuals was classified into three groups with MMSE baseline scores above impairement levels, who showed a more preserved cognition or a decline at relatively slow or faster annual rate. The fourth class was comprised of individuals who at study entry already had a low MMSE score and who thereafter declined at a faster rate. This may be a consequence of a healthy survivor effect of oldest-old individuals, as the inclusion criteria also required participation of both partners in a twin pair. The overall MMSE score for the entire sample was 26.3 (SD=3.9), which suggests that many individuals had a fairly good global cognition when they entered the study. Previous studies have investigated the heterogeneity of aging-related cognitive decline measured by the MMSE and reported the existence of groups of individuals whose trajectories follow different patterns of change (26, 27). For example, Muniz Terrera et al. (26) studied a sample of British individuals aged 75 years old and older at study entry and identified 3 distinct patterns of MMSE change, Min (28) studied a sample of healthy Koreans aged 60 and over at baseline and identified 2 groups and Leoutsakos et al. (29) analysed a sample of American adults aged 65 and over at study entry and identified 4 different MMSE patterns of change. However, differences in study designs, features of the samples tend to make comparisons difficult. For example, whether individuals with dementia at baseline or later were included, and the different rates of non- participation at follow-ups may explain some of these inconsistencies. In addition, the analytical decisions made in each study (such as the adjustment for different variables) preclude the direct comparison of published results across publications. Despite these differences, studies provide evidence of multiple and distinct patterns of MMSE change over time. Noteworthy, our findings about the distribution of twins across the four classes showed that the majority of twins were not assigned to the same class as their co-twin. This outcome provides evidence in support of a greater role for lifestyle and environmental exposures in late life cognitive change, than for genetic influences. This is further reinforced by the finding demonstrating an independence between zygosity and class. A large effect of genetics would otherwise have shown that monozygotic twins were more likely to be assigned to the same change trajectory class. Our findings are, therefore, in support of a nurture rather than a nature effect. Yet, given the relatively small sample and the inclusion only of the oldest old age segment in our study, further research is necessary to provide better understanding of the relative contributions of genetic and environmental influences on late life cognitive change. Furthermore, the effect of examined risk factors on class specific level and rate of change was not clear and consistent across classes. A diagnosis of dementia also showed different effects across the four classes. In the High Performers with Slow Decline and High Performers with Fast Decline classes, but not in the class of Impaired and High Performers Stable Class , individuals who received a diagnosis of dementia declined at a faster rate than those who remained non-demented. In the High Performers and Stable Class , the performance at study entry was unexpectedly almost half an MMSE point below the performance of individuals who in fact later received a diagnosis of dementia. It is possible that they were diagnosed later although demonstrating a compromised cognitive health already at baseline. Interestingly, older age at study entry emerged as negatively associated with MMSE performance only in the High Performers with Slow Decline and in the High Performers Stable Class . In the latter, we found that education had a protective effect. This is not unexpected, as other publications quite consistently have shown that education is associated with level, but not with rate of change. Further, this result is in agreement with Muniz Terrera et al. (26), who identified 3 classes of individuals with similar MMSE trajectories and reported an association of education with baseline MMSE in the class of individuals who preserved cognitive function over time, but not with baseline MMSE or rate of change in the other 2 classes. These findings are partly supportive of the theory of passive reserve (30) suggesting that individuals with higher educational attainment will consistently perform at a higher cognitive level as they age given their greater baseline cognitive reserve, although they decline at a similar rate with their lower educated peers. Our results about the effect of lifestyle factors on the probability of class assignment provide partial support to the hypothesis that lifestyle factors may have a protective effect on cognitive function. The findings that being physically active increases the probability of being assigned to the High Performers and Stable Class, compared to the class of High Performers with fast Decline, but not to the Impaired Decliners or High Performers with Slow Decline is somehow unexpected. In our study, physical activity was only measured by asking participants “Are you presently doing or have you previously done anything special to train your body or keep your body fit?”. Hence, the opportunities to detect and evaluate the long-term effect of physical activity is limited as the question only captures the individuals’ engagement on physical activities closer to study entry, and less about the intensity and life-course engagement in these activities. Unfortunately, dose (intensity, duration, frequency) and mode of the activities performed (balance, flexibility, resistance) are not captured by our global question. The literature on the mechanisms by which physical activity may have a protective effect on cognitive function in old age shows that this effect varies by dose, mode and cognitive function evaluated (31). Our study also has some other limitations. Despite that the sample size of our study is large, considering the advanced age of study participants, models with 5 and more classes failed to identify meaningful classes as the classes identified were very small classes and models failed to converge even after fixing various model parameters. Further, GMM models were fitted under a missing at random assumption which may not be fully justified. It is also most likely that our questions about engagement in physical and cognitively stimulating activities are far from optimal to capture the role of these life-style behaviors nowadays given a crucial role also for late life cognitive functioning. However, this study was initiated already in 1991, when research about their effect on cognitive health was still in early stages. In sum, this is the first investigation based on a classification of a twin sample into distinct groups defined by their longitudinal MMSE scores. Our analyses of similarities and differences between monozygotic and same-sex dizygotic twin pairs suggest a more minor role of genetic effects in late life cognitive change. Declarations Ethics approval and consent to participate The OCTO-Twin Study received approval from the Ethics Committee at the Karolinska Institute in Stockholm and from the Swedish Data Inspection Authority. Informed written consent was obtained from all participants or their relative or caregiver where capacity to consent was questionable, for example, due to severe cognitive impairment or dementia. Consent for publication Not applicable Availability of data and materials The data that support the findings of this study are not freely available, which were used under license for the current study, and so are not publicly available. However, data analytics and study materials can be shared by contacting the corresponding author. Competing interests The authors declare that they have no conflict of interest. Funding This work was funded by NIH/NIA Program Project Grant (P01AG043362; 2013-2018). The OCTO Twin Study was originally supported by a grant from NIA (AG 08861). Authors' contributions GM designed the project, performed the main analysis and wrote the paper. AR contributed to the discussion of the paper and editing. JG contributed to the data analysis, contributed to the discussion and edited the paper. FM contributed to the discussion and editing of the paper. BJ designed and collected the data and contributed to the discussion and editing of the paper. References McGue M, Christensen K. The heritability of cognitive functioning in very old adults: Evidence from Danish twins aged 75 years and older. Psychology and Aging. 2001;16(2):272-80. doi:10.1037/0882-7974.16.2.272 McClearn GE, Johansson B, Berg S, et al. Substantial Genetic Influence on Cognitive Abilities in Twins 80 or More Years Old. Science. 1997;276(5318):1560. doi:10.1126/science.276.5318.1560 Petrill SA, Johansson B, Pedersen NL, et al. Low cognitive functioning in nondemented 80+-year-old twins is not heritable. Intelligence. 2001;29(1):75-83. doi:https://doi.org/10.1016/S0160-2896(00)00047-7 Packard CJ, Westendorp RG, Stott DJ, et al. Association between apolipoprotein E4 and cognitive decline in elderly adults. Journal of the American Geriatrics Society. 2007;55(11):1777-85. doi:10.1111/j.1532-5415.2007.01415.x Sadigh-Eteghad S, Talebi M, Farhoudi M. Association of apolipoprotein E epsilon 4 allele with sporadic late onset Alzheimer`s disease. A meta-analysis. Neurosciences (Riyadh, Saudi Arabia). 2012;17(4):321-6. Wang CC, Lu TH, Liao WC, et al. Cigarette smoking and cognitive impairment: a 10-year cohort study in Taiwan. Archives of gerontology and geriatrics. 2010;51(2):143-8. doi:10.1016/j.archger.2009.09.041 Wingbermühle R, Wen KX, Wolters FJ, Ikram MA, Bos D. Smoking, APOE Genotype, and Cognitive Decline: The Rotterdam Study. Journal of Alzheimer's disease : JAD. 2017;57(4):1191-5. doi:10.3233/jad-170063 Ferreira N, Owen A, Mohan A, Corbett A, Ballard C. Associations between cognitively stimulating leisure activities, cognitive function and age-related cognitive decline. International Journal of Geriatric Psychiatry. 2015;30(4):422-30. doi:10.1002/gps.4155 Hassing LB. Gender Differences in the Association Between Leisure Activity in Adulthood and Cognitive Function in Old Age: A Prospective Longitudinal Population-Based Study. The Journals of Gerontology: Series B. 2017. doi:10.1093/geronb/gbx170 Hughes TF, Sun Z, Chang C-CH, Ganguli M. Change in Engagement in Cognitive Activity and Risk for Mild Cognitive Impairment in a Cohort of Older Adults: The Monongahela-Youghiogheny Healthy Aging Team (MYHAT) Study. Alzheimer Disease & Associated Disorders. 2018;32(2):137-44. doi:10.1097/wad.0000000000000214 Kivipelto M, Mangialasche F, Ngandu T. Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease. Nature Reviews Neurology. 2018;14(11):653-66. doi:10.1038/s41582-018-0070-3 Krell-Roesch J, Vemuri P, Pink A, et al. Association Between Mentally Stimulating Activities in Late Life and the Outcome of Incident Mild Cognitive Impairment, With an Analysis of the APOE ε4 Genotype. JAMA Neurology. 2017;74(3):332-8. doi:10.1001/jamaneurol.2016.3822 Yates LA, Ziser S, Spector A, Orrell M. Cognitive leisure activities and future risk of cognitive impairment and dementia: systematic review and meta-analysis. International Psychogeriatrics. 2016;28(11):1791-806. doi:10.1017/S1041610216001137 Hamer M, Muniz Terrera G, Demakakos P. Physical activity and trajectories in cognitive function: English Longitudinal Study of Ageing. Journal of Epidemiology and Community Health. 2018;72(6):477. doi:10.1136/jech-2017-210228 Robitaille A, Muniz Terrera G, Lindwall M, et al. Physical activity and cognitive functioning in the oldest old: within- and between-person cognitive activity and psychosocial mediators. European Journal of Ageing. 2014;11(4):333-47. doi:10.1007/s10433-014-0314-z Muthén B, Shedden K. Finite Mixture Modeling with Mixture Outcomes Using the EM Algorithm. Biometrics. 1999;55(2):463-9. doi:10.1111/j.0006-341X.1999.00463.x Muniz Terrera G, Matthews F, Brayne C. A comparison of parametric models for the investigation of the shape of cognitive change in the older population. BMC Neurology. 2008;8(1):16. doi:10.1186/1471-2377-8-16 Folstein MF, Folstein SE, McHugh PR. "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. Journal of psychiatric research. 1975;12(3):189-98. doi:10.1016/0022-3956(75)90026-6 Olaya B, Bobak M, Haro JM, Demakakos P. Trajectories of Verbal Episodic Memory in Middle-Aged and Older Adults: Evidence from the English Longitudinal Study of Ageing. Journal of the American Geriatrics Society. 2017;65(6):1274-81. doi:10.1111/jgs.14789 Hayden KM, Reed BR, Manly JJ, et al. Cognitive decline in the elderly: an analysis of population heterogeneity. Age and Ageing. 2011;40(6):684-9. doi:10.1093/ageing/afr101 Cederlof R, Lorich U. The Swedish Twin Registry. Progress in clinical and biological research. 1978;24 Pt B:189-95. Pedersen NL, Lichtenstein P, Svedberg P. The Swedish Twin Registry in the Third Millennium. Twin Research. 2012;5(5):427-32. doi:10.1375/twin.5.5.427 Johansson B, Hofer SM, Allaire JC, et al. Change in Cognitive Capabilities in the Oldest Old: The Effects of Proximity to Death in Genetically Related Individuals Over a 6-Year Period. Psychology and Aging. 2004;19(1):145-56. doi:10.1037/0882-7974.19.1.145 Kandauda K.A.S. Wickrama TKL, Catherine Walker O'Neal, Frederick O. Lorenz. Growth Mixture Modeling. Higher-Order Growth Curves and Mixture Modeling with Mplus: A Practical Guide. New York: Routledge Taylor and Francis Group; 2016. Muthén LK, Muthén, B.O. Mplus User’s Guide. Eighth Edition ed. Los Angeles, CA: 1998-2017. Muniz Terrera G, Brayne C, Matthews F. One size fits all? Why we need more sophisticated analytical methods in the explanation of trajectories of cognition in older age and their potential risk factors. International Psychogeriatrics. 2009;22(2):291-9. doi:10.1017/S1041610209990937 Wilkosz PA, Seltman HJ, Devlin B, et al. Trajectories of cognitive decline in Alzheimer's disease. International Psychogeriatrics. 2009;22(2):281-90. doi:10.1017/S1041610209991001 Min JW. A longitudinal study of cognitive trajectories and its factors for Koreans aged 60 and over: A latent growth mixture model. International Journal of Geriatric Psychiatry. 2018;33(5):755-62. doi:10.1002/gps.4855 Leoutsakos J-MS, Forrester SN, Corcoran CD, et al. Latent classes of course in Alzheimer's disease and predictors: the Cache County Dementia Progression Study. International Journal of Geriatric Psychiatry. 2015;30(8):824-32. doi:10.1002/gps.4221 Katzman R. Education and the prevalence of dementia and Alzheimer’s disease. Neurology. 1993;43(1 Part 1):13. doi:10.1212/WNL.43.1_Part_1.13 Netz Y. Is There a Preferred Mode of Exercise for Cognition Enhancement in Older Age?-A Narrative Review. Front Med (Lausanne). 2019;6:57-. doi:10.3389/fmed.2019.00057 Cite Share Download PDF Status: Published Journal Publication published 31 Oct, 2020 Read the published version in Age and Ageing → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-13154","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":328427,"identity":"c2c5823a-1bd0-443b-9431-681720e48159","order_by":1,"name":"Graciela Muniz-Terrera","email":"","orcid":"","institution":"The University of Edinburgh","correspondingAuthor":false,"prefix":"","firstName":"Graciela","middleName":"","lastName":"Muniz-Terrera","suffix":""},{"id":328428,"identity":"ef7e87c7-fcbb-43a8-a561-7d338fd3bdb5","order_by":2,"name":"Annie Robitaille","email":"","orcid":"","institution":"Universite du Quebec a Montreal","correspondingAuthor":false,"prefix":"","firstName":"Annie","middleName":"","lastName":"Robitaille","suffix":""},{"id":328429,"identity":"8ca5f77e-7441-40a4-ae57-3108533fadf2","order_by":3,"name":"Jantje Goerdten","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEUlEQVRIie2RsWrDMBCGzwjsMatMoXkFCUNxSYhfRcYQL0lnDxk0OYuCV+ct+ggpAmdxd0ELTZZMGQxdAoVQqbShi5y1UH2DxKH7+E8cgMPxB/G4PvB3Ye5bAPZVkB7F4xdlAxBdVX6CLkrKrylo+bzdxQVMqmC1f+mK17wKmNedQEbWCPGQctxCthbbKN60h/la7FAoQN7Zp5pRHpaQETX18VMp54+KwQ2AHFuV6qiVs1beDlo5yzxRDH30KrVJ4TAhytcKl4xg5psU+2D1kda4wSwUUxS3jaR1uy/vBcmt36fVjLzjxTgZBI2nioUcDpaZVKdiRLlN0Q8IA05/NZhF9SxyaFo6gMTe4nA4HP+eTzKtWSxsX/URAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-7814-1802","institution":"The University of Edinburgh","correspondingAuthor":true,"prefix":"","firstName":"Jantje","middleName":"","lastName":"Goerdten","suffix":""},{"id":328430,"identity":"7668fa52-f0c8-48d2-a7b3-3a7375c03ec6","order_by":4,"name":"Fernando Massa","email":"","orcid":"","institution":"Universidad de la Republica Uruguay","correspondingAuthor":false,"prefix":"","firstName":"Fernando","middleName":"","lastName":"Massa","suffix":""},{"id":328431,"identity":"acdf50a7-07f9-4224-ad1c-b3aedb6f3a6e","order_by":5,"name":"Boo Johansson","email":"","orcid":"","institution":"Goteborgs Universitet","correspondingAuthor":false,"prefix":"","firstName":"Boo","middleName":"","lastName":"Johansson","suffix":""}],"badges":[],"createdAt":"2020-02-02 13:09:47","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.2.22580/v1","doiUrl":"https://doi.org/10.21203/rs.2.22580/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1093/ageing/afaa239","type":"published","date":"2020-10-31T19:36:04+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":444519,"identity":"231d126d-9e86-48b5-a3a7-167b918a3c37","added_by":"auto","created_at":"2020-02-04 15:11:20","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":56459,"visible":true,"origin":"","legend":"MMSE observed and model predicted class-specific trajectories plotted as a function of time (years past since baseline)","description":"","filename":"Fig1.jpeg","url":"https://assets-eu.researchsquare.com/files/4af19e18-79fb-478c-930c-3004cd8b6a8b/v1/Fig1.jpeg"},{"id":444520,"identity":"1f696aa7-24fe-4117-a125-acaf5567d743","added_by":"auto","created_at":"2020-02-04 15:11:20","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":33534,"visible":true,"origin":"","legend":"Frequency of Monozygotic and Dizygotic Individuals across MMSE classes","description":"","filename":"Fig2.jpeg","url":"https://assets-eu.researchsquare.com/files/4af19e18-79fb-478c-930c-3004cd8b6a8b/v1/Fig2.jpeg"},{"id":13489048,"identity":"164efc53-3c2a-453d-8a1d-353638055d62","added_by":"auto","created_at":"2021-09-16 22:17:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":402424,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-13154/v1/1b7e4230-2770-4253-bddf-b03ea20e78ab.pdf"}],"financialInterests":"","formattedTitle":"Do I Lose Cognitive Function as Fast as my Twin Partner? Analyses Based on Classes of MMSE Trajectories of Twins Aged 80 and older","fulltext":[{"header":"Introduction","content":"\u003cp\u003eTwins provide a unique and valuable source of information to better estimate the relative importance of genetic and environmental influences on various traits and functions. However, it is becoming increasingly apparent that the genetic setup can account only for a portion of the observed variance in most processes related to development, function, and disease. Monozygotic twin pairs (MZ), despite sharing identical DNA sequences, are often discordant, indicating that the same genotype in fact can produce distinct phenotypes. This points towards the involvement of environmental influences and gene-environmental (GxE) interactions. It is therefore quite unlikely that the unique sequence of our genomes provides the full blueprint for observed traits and functioning.\u003c/p\u003e\n\u003cp\u003eCognitive health and functioning are domains shown to be influenced by genetics as well as modifiable environmental risk factors. Twin studies converge on the conclusion that cognitive abilities are quite heritable also in later life (e.g. McGue and Christensen (1); McClearn et al. (2) using baseline data from the sample in the present). There are, however, differences related to specific ability under study. Analyses of subgroups defined by their actual cognitive level can present a more differential picture. For example, analyses by Petrill et al. (3), using baseline data from the sample used in the present study, showed high heritability for the high end of the distribution, but very low heritability at the low performance continuum. Longitudinal studies have shown that the E4 variant of the Apolipoprotein E allele is associated with greater cognitive decline among individuals without dementia (4). There is also a substantially increased risk among E4 variant carriers, especially in those with two \u0026epsilon;4 alleles, to develop dementia (5). Although the E4 allele is known as the single most influential genetic risk factor for late-onset sporadic Alzheimer's disease (AD), it cannot be considered as the determinant of the disease.\u003c/p\u003e\n\u003cp\u003eMany studies have shown that healthy lifestyle behaviors have a protective role. Individuals who engage in these behaviors typically perform better on cognitive tests and decline at a slower rate than those with a less healthy lifestyle. For instance, nonsmokers have been shown to decline at a slower rate in specific and global cognitive functions compared with smokers (6, 7). Similarly, it has been shown that individuals who engage in cognitively stimulating activities decline at a slower rate than individuals who do not stimulate their brains (8-10). They also have a lower risk of subsequent cognitive impairment and dementia (10-13). Furthermore, individuals with a physically active lifestyle decline at a slower rate than more sedentary individuals (14, 15). Existing evidence has examined the role of many modifiable risk factors on cognitive trajectories in older adults. But, these studies have often neglected the heterogeneity which is likely to produce subgroups of individuals with distinct cognitive trajectories (classes). The question is whether a classification of individuals into different subgroups, defined by their exposures to potential risk factors, can inform us about the relative contribution of environmental and underlying genetic influences.\u003c/p\u003e\n\u003cp\u003eA first step toward an improved understanding of the observed heterogeneity of cognitive change is to cluster individuals according to their trajectories over time and then to identify distinguishing factors that contribute to the classification of individuals into clusters. Growth mixture models, GMM (16), offer analytical models specifically developed to identify groups of individuals (latent classes) who change in a similar manner. A multinomial logistic model with covariates can also produce a probabilistic classification of individuals into each of the classes identified.\u003c/p\u003e\n\u003cp\u003eSeveral studies have employed this methodology to improve knowledge about aging related cognitive decline. For example, Muniz Terrera, Matthews , and Brayne (17) fitted GMM to Mini Mental State Exam scores (18) from a British sample aged 75 years and older at study entry. They identified a group of individuals whose Mini-Mental-State-Examination (MMSE) scores remained stable over time, another group that declined at fast rate and a third group of medium rate decliners. Olaya, Bobak, Haro, and Demakakos (19) analysed episodic memory scores from participants of the English Longitudinal Study of Ageing and identified 4 groups of individuals (low/decline, low/stable, average/stable and good/stable group) in the sample of individuals who entered the study aged 59-64 years old; whilst in the group of older adults (65-79 years at study entry), they identified 4 groups characterized as very low/rapid decline, low/decline, average/stable and good/stable. Hayden et al. (20), in an analysis of a global composite cognitive score, derived from a battery of 19 neuropsychological tests administered in the Religious Order Study, identified 3 groups; individuals whose trajectories over time were characterized with slow decline from a slightly above average baseline score, a group of moderate decliners, and a third group of individuals whose baseline score were low followed by a fast decline.\u0026nbsp; The literature provides increasing evidence demonstrating a great heterogeneity of cognitive trajectories in older adults. However, research efforts focusing specifically on heterogeneity in the segment of the oldest old is limited. In addition, we lack knowledge about whether pairs of twins in this segment of the population show similar trajectories.\u003c/p\u003e\n\u003cp\u003eIn this paper, we used data from the OCTO Twin Study, a longitudinal study of Swedish twins aged 80 and older, to examine whether: \u003cem\u003e(i)\u003c/em\u003e we can identify distinct classes or clusters of individuals with similar cognitive trajectories, defined by their scores on the Mini Mental State Exam (MMSE), \u003cem\u003e(ii) \u003c/em\u003epairs of monozygotic twins (MZ) are more likely than pairs of same-sex dizygotic twins (DZ) to be assigned to the same class, and (\u003cem\u003eiii\u003c/em\u003e) a list of a set of previously identified and modifiable risk factors are relevant for the assignment of individuals into various classes.\u003c/p\u003e"},{"header":"Analytical Methods","content":"\u003cp\u003e\u003cstrong\u003eOCTO Twin Study\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe sample used in these analyses was drawn from the comprehensive longitudinal Origins of Variance in the Old-Old: Octogenarian Twins (known as the OCTO-Twin Study) based on the oldest cohort of the Swedish Twin Registry (21). The sample includes 702 participants, with 351 complete twin pairs (149 identical (monozygotic) and 202 same-sex fraternal (dizygotic pairs)), born in 1913 and earlier, who were, or became, 80 years of age during the first wave of data collection (1991-1993). Participants were re-assessed biannually (over an 8 year period) at their homes or place of residency by medical research nurses specially trained for the study. The average rate of attrition from one wave of examination to the next was 20% (10% per year), primarily due to death. Full details of the study population characteristics have been published previously (2, 21, 22), including findings on cognitive performances relative to survival (see Johansson et al. (23)).\u003c/p\u003e\n\u003cp\u003eGlobal cognitive function was assessed using the Mini-Mental State Examination MMSE screening device (18), which has become a frequently used screening device for overall cognitive function in clinical and research samples. The MMSE measures various domains including orientation, registration (immediate memory), short-term memory (but not long-term memory), attention, the ability to follow verbal and written commands, writing and copying. Scores range from 0\u0026ndash;30 and high values indicate better cognitive status. The observed trajectories and scores in our sample, plotted against years past from baseline, are depicted in Figure 1.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;In addition to socio demographic information about participants such as age, sex and years of education, whether or not they ever received a dementia diagnosis, lifestyle information was also collected. Specifically, smoking habits were assessed by asking whether participants ever smoked, they smoked \u0026ldquo;now and then\u0026rdquo;, they had been smokers but quitted or whether they were current smokers. Participants were also asked about whether they had or presently stimulated their brains to some or a large extent in cognitively demanding activities. They were also asked whether they trained and stimulated their bodies to some or a large extent. Table 1 presents the descriptive characteristics of the sample.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe OCTO-Twin Study received approval from the Ethics Committee at the Karolinska Institute in Stockholm and from the Swedish Data Inspection Authority. Informed written consent was obtained from all participants or their relative or caregiver where capacity to consent was questionable, for example, due to severe cognitive impairment or dementia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe fitted a series of growth mixture models (GMM) to MMSE scores aligned as a function of number of years past from study entry to identify subgroups (classes) of individuals with similar MMSE trajectories. The number of available time points (i.e. 5 waves) allowed us to examine linear as well as accelerating patterns of change. Class specific intercepts and slopes were adjusted for sociodemographic factors (age, sex and education) and a dementia indicator variable. To learn about the role of these sociodemographic factors and of lifestyle factors on class assignment, we adjusted the multinomial logistic model for class probability for baseline age, education, sex, smoking status, physical activity and engagement in cognitively stimulating activities.\u003c/p\u003e\n\u003cp\u003eBaseline age and education (measured in years) were modelled as continuous variables centered at the sample median values, 83 years of age and 7 years of education respectively. A dementia indicator was coded as 1 if an individual ever received a diagnosis of dementia and 0 if the individual never was diagnosed with dementia during the study period. Sex was coded as 0 for a male participant and 1 for a female participant. Binary indicators were derived to describe lifestyle factors and coded as follows: individuals who ever smoked were coded as 1 and those who never smoked were coded as 0; individuals who never trained their brains were coded as 1 and those who said they did were coded as 0. Similarly, individuals who did not engage in any physical training were coded as 0 and those who did were coded as 1.\u003c/p\u003e\n\u003cp\u003eWe followed recommended practice to select the optimal model, including the identification of the number of classes. We fitted a series of models with an increasing number of classes and selected the best fitting model by comparing model fit indices, evaluating of entropy values and considering interpretability of each class (24). Specifically, we inspected the Bayesian Information Criterion (BIC), the sample-size adjusted BIC (SSABIC), entropy values and the Lo-Mendel-Rubin likelihood ratio test (LMR-LRT). Lower BIC and SSABIC values indicate a more parsimonious and better fitting model, whereas higher entropy values signal better class separation.\u003c/p\u003e\n\u003cp\u003eOnce the best fitting model was identified, an a posteriori analysis of the distribution of twins across classes and the distribution of pairs of twins and their zygosity by class was conducted to investigate if monozygotic pairs were more likely to be assigned to the same class than dizygotic pairs.\u003c/p\u003e\n\u003cp\u003eModels were estimated in Mplus v8.0 by full maximum likelihood (FML) and robust standard errors (MLR) to non-normality and non-independence of observations (25). Missing data are assumed to be missing at random. To avoid local maxima for the EM (expectation-maximization) algorithm, we estimated the models with up to 1000 random starting values. The MMSE is known to produce ceiling and floor effects. To investigate whether our results were sensitive to these effects, we fitted Tobit Growth Mixture models and compared results to the ones generated by the traditional GMM formulation.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eOur analytical sample comprised of 628 individuals, of whom 220 (35%) were men and 408 (64%) women. Women were older than men (women: 83.61 (SD=3.17) yrs. old vs men: 82.95 (SD=2.76) yrs. old, t-test, p-value=0.007) and had fewer years of education than men (women: 6.96 (SD=1.89), men: 7.51 (SD=2.90), t-test, p-value=0.01). More than 73% of the sample (n=463) remained free of dementia over the study follow-up period. See Table 1 for descriptive sample characteristics. The sample included 272 (43%) monozygotic and 356 (57%) dizygotic individuals. Sixty-three individuals (10% of total sample, 24 monozygotic and 39 dizygotic twins) were excluded due to missing data for their co-twin. Monozygotic twins were slightly more educated than dizygotic twins (7.50 (SE=0.16) years of education vs 6.89 (SE=0.10) years of education respectively, t-test, p-value=0.0009) and a larger proportion of monozygotic twins were sedentary compared to dizygotic twins (63% vs 53% respectively, chi square test, p-value=0.02). Sixty per cent (60%) of monozygotic and 68% of dizygotic individuals were women.\u003c/p\u003e\n\u003cp\u003eInspection of BIC, SSABIC, and the Lo-Mendel-Rubin likelihood ratio test values resulted in the identification of a 4-class model as the best fitting model. The entropy for this model was 0.74, a value that suggests a good discrimination of individuals into these 4 classes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1\u003c/strong\u003e \u003cem\u003eDescriptive statistics of the OCTO-Twin sample\u003c/em\u003e\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse; border: none;\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.1pt; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.5pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"141\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eVariables\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.5pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eN\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.5pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eMean (SD)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 141.75pt; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.5pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"189\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eBaseline characteristics\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 82.5pt; border-top: solid windowtext 1.5pt; border-left: none; border-bottom: solid windowtext 1.5pt; border-right: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"110\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eN (%)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.1pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"141\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003eMMSE 1\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003e628\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003e26.3 (3.9)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 141.75pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"189\"\u003e\n\u003cp style=\"line-height: 150%;\"\u003e\u003cem\u003eMonozygotic\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 82.5pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"110\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003e272 (43.0)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.1pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"141\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003eMMSE 2 \u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003e524\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003e24.9 (6.2)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 141.75pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"189\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003eFemale\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 82.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"110\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003e408 (65.0)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.1pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"141\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003eMMSE 3\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003e404\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003e24.4 (7.1)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 141.75pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"189\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003eSmoker\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 82.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"110\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003e248 (39.5)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.1pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"141\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003eMMSE 4\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003e298\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003e23.7 (7.5)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 141.75pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"189\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003eStimulates the body\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 82.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"110\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003e266 (42.4)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.1pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"141\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003eMMSE 5\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003e217\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003e22.3 (7.8)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 141.75pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"189\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003eStimulates brain\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 82.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"110\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003e416 (66.3)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 106.1pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"141\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003eEducation (years)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.5pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"57\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003e\u0026nbsp; 7.5 (2.3)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 141.75pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"189\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003eDiagnosed with dementia\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 82.5pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"110\"\u003e\n\u003cp style=\"margin-top: 0in; line-height: 150%;\"\u003e\u003cem\u003e165 (26.3)\u003c/em\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eMMSE 1-5 are the MMSE scores at every follow-up. SD standard deviation\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMMSE trajectory classes and characteristics \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFirst, we examine the characteristics revealed in the 4 class model (see Table 2). In Figure 1 we show a graphical illustration of the observed and estimated MMSE trajectories in our analytical sample.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2 \u003c/strong\u003e\u003cem\u003eResults from the 4- class growth mixture model that best fitted the OCTO-Twin sample\u003c/em\u003e\u003c/p\u003e\n\u003ctable style=\"width: 545.8pt; border-collapse: collapse; border: none;\" width=\"728\"\u003e\n\u003ctbody\u003e\n\u003ctr style=\"height: 31.75pt;\"\u003e\n\u003ctd style=\"width: 77.95pt; border: none; border-top: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: .5in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 114.25pt; border: none; border-top: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" colspan=\"2\" width=\"152\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"line-height: 150%; font-family: 'Times New Roman',serif;\"\u003eHigh performers and stable\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"line-height: 150%; font-family: 'Times New Roman',serif;\"\u003eN=198\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 114.0pt; border: none; border-top: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" colspan=\"2\" width=\"152\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"line-height: 150%; font-family: 'Times New Roman',serif;\"\u003eHigh performers with slow decline N=194\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 121.35pt; border: none; border-top: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" colspan=\"2\" width=\"162\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"line-height: 150%; font-family: 'Times New Roman',serif;\"\u003eHigh performers with fast decline\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"line-height: 150%; font-family: 'Times New Roman',serif;\"\u003eN=181\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 118.25pt; border: none; border-top: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" colspan=\"2\" width=\"158\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"line-height: 150%; font-family: 'Times New Roman',serif;\"\u003eImpaired very fast decline\u003c/span\u003e\u003c/p\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"line-height: 150%; font-family: 'Times New Roman',serif;\"\u003eN=55\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 31.75pt;\"\u003e\n\u003ctd style=\"width: 77.95pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.45pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026beta; (SE)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003ep\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.2pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026beta; (SE)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003ep\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026beta; (SE)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 43.4pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"58\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003ep\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.05pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"101\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026beta; (SE)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.2pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"56\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003ep\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 31.75pt;\"\u003e\n\u003ctd style=\"width: 77.95pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eFixed effects\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.45pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 43.4pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"58\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.05pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"101\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.2pt; border: none; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"56\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 31.75pt;\"\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eMMSE Level\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.45pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e28.9 (0.14)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e27.62 (0.32)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e26.34 (0.59)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 43.4pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"58\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.05pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"101\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e19.30 (2.18)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"56\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 31.75pt;\"\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-left: 17.0pt; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eBaseline age\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.45pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-0.08 (0.03)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-0.16 (0.07)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.02\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-0.18 (0.12)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 43.4pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"58\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.12\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.05pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"101\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.28 (0.23)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"56\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.24\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 31.75pt;\"\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-left: 17.0pt; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eEducation\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.45pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.04 (0.02)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.04\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.09 (0.08)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.26\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.30 (0.17)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 43.4pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"58\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.09\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.05pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"101\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.73 (0.62)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"56\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.23\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 31.75pt;\"\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-left: 17.0pt; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eWomen\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.45pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.26 (0.13)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.06\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.24 (0.37)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.51\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-0.15 (0.72)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 43.4pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"58\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.83\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.05pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"101\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e2.71 (2.26)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"56\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.23\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 31.75pt;\"\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-left: 17.0pt; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eDementia\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.45pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-0.50 (0.09)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.02\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.13 (0.42)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.75\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-1.18 (0.74)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 43.4pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"58\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.11\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.05pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"101\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-4.29 (1.28)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"56\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 31.75pt;\"\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eLinear Slope\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.45pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-0.04 (0.04)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.30\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-0.31 (0.09)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-0.96 (0.14)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 43.4pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"58\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.05pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"101\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-2.95 (0.86)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"56\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 31.75pt;\"\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-left: 17.0pt; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eBaseline age\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.45pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00 (0.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.60\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-0.04 (0.08)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.82\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-0.02 (0.03)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 43.4pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"58\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.47\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.05pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"101\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-0.02 (0.09)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"56\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.77\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 31.75pt;\"\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-left: 17.0pt; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eEducation\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.45pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00 (0.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.42\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-0.01 (0.02)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.51\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-0.08 (0.05)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 43.4pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"58\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.11\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.05pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"101\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-0.84 (0.53)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"56\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.10\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 31.75pt;\"\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-left: 17.0pt; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eWomen\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.45pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.02 (0.04)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.61\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.03 (0.10)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.72\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.10 (0.18)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 43.4pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"58\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.57\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.05pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"101\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-0.06 (1.03)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"56\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.95\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 31.75pt;\"\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"margin-left: 17.0pt; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eDementia\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.45pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-0.11 (0.09)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.23\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-0.76 (0.14)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-1.40 (0.18)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 43.4pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"58\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.05pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"101\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e-0.76 (0.52)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"56\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.15\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 31.75pt;\"\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eRandom effects\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.45pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 43.4pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"58\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.05pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"101\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"56\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 31.75pt;\"\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eLevel\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.45pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.06 (0.08)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.42\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.06 (0.08)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.42\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.06 (0.08)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 43.4pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"58\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.42\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.05pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"101\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.06 (0.08)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"56\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.42\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 31.75pt;\"\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eLinear Slope\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.45pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.02 (0.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.02 (0.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.02 (0.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 43.4pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"58\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.05pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"101\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.02 (0.00)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.2pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"56\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr style=\"height: 31.75pt;\"\u003e\n\u003ctd style=\"width: 77.95pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eError\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.45pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.66 (0.06)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.2pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"103\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e5.30 (0.48)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 36.8pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"49\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 77.95pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"104\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e22.24 (2.43)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 43.4pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"58\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 76.05pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"101\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e27.11 (3.72)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 42.2pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt; height: 31.75pt;\" width=\"56\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh Performers and Stable class\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe largest class was comprised of 32% of the sample (n=198). A reference individual in this class is a man aged 83 years at study entry with 7 years of education with an average MMSE score at study entry of 28.9 (SE=0.1), and who remained free of dementia over the study period.\u0026nbsp; The annual rate of MMSE change was only -0.04 (SE=0.04), an estimate that did not reach conventional significance thresholds. In this class, older baseline age was associated with a lower baseline MMSE performance (\u0026szlig;=-0.08 (SE=0.03), while education was associated with higher baseline MMSE score (\u0026szlig;=0.04 (SE=0.02)). Individuals who later received a diagnosis of dementia had poorer MMSE performance at study entry than individuals who remained free of dementia (\u0026szlig;=-0.48, SE=0.10))\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh Performers with Slow Decline class\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThirty-one per cent (31%, n=194) of the sample were assigned to a class with an average MMSE score of 27.6 (SE=0.3) at study entry. Their annual decline was -0.3(0.09) MMSE points. Age was associated with poorer baseline MMSE performance, and those who ever received a diagnosis of dementia declined at a faster rate than those who remained free from dementia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eHigh Performers with Fast Decline class\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTwenty-nine per cent (29%, n=181) of the sample was assigned to a class with a slightly lower baseline MMSE score than the other class of high performing individuals, but they declined at a faster rate. Specifically, in this class, the reference individual had an average MMSE score at study entry of 26.3 (SE=0.6) with an annual decline of -0.9 (SE=0.1) MMSE points. Individuals who received a diagnosis of dementia declined 1.4 MMSE points faster per year than those who remained non-demented. None of the risk factors emerged as significantly associated with MMSE baseline performance, nor with rate of change.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eImpaired Very Fast Decline class\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFinally, 8 % (n=55) of the sample was assigned to a class characterized by low baseline scores and more substantial decline.\u0026nbsp; Their average MMSE score at study entry was 19.3 (SE=2.2), followed by an annual decline of -2.9 (SE=0.8). Individuals who received a diagnosis of dementia had even poorer baseline MMSE performance, compared with those who remained free from dementia. None of the other risk factors reached significance levels.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRisk factors and class assignment probability \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNext, we examine the effect of risk factors in relation to the above classification (see Table 3). Compared with the high performing and stable class and as\u0026nbsp;\u0026nbsp; expected, older age at study entry, was associated with higher odds of being in the class of impaired performers with very fast decline. This was also the case in the two classes of high performing individuals. Women and more educated individuals had lower odds of being in the class of \u003cem\u003eHigh Performers with Fast decline \u003c/em\u003eindividuals\u003cem\u003e, \u003c/em\u003ethan in the \u003cem\u003eHigh Performers and Stable class\u003c/em\u003e of individuals. Individuals who did not engage in physical activity were more likely to be in the \u003cem\u003eHigh Performing with Fast Decline \u003c/em\u003eclass, compared to the \u003cem\u003eHigh Performing and Stable class\u003c/em\u003e of individuals\u003cem\u003e, \u003c/em\u003ea finding that suggests a partial protective effect of education and physical activity.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eTable 3 \u003c/strong\u003e\u003c/em\u003eOdds ratio results from multinomial model for class assignment with reference to the High Performers and Stable class\u003c/p\u003e\n\u003ctable style=\"border-collapse: collapse; border: none;\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 112.7pt; border: none; border-top: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"150\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 112.7pt; border: none; border-top: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"150\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eHigh performers with slow decline\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 112.7pt; border: none; border-top: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"150\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eHigh performers with fast decline\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 112.7pt; border: none; border-top: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" colspan=\"2\" width=\"150\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eImpaired very fast decline\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 112.7pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"150\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.6pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"95\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eOR (SE)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 41.1pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"55\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003ep\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 72.3pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"96\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eOR (SE)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 40.4pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"54\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003ep\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 73.0pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"97\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eOR (SE)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 39.7pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"53\"\u003e\n\u003cp style=\"text-align: center; text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003ep\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 112.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"150\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eBaseline age\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.6pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"95\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e1.12 (0.06)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 41.1pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"55\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.05\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 72.3pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"96\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e1.17 (0.07)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 40.4pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"54\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.01\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 73.0pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"97\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e1.22 (0.09)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 39.7pt; border: none; padding: 0in 5.4pt 0in 5.4pt;\" width=\"53\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 112.7pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"150\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eEducation\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.6pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"95\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.92 (0.05)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 41.1pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"55\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.11\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 72.3pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"96\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.75 (0.08)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 40.4pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"54\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 73.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"97\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.75 (0.11)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 39.7pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"53\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.03\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 112.7pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"150\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eWomen\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.6pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"95\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.88 (0.28)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 41.1pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"55\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.67\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 72.3pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"96\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.51 (0.18)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 40.4pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"54\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.00\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 73.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"97\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e1.04 (0.62)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 39.7pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"53\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.93\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 112.7pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"150\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eSmoking\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.6pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"95\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e1.18 (0.34)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 41.1pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"55\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.60\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 72.3pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"96\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.96(0.32)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 40.4pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"54\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.92\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 73.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"97\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e1.08 (0.57)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 39.7pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"53\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.88\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 112.7pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"150\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eStimulates the body\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.6pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"95\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e1.12 (0.33)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 41.1pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"55\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.71\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 72.3pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"96\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e2.28 (0.60)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 40.4pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"54\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.03\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 73.0pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"97\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e5.20 (2.36)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 39.7pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"53\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.07\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd style=\"width: 112.7pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"150\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003eStimulates the brain\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 71.6pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"95\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e1.31 (0.36)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 41.1pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"55\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.38\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 72.3pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"96\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e1.89 (0.54)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 40.4pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"54\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.10\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 73.0pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"97\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e6.73 (4.84)\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd style=\"width: 39.7pt; border: none; border-bottom: solid windowtext 1.5pt; padding: 0in 5.4pt 0in 5.4pt;\" width=\"53\"\u003e\n\u003cp style=\"text-indent: 0in; line-height: 150%;\"\u003e\u003cspan style=\"font-family: 'Times New Roman',serif;\"\u003e0.23\u003c/span\u003e\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eOR\u003c/em\u003e odds ratio; \u003cem\u003eSE\u003c/em\u003e standard error\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDistribution of twins across classes \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the next step, we examine the distribution of twins and partners across the four classes. In the high performing and stable class there were 47 twin pairs (i.e., 94 individuals out of 198). In the classes of \u003cem\u003eHigh Performers with Slow Decline\u003c/em\u003e and \u003cem\u003eHigh Performers with Fast Decline, \u003c/em\u003ethere were 27 twin pairs (54 individuals out of 194) and 23 pairs (46 individuals out of 181), respectively. In the class of \u003cem\u003eImpaired individuals with Very Fast Decline\u003c/em\u003e, there were 4 pairs of twins (8 individuals out of 55). These numbers indicate that 47.5 % of the individuals in the\u003cem\u003e High Performers and Stable Class\u003c/em\u003e in fact had a twin partner in the same class. The corresponding proportion of having a twin in the same class \u003cem\u003ewas \u003c/em\u003e23.7% among the \u003cem\u003eHigh Performers with Slow Decline, and \u003c/em\u003e29.8% in the \u003cem\u003eclass\u003c/em\u003e of \u003cem\u003eHigh Performers with Fast Decline. \u003c/em\u003eLastly, in the \u003cem\u003eImpaired and Fast Declining\u003c/em\u003e class 14.4 % of individuals had a co-twin in the same class.\u003c/p\u003e\n\u003cp\u003eIn the final step we conducted posteriori analyses, to test whether zygosity was associated with the likelihood of being assigned to a certain class (see Figure 2). Our analyses, however, failed to find evidence in support of an association (\u003cem\u003eX\u003csup\u003e2\u003c/sup\u003e\u003csub\u003e(3 \u003c/sub\u003e\u003c/em\u003ep=0.46), which means that the likelihood for being in a certain class was similar for MZ and same-sex DZ twins.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the present study we investigated the heterogeneity change trajectories in the Mini-Mental-State Examination Screening Test (MMSE, (18)) in a sample of oldest-old monozygotic and same-sex dizogtic Swedish twins. More specifically, we evaluated whether a sub-classification of individuals into various change trajectories (classes) also could provide information about the likelihood for genetic resemblance and risk factor exposures.\u003c/p\u003e\n\u003cp\u003eWe first identified 4 distinct subgroups of individuals with similar change trajectories. The majority of individuals was classified into three groups with MMSE baseline scores above impairement levels, who showed a more preserved cognition or a decline at relatively slow or faster annual rate. The fourth class was comprised of individuals who at study entry already had a low MMSE score and who thereafter declined at a faster rate. This may be a consequence of a healthy survivor effect of oldest-old individuals, as the inclusion criteria also required participation of both partners in a twin pair. The overall MMSE score for the entire sample was 26.3 (SD=3.9), which suggests that many individuals had a fairly good global cognition when they entered the study.\u003c/p\u003e\n\u003cp\u003ePrevious studies have investigated the heterogeneity of aging-related cognitive decline measured by the MMSE and reported the existence of groups of individuals whose trajectories follow different patterns of change (26, 27). For example, Muniz Terrera et al. (26) studied a sample of British individuals aged 75 years old and older at study entry and identified 3 distinct patterns of MMSE change, Min (28) studied a sample of healthy Koreans aged 60 and over at baseline and identified 2 groups and Leoutsakos et al. (29) analysed a sample of American adults aged 65 and over at study entry and identified 4 different MMSE patterns of change. However, differences in study designs, features of the samples tend to make comparisons difficult. For example, whether individuals with dementia at baseline or later were included, and the different rates of non- participation at follow-ups may explain some of these inconsistencies. In addition, the analytical decisions made in each study (such as the adjustment for different variables) preclude the direct comparison of published results across publications. Despite these differences, studies provide evidence of multiple and distinct patterns of MMSE change over time.\u003c/p\u003e\n\u003cp\u003eNoteworthy, our findings about the distribution of twins across the four classes showed that the majority of twins were not assigned to the same class as their co-twin. This outcome provides evidence in support of a greater role for lifestyle and environmental exposures in late life cognitive change, than for genetic influences. This is further reinforced by the finding demonstrating an independence between zygosity and class. A large effect of genetics would otherwise have shown that monozygotic twins were more likely to be assigned to the same change trajectory class. Our findings are, therefore, in support of a nurture rather than a nature effect. Yet, given the relatively small sample and the inclusion only of the oldest old age segment in our study, further research is necessary to provide better understanding of the relative contributions of genetic and environmental influences on late life cognitive change.\u003c/p\u003e\n\u003cp\u003eFurthermore, the effect of examined risk factors on class specific level and rate of change was not clear and consistent across classes. A diagnosis of dementia also showed different effects across the four classes. In the \u003cem\u003eHigh Performers with Slow Decline\u003c/em\u003e and \u003cem\u003eHigh Performers with Fast Decline\u003c/em\u003e classes, but not in the class of \u003cem\u003eImpaired\u003c/em\u003e and\u003cem\u003e High Performers Stable Class\u003c/em\u003e, individuals who received a diagnosis of dementia declined at a faster rate than those who remained non-demented. In the \u003cem\u003eHigh Performers and Stable Class\u003c/em\u003e, the performance at study entry was unexpectedly almost half an MMSE point below the performance of individuals who in fact later received a diagnosis of dementia. It is possible that they were diagnosed later although demonstrating a compromised cognitive health already at baseline.\u003c/p\u003e\n\u003cp\u003eInterestingly, older age at study entry emerged as negatively associated with MMSE performance only in the \u003cem\u003eHigh Performers with Slow Decline\u003c/em\u003e and in the \u003cem\u003eHigh Performers Stable Class\u003c/em\u003e. In the latter, we found that education had a protective effect. This is not unexpected, as other publications quite consistently have shown that education is associated with level, but not with rate of change. Further, this result is in agreement with Muniz Terrera et al. (26), who identified 3 classes of individuals with similar MMSE trajectories and reported an association of education with baseline MMSE in the class of individuals who preserved cognitive function over time, but not with baseline MMSE or rate of change in the other 2 classes. These findings are partly supportive of the theory of passive reserve (30) suggesting that individuals with higher educational attainment will consistently perform at a higher cognitive level as they age given their greater baseline cognitive reserve, although they decline at a similar rate with their lower educated peers.\u003c/p\u003e\n\u003cp\u003eOur results about the effect of lifestyle factors on the probability of class assignment provide partial support to the hypothesis that lifestyle factors may have a protective effect on cognitive function. The findings that being physically active increases the probability of being assigned to the \u003cem\u003e\u0026nbsp;High Performers and Stable Class, \u003c/em\u003ecompared to the class of \u003cem\u003eHigh Performers with fast Decline,\u003c/em\u003e but not to the Impaired Decliners or \u003cem\u003eHigh Performers with Slow Decline\u003c/em\u003e is somehow unexpected. In our study, physical activity was only measured by asking participants \u003cem\u003e\u0026ldquo;Are you presently doing or have you previously done anything special to train your body or keep your body fit?\u0026rdquo;. \u003c/em\u003eHence, the opportunities to detect and evaluate the long-term effect of physical activity is limited as the question only captures the individuals\u0026rsquo; engagement on physical activities closer to study entry, and less about the intensity and life-course engagement in these activities. Unfortunately, dose (intensity, duration, frequency) and mode of the activities performed (balance, flexibility, resistance) are not captured by our global question. The literature on the mechanisms by which physical activity may have a protective effect on cognitive function in old age shows that this effect varies by dose, mode and cognitive function evaluated (31).\u003c/p\u003e\n\u003cp\u003eOur study also has some other limitations. Despite that the sample size of our study is large, considering the advanced age of study participants, models with 5 and more classes failed to identify meaningful classes as the classes identified were very small classes and models failed to converge even after fixing various model parameters. Further, GMM models were fitted under a missing at random assumption which may not be fully justified. It is also most likely that our questions about engagement in physical and cognitively stimulating activities are far from optimal to capture the role of these life-style behaviors nowadays given a crucial role also for late life cognitive functioning. However, this study was initiated already in 1991, when research about their effect on cognitive health was still in early stages.\u003c/p\u003e\n\u003cp\u003eIn sum, this is the first investigation based on a classification of a twin sample into distinct groups defined by their longitudinal MMSE scores. Our analyses of similarities and differences between monozygotic and same-sex dizygotic twin pairs suggest a more minor role of genetic effects in late life cognitive change.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe OCTO-Twin Study received approval from the Ethics Committee at the Karolinska Institute in Stockholm and from the Swedish Data Inspection Authority. Informed written consent was obtained from all participants or their relative or caregiver where capacity to consent was questionable, for example, due to severe cognitive impairment or dementia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are not freely available, which were used under license for the current study, and so are not publicly available. However, data analytics and study materials can be shared by contacting the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was funded by NIH/NIA Program Project Grant (P01AG043362; 2013-2018).\u003c/p\u003e\n\u003cp\u003eThe OCTO Twin Study was originally supported by a grant from NIA (AG 08861).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGM designed the project, performed the main analysis and wrote the paper. AR contributed to the discussion of the paper and editing. JG contributed to the data analysis, contributed to the discussion and edited the paper. FM contributed to the discussion and editing of the paper. BJ designed and collected the data and contributed to the discussion and editing of the paper.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMcGue M, Christensen K. The heritability of cognitive functioning in very old adults: Evidence from Danish twins aged 75 years and older. Psychology and Aging. 2001;16(2):272-80. doi:10.1037/0882-7974.16.2.272\u003c/li\u003e\n\u003cli\u003eMcClearn GE, Johansson B, Berg S, et al. Substantial Genetic Influence on Cognitive Abilities in Twins 80 or More Years Old. Science. 1997;276(5318):1560. doi:10.1126/science.276.5318.1560\u003c/li\u003e\n\u003cli\u003ePetrill SA, Johansson B, Pedersen NL, et al. Low cognitive functioning in nondemented 80+-year-old twins is not heritable. Intelligence. 2001;29(1):75-83. doi:https://doi.org/10.1016/S0160-2896(00)00047-7\u003c/li\u003e\n\u003cli\u003ePackard CJ, Westendorp RG, Stott DJ, et al. Association between apolipoprotein E4 and cognitive decline in elderly adults. Journal of the American Geriatrics Society. 2007;55(11):1777-85. doi:10.1111/j.1532-5415.2007.01415.x\u003c/li\u003e\n\u003cli\u003eSadigh-Eteghad S, Talebi M, Farhoudi M. Association of apolipoprotein E epsilon 4 allele with sporadic late onset Alzheimer`s disease. A meta-analysis. Neurosciences (Riyadh, Saudi Arabia). 2012;17(4):321-6.\u003c/li\u003e\n\u003cli\u003eWang CC, Lu TH, Liao WC, et al. Cigarette smoking and cognitive impairment: a 10-year cohort study in Taiwan. Archives of gerontology and geriatrics. 2010;51(2):143-8. doi:10.1016/j.archger.2009.09.041\u003c/li\u003e\n\u003cli\u003eWingberm\u0026uuml;hle R, Wen KX, Wolters FJ, Ikram MA, Bos D. Smoking, APOE Genotype, and Cognitive Decline: The Rotterdam Study. Journal of Alzheimer's disease : JAD. 2017;57(4):1191-5. doi:10.3233/jad-170063\u003c/li\u003e\n\u003cli\u003eFerreira N, Owen A, Mohan A, Corbett A, Ballard C. Associations between cognitively stimulating leisure activities, cognitive function and age-related cognitive decline. International Journal of Geriatric Psychiatry. 2015;30(4):422-30. doi:10.1002/gps.4155\u003c/li\u003e\n\u003cli\u003eHassing LB. Gender Differences in the Association Between Leisure Activity in Adulthood and Cognitive Function in Old Age: A Prospective Longitudinal Population-Based Study. The Journals of Gerontology: Series B. 2017. doi:10.1093/geronb/gbx170\u003c/li\u003e\n\u003cli\u003eHughes TF, Sun Z, Chang C-CH, Ganguli M. Change in Engagement in Cognitive Activity and Risk for Mild Cognitive Impairment in a Cohort of Older Adults: The Monongahela-Youghiogheny Healthy Aging Team (MYHAT) Study. Alzheimer Disease \u0026amp; Associated Disorders. 2018;32(2):137-44. doi:10.1097/wad.0000000000000214\u003c/li\u003e\n\u003cli\u003eKivipelto M, Mangialasche F, Ngandu T. Lifestyle interventions to prevent cognitive impairment, dementia and Alzheimer disease. Nature Reviews Neurology. 2018;14(11):653-66. doi:10.1038/s41582-018-0070-3\u003c/li\u003e\n\u003cli\u003eKrell-Roesch J, Vemuri P, Pink A, et al. Association Between Mentally Stimulating Activities in Late Life and the Outcome of Incident Mild Cognitive Impairment, With an Analysis of the APOE \u0026epsilon;4 Genotype. JAMA Neurology. 2017;74(3):332-8. doi:10.1001/jamaneurol.2016.3822\u003c/li\u003e\n\u003cli\u003eYates LA, Ziser S, Spector A, Orrell M. Cognitive leisure activities and future risk of cognitive impairment and dementia: systematic review and meta-analysis. International Psychogeriatrics. 2016;28(11):1791-806. doi:10.1017/S1041610216001137\u003c/li\u003e\n\u003cli\u003eHamer M, Muniz Terrera G, Demakakos P. Physical activity and trajectories in cognitive function: English Longitudinal Study of Ageing. Journal of Epidemiology and Community Health. 2018;72(6):477. doi:10.1136/jech-2017-210228\u003c/li\u003e\n\u003cli\u003eRobitaille A, Muniz Terrera G, Lindwall M, et al. Physical activity and cognitive functioning in the oldest old: within- and between-person cognitive activity and psychosocial mediators. European Journal of Ageing. 2014;11(4):333-47. doi:10.1007/s10433-014-0314-z\u003c/li\u003e\n\u003cli\u003eMuth\u0026eacute;n B, Shedden K. Finite Mixture Modeling with Mixture Outcomes Using the EM Algorithm. Biometrics. 1999;55(2):463-9. doi:10.1111/j.0006-341X.1999.00463.x\u003c/li\u003e\n\u003cli\u003eMuniz Terrera G, Matthews F, Brayne C. A comparison of parametric models for the investigation of the shape of cognitive change in the older population. BMC Neurology. 2008;8(1):16. doi:10.1186/1471-2377-8-16\u003c/li\u003e\n\u003cli\u003eFolstein MF, Folstein SE, McHugh PR. \"Mini-mental state\". A practical method for grading the cognitive state of patients for the clinician. Journal of psychiatric research. 1975;12(3):189-98. doi:10.1016/0022-3956(75)90026-6\u003c/li\u003e\n\u003cli\u003eOlaya B, Bobak M, Haro JM, Demakakos P. Trajectories of Verbal Episodic Memory in Middle-Aged and Older Adults: Evidence from the English Longitudinal Study of Ageing. Journal of the American Geriatrics Society. 2017;65(6):1274-81. doi:10.1111/jgs.14789\u003c/li\u003e\n\u003cli\u003eHayden KM, Reed BR, Manly JJ, et al. Cognitive decline in the elderly: an analysis of population heterogeneity. Age and Ageing. 2011;40(6):684-9. doi:10.1093/ageing/afr101\u003c/li\u003e\n\u003cli\u003eCederlof R, Lorich U. The Swedish Twin Registry. Progress in clinical and biological research. 1978;24 Pt B:189-95.\u003c/li\u003e\n\u003cli\u003ePedersen NL, Lichtenstein P, Svedberg P. The Swedish Twin Registry in the Third Millennium. Twin Research. 2012;5(5):427-32. doi:10.1375/twin.5.5.427\u003c/li\u003e\n\u003cli\u003eJohansson B, Hofer SM, Allaire JC, et al. Change in Cognitive Capabilities in the Oldest Old: The Effects of Proximity to Death in Genetically Related Individuals Over a 6-Year Period. Psychology and Aging. 2004;19(1):145-56. doi:10.1037/0882-7974.19.1.145\u003c/li\u003e\n\u003cli\u003eKandauda K.A.S. Wickrama TKL, Catherine Walker O'Neal, Frederick O. Lorenz. Growth Mixture Modeling. Higher-Order Growth Curves and Mixture Modeling with Mplus: A Practical Guide. New York: Routledge Taylor and Francis Group; 2016.\u003c/li\u003e\n\u003cli\u003eMuth\u0026eacute;n LK, Muth\u0026eacute;n, B.O. Mplus User\u0026rsquo;s Guide. Eighth Edition ed. Los Angeles, CA: 1998-2017.\u003c/li\u003e\n\u003cli\u003eMuniz Terrera G, Brayne C, Matthews F. One size fits all? Why we need more sophisticated analytical methods in the explanation of trajectories of cognition in older age and their potential risk factors. International Psychogeriatrics. 2009;22(2):291-9. doi:10.1017/S1041610209990937\u003c/li\u003e\n\u003cli\u003eWilkosz PA, Seltman HJ, Devlin B, et al. Trajectories of cognitive decline in Alzheimer's disease. International Psychogeriatrics. 2009;22(2):281-90. doi:10.1017/S1041610209991001\u003c/li\u003e\n\u003cli\u003eMin JW. A longitudinal study of cognitive trajectories and its factors for Koreans aged 60 and over: A latent growth mixture model. International Journal of Geriatric Psychiatry. 2018;33(5):755-62. doi:10.1002/gps.4855\u003c/li\u003e\n\u003cli\u003eLeoutsakos J-MS, Forrester SN, Corcoran CD, et al. Latent classes of course in Alzheimer's disease and predictors: the Cache County Dementia Progression Study. International Journal of Geriatric Psychiatry. 2015;30(8):824-32. doi:10.1002/gps.4221\u003c/li\u003e\n\u003cli\u003eKatzman R. Education and the prevalence of dementia and Alzheimer\u0026rsquo;s disease. Neurology. 1993;43(1 Part 1):13. doi:10.1212/WNL.43.1_Part_1.13\u003c/li\u003e\n\u003cli\u003eNetz Y. Is There a Preferred Mode of Exercise for Cognition Enhancement in Older Age?-A Narrative Review. Front Med (Lausanne). 2019;6:57-. doi:10.3389/fmed.2019.00057\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Twins, Growth Mixture Models, Cognitive trajectories","lastPublishedDoi":"10.21203/rs.2.22580/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.22580/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Aging is associated with an increasing risk of decline in cognitive abilities. The decline is, however, not a homogeneous process. There are substantial differences across individuals although previous investigations have identified individuals with distinct cognitive trajectories. Evidence is accumulating that lifestyle contributes significantly to the classification of individuals into various clusters. How and whether genetically related individuals, like twins, change in a more similar manner is yet not fully understood. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e In this study, we fitted growth mixture models to Mini Mental State Exam scores (MMSE) from participants of the Swedish OCTO Twin study of oldest old monozygotic (MZ) and same-sex dizygotic (DZ) twins with the purpose of investigating whether twin pairs can be\u0026nbsp;assigned to the same class of cognitive change. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e We identified 4 distinct groups (latent classes) whose MMSE trajectories followed various patterns of change over time: a class of stable and high performing individuals, two groups of high performers who declined at different annual rates, and a small group of impaired individuals who declined more rapidly. Notably, our analyses show that few individuals in fact could be assigned to the same class as their co-twin. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e Our study provides evidence for more substantial impact of environmental, rather than genetic, influences on cognitive change trajectories in later life.\u0026nbsp;\u003c/p\u003e","manuscriptTitle":"Do I Lose Cognitive Function as Fast as my Twin Partner? Analyses Based on Classes of MMSE Trajectories of Twins Aged 80 and older","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-02-04 15:11:19","doi":"10.21203/rs.2.22580/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"acb13c00-5372-449c-ba8c-774d67a72ff2","owner":[],"postedDate":"February 4th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":55492,"name":"Geriatrics \u0026 Gerontology"}],"tags":[],"updatedAt":"2021-07-22T19:36:04+00:00","versionOfRecord":{"articleIdentity":"rs-13154","link":"https://doi.org/10.1093/ageing/afaa239","journal":{"identity":"age-and-ageing","isVorOnly":true,"title":"Age and Ageing"},"publishedOn":"2020-10-31 19:36:04","publishedOnDateReadable":"October 31st, 2020"},"versionCreatedAt":"2020-02-04 15:11:19","video":"","vorDoi":"10.1093/ageing/afaa239","vorDoiUrl":"https://doi.org/10.1093/ageing/afaa239","workflowStages":[]},"version":"v1","identity":"rs-13154","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-13154","version":["v1"]},"buildId":"J0_U0BvcaRcwD8yVFaRlm","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}