Longitudinal Trajectories of Episodic Memory in Older Adults in Preclinical stages depending on whether they remain Stable or Progress to Mild Cognitive Impairment: Evidence from the CompAS and CIMA-Q cohorts

Longitudinal Trajectories of Episodic Memory in Older Adults in Preclinical stages depending on whether they remain Stable or Progress to Mild Cognitive Impairment: Evidence from the CompAS and CIMA-Q cohorts | 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 Longitudinal Trajectories of Episodic Memory in Older Adults in Preclinical stages depending on whether they remain Stable or Progress to Mild Cognitive Impairment: Evidence from the CompAS and CIMA-Q cohorts Sonali Arora, María Campos-Magdaleno, Lucía Pérez-Blanco, Samira Mellah, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8933401/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Subjective Cognitive Decline (SCD) refers to self-perceived decline in the absence of objective cognitive impairment, but whether longitudinal decline differentiates stable and progressing Cognitively Unimpaired (CU) and SCD individuals remains unclear. We aimed to analyse longitudinal differences in memory trends in stable and progressing CU and SCD participants to Mild Cognitive Impairment (MCI) from two methodologically similar cohorts, Compostela Aging Study (CompAS) and Consortium for the Early Identification of Alzheimer's Disease (CIMA-Q). 216 participants (67.09 ± 8.29 years) without objective cognitive impairment were classified into four groups considering baseline diagnosis and progression at two follow-ups: CU-S (CU who remained stable), SCD-S (SCD who remained stable), CU-P (CU who progressed to SCD/MCI), and SCD-P (SCD who progressed to MCI). Memory was assessed using immediate, short-, and long-delay free recall measures. Longitudinal memory trends were evaluated considering time as within-subject factor, group as between-subject factor, and schooling, age, and comorbidity as covariates. Longitudinal episodic memory declines were larger in CU-P in long-delay and, particularly, in SCD-P in all three memory measures compared to stables. For immediate memory, slope decline was similar in SCD-P, but the group effect also indicated lower performance in SCD-P at baseline. Long-delay measure was able to differentiate longitudinal memory decline between SCD-P and CU-P groups. Our results suggest that longitudinal change in delay measures is concurrent with diagnostic change in at-risk SCD participants. Immediate memory might be more discriminative as early risk marker, but not intense enough to detect worsening in at-risk SCD or differentiate it from at-risk CU group. Subjective Cognitive Decline (SCD) episodic memory immediate recall longitudinal design Cognitively Unimpaired (CU) older adults Figures Figure 1 Figure 2 1. Introduction Subjective cognitive decline (SCD) refers to a condition characterized by the presence of cognitive complaints and a persistent feeling of cognitive decline compared to previously normal functioning, in the absence of any objective cognitive impairment on neuropsychological tests and unrelated to an acute event (Jessen et al. 2014 , 2023 ). According to the National Institute on Aging and Alzheimer’s Association (NIA-AA) diagnostic framework, including its updated 2024 revision (Jack et al. 2018 , 2024 ), SCD falls between the normative aging decline (i.e., Cognitively Unimpaired, CU) and prodromic (i.e., Mild Cognitive Impairment, MCI) stages of the continuum the age-associated cognitive decline (Sperling et al. 2011 ). To address some of the challenges related to the standardization of SCD (Molinuevo et al. 2017 ), a flexible criterion for classification was proposed by the International Working Group of AD researchers in 2014 called the SCD Initiative that provided a conceptual framework and consensus terminology for SCD diagnosis in preclinical AD (Jessen et al. 2014 ). However, it is just a provisional diagnosis as SCD lacks a gold standard measurement criterion and can be influenced by factors that affect its prevalence and predictive value (Jessen et al. 2020 ; Slot et al. 2019 ). Epidemiologically, the criteria for diagnosing SCD are not yet well-established or agreed upon as definitions, age ranges, inclusion/exclusion criteria, and measurement tools vary considerably across studies (Parnetti et al. 2019 ; Rabin et al. 2015 ). This lack of consensus results in wide-ranging prevalence across studies. For example, a recent meta-analysis of 16 international population-based cohort studies from 15 countries found that SCD prevalence ranges between 7.8–52.7% in individuals over 60 (Röhr et al. 2020 ). Moreover, SCD is an unspecific symptom as it can be a result of the normative as well as pathological aging process and can be influenced by sociodemographic variables like age, education, health variables like comorbidity, and depression and anxiety (Arora et al. 2024 ; Crumley et al. 2014 ; Tank et al. 2024 ). Some studies suggest that subtle decline in memory performance, especially episodic memory, is a common feature in SCD individuals and could predict progression from SCD to objective cognitive decline (Bessi et al. 2018 ; Jessen et al. 2018 ; Jester et al. 2022 ). This requires examining memory of people with SCD using longitudinal design (Mitchell et al. 2014 ). Longitudinal studies and meta-analysis suggest that greater memory decline over time in SCD individuals is associated with an increased risk of future objective cognitive decline and dementia (Bessi et al. 2018 ; Rabin et al. 2017 ; Tallman et al. 2025 ). However, evidence also suggests that baseline memory performance may already be slightly lower on sensitive memory tasks in SCD individuals compared to cognitively healthy controls (Morrison and Oliver 2023 ), even though at this stage it may be largely compensated (Arora et al. 2026 ; Erk et al. 2011 ) or affected by factors related to repeated testing (Campos-Magdaleno et al. 2017 ; Machulda et al. 2013 ). For example, a study on a longitudinal German cohort over an 8-year follow-up period showed that baseline performance in the SCD group was lower and declined more steeply in immediate and delayed verbal episodic memory recall compared to the control group in predicting future memory decline (Koppara et al. 2015 ). Similarly, a Spanish population-based study found that individuals with SCD showed significantly lower performance at baseline on episodic memory and executive function tasks compared to non-SCD participants, in predicting cognitive decline (Sánchez et al. 2018). In line with these findings, a recent six-year longitudinal study from Montreal, found that older adults with SCD already showed subtle baseline declines across several cognitive domains, including episodic and semantic memory, compared to those without SCD, and showed accelerated decline over the follow-ups in predicting progression to future cognitive impairment (Morrison and Oliver 2023 ). Similarly, a Spanish three-year longitudinal study identified a subgroup with SCD participants who showed difficulties in cognitive domains of language and working memory at baseline, and this subgroup also showed a larger risk of progression over-the follow up to MCI and dementia relative to SCD with no impairment (Picón et al. 2019 ). However, evidence is mixed, and it remains unclear whether baseline performance or longitudinal changes in episodic memory are more informative in anticipating future clinical stability or progression (Koppara et al. 2015 ; Morrison and Oliver 2023 ). Identifying subtle cognitive changes during earlier stages, such as CU and SCD to MCI stage may hold greater clinical relevance for early detection and intervention. Besides, longitudinal cross-cultural studies using harmonized methods across cohorts remain scarce, despite being recommended for SCD research (Jessen et al. 2020 ; Rabin et al. 2017 ). We aim to explore baseline and longitudinal differences in episodic memory trends between CU and SCD participants who remain stable or progress to MCI in samples from two methodologically similar study cohorts: The CompAS and the CIMA-Q studies, respectively carried out in Spain and Canada. 2. Methods 2.1. Cohort Information The data for this study was selected for cross-cultural collaborative research using harmonized datasets from two longitudinal cohorts on aging research: the Compostela Aging Study (CompAS; Juncos-Rabadán et al. 2014 ) based in Galicia, Spain, and the Consortium for the Early Identification of Alzheimer's Disease-Quebec (CIMA-Q; Belleville et al. 2019 ) based in the province of Quebec, Canada. The CompAS cohort is an ongoing longitudinal study initiated in 2008, focusing on the detection of cognitive impairment in middle-aged and older community-dwelling adults (> 50 years) attending primary care centers in Galicia (an autonomous region in northwestern Spain) (Juncos-Rabadán et al. 2014 ). The CIMA-Q longitudinal study is composed of community-dwelling adults aged 65 and over from Montreal, Sherbrooke, and Quebec City in Canada (Belleville et al. 2019 ). In both cohorts, participants included are cognitively unimpaired and with SCD. The data used in this manuscript were obtained in part through the Consortium for the Early Identification of Alzheimer’s Disease - Québec (CIMA-Q). The primary objective of CIMA-Q is the longitudinal characterization of an observational cohort of more than 350 aging women and men who are cognitively healthy, with subjective cognitive impairments, with mild cognitive impairments or with a dementia resulting from a probable AD. CIMA-Q gathers clinical, cognitive, biological, radiological and pathological data from these participants in order to (1) establish early AD diagnosis; (2) make a cohort with specific characteristics available to the scientific community; (3) identify new therapeutic targets enabling to prevent or slow cognitive decline and AD; and (4) support new clinical studies of these targets (Belleville et al, 2019 ). 2.2. Study design and participants A sample of 216 participants without objective cognitive impairment (mean age: 66.66 ± 8.28), who completed at least two follow-ups, were selected from the CompAS (n = 124) and CIMA-Q (n = 92) cohort studies. Participant met the following exclusion criteria: prior diagnosis of dementia, psychiatric or neurological disorders, severe illness, sensory deficits (e.g., deafness of blindness), substance abuse, or if they were undergoing chemotherapy. Additionally, CIMA-Q participants were excluded if they planned to move out of Quebec within three years, had a Patient Health Questionnaire-9 (Kroenke et al. 2001 ) score of 20 or higher, or any condition that could compromise their participation in the study. All participants completed clinical and neuropsychological assessments at baseline (T0) and at follow-ups assessments: T1 conducted 18–24 months after baseline and T2 conducted 48–70 months after baseline in the CompAS; and T1 and T2, conducted approximately 24 and 48 months after baseline in the CIMA-Q. Mean follow-up across both cohorts was 21.53 months for T1 and 56.57 months for T2. All participants gave written informed consent prior to participation in the study. Ethics approval was granted by the Galician Clinical Research Ethics Committee (Xunta de Galicia, Spain) and the Committee of the Institut universitaire de gériatrie de Montréal (IUGM), both in accordance with the ethical standards outlined in the Declaration of Helsinki as revised in Fortaleza, Brazil, in 2013. Trained psychologists or psychometrician carried out extensive clinical and cognitive assessments of the participants, who were classified as CU or SCD at a special meeting held by the research team. To identify SCD, participants of both studies fulfilled the SCD-I criteria (Jessen et al. 2014 ) which consisted of reporting cognitive concerns and the absence of objective cognitive impairment (applying the appropriate age and education adjustments). In addition, a psychometric criterion was applied: SCD participants had to report cognitive complaints above the 5th percentile (age-adjusted) on total scores of the complaint’s questionnaire, which has been found to be a valid measure of subjective cognitive complaints for improving the prediction of progression to MCI and dementia (Pereiro et al. 2021 ). Alternatively, participants were categorized as CU if their cognitive objective performance was under the normal range (considering adjustments), and cognitive complaints scores did not exceed the proposed cut-off (see Instruments subsection). To assess cognitive worsening in the follow-up evaluations, MCI criteria was considered. The MCI diagnosis was made according to the standard criteria established by the National Institute on Aging and the Alzheimer’s Association (NIA-AA; Albert et al. 2011 ) based on Petersen ( 2004 ) standards: presence of cognitive complaints, an objective impairment 1–2 standard deviations below the expected for their age and educational level, and preserved instrumental activities of daily living or minimally affected (see Instrument subsection). To avoid circularity, independent memory tests were used for the diagnostic criteria and for the dependent variable measuring memory decline in our analyses. The participants were grouped based on the change of their diagnostic status at any time between baseline (T0) and follow-ups (T1 and T2): stability (no change in diagnosis), progression (diagnostic worsening), or reversion (diagnostic improvement) (see the flowchart of the grouping process in Fig. 1 ). The definition of stability vs progression was made on the diagnostic criteria and independent of the dependent variable used in the study. The diagnosis at baseline was conservatively adjusted when diagnosis at the first follow-up (18–24 months after baseline) showed an unexpected cognitive recovery (i.e., from MCI to SCD and/or CU; from SCD to CU) (Pereiro et al. 2021 ). Stable groups included CU participants who did not change diagnostic criteria (CU-S: 68 participants) and SCD participants who remained stable (SCD-S: 84 participants). The worsening groups included CU participants who progressed to SCD/MCI (CU-P, 29 participants) and SCD participants who progressed to MCI (SCD-P, 2 participants). Among the SCD participants, 9 (4.16%) reverted to a CU at the follow-ups and were excluded from the main analyses. In the CompAS cohort, 13 participants (10.48%) progressed to dementia and in the CIMA-Q cohort, 5 participants (5.43%) progressed to dementia at the second follow up, but these participants were excluded from the main analyses as this was not the objective of the study. --INSERT FIGURE 1 -- Descriptive statistics and diagnostic changes by cohort are shown in Table 1 . Table 1 Descriptive statistics (proportions, Mean, SD) and diagnostic progression for the total sample and by study (CompAS and CIMA-Q) Total CompAS CIMA-Q N 216 (CU = 97, SCD = 119) 124 (CU = 79, SCD = 45) 92 (CU = 18, SCD = 74) Age M(SD) 67.09 (8.29) 63.15 (8.22) 72.40 (4.62) Sex (% women) 74.5% 77.4% 70.6% CU-S 68 (70.1%) 51 (64.55% of CU) 17 (94.44% of CU) SCD-S 84 (70.5%) 33 (73.33% of SCD) 51 (68.91% of SCD) CU-P 29 (29.8%) 28 (35.44% of CU) 1 (5.55% of CU) SCD-P 26 (21.8%) 11(24.44% of SCD) 15 (20.27% of SCD) Note : CU-S: CU who remained stable; SCD-S = SCD who remained stable; CU-P = CU who progress to SCD/MCI; SCD-P = SCD who progress to MCI. --INSERT Table 1 -- 2.3. Instruments and harmonization procedure At baseline, the participants completed a comprehensive neuropsychological battery including sociodemographic, affective, neuropsychiatric, health, and cognitive tests and measures. Sociodemographic variables were collected using an ad hoc questionnaire, including age, sex, years of schooling, and professional attainment in both studies and were used to characterize between group differences. Professional attainment was standardized across studies by unifying four categories. We used Cognitive Reserve Index questionnaire (CRIq; Nucci et al. 2012 ) in the CompAS and Cognitive Reserve Questionnaire (CRQ, adapted in French by Eduardo Cisneros; Rami et al. 2011 ) used in CIMA-Q which defined the four categories as (1) Unskilled worker or homemaker (e.g., farmer, gardener, baby-sitter); (2) Skilled manual worker (e.g., tailor, hairdresser, military); (3) Skilled non-manual worker (e.g., teacher, musician, commercial agent); (4) Mid-level professional (e.g., doctor, psychologist, lawyer); and (5) Executive or management work (e.g., researcher, surgeon, CEO). Depressive symptomatology was assessed using the short form of the Geriatric Depression Scale (GDS-15, Sheikh and Yesavage 1986 , Spanish validation by Martínez de la Iglesia et al. 2002). Health was assessed using the Charlson Comorbidity Index (CCI; Charlson et al. 1987 ), which quantifies the individual's burden of disease from the patient's medical history. The severity and stress of neuropsychiatric symptoms were measured using the Neuropsychiatric Inventory Questionnaire (NPI-Q; Kaufer et al. 2000 ; Spanish validation by Boada et al. 2002 ). These measures were assessed at baseline and included in the analyses to study the between-group differences in CU and SCD participants. For this study, cognitive complaints were measured using the Memory Failures of Everyday questionnaire (MFE; Sunderland et al. 1984 ; Spanish adaptation by Montejo Carrasco et al. 2012 ) from the CompAS and a short version of the Questionnaire D’auto-évaluation de la Mémoire (Clément et al. 2008 ) from the CIMA-Q study. For the harmonization process, equivalent items (two related to conversation, and three related to movies and reading) from both instruments were identified and matched. The items were: (1) “Do you have difficulty following a conversation going on with one person because you forget what has just been said?” (MFE item 16, QAM item 1); (2) “During a conversation, do you repeat many times the same thing because you forgot that you have just said it?” (MFE item 28, QAM item 3); (3) “Do you have difficulty in reading because you forget what you have just read, which obliges you to read the text again?” (MFE item 17, QAM item 7); (4) “Do you have difficulty in remembering what you have read a few days before?” (MFE item 9, QAM item 8); and (5) “Do you have difficulty in following a movie or a TV program because you forget what just happened?” (MFE item 3, QAM item 9). To harmonize the scales, QAM responses (Likert 1–6; 1 = never, 6 = always) were recoded to match the MFE scale (0–2; 0 = never/ rarely, 1 = sometimes, 2 = always), such that scores 1–2 were coded as 0, 3–4 as 1, and 5–6 as 2. A total cognitive complaints score was calculated by summing the harmonized items across both studies. For this study, we measured general cognition using data from the Cambridge Cognitive Assessment Revised (CAMCOG-R; Roth et al. 1986 ). Spanish age and education norms (Pereiro et al. 2015 ) to obtain a total score and to evaluate cognitive performance by domains (orientation, language, memory, attention/calculation, praxis, abstract thinking, perception, and executive functions) in the CompAS cohort. For the CIMA-Q cohort, we used the Montreal Cognitive Assessment to measure general cognition (MoCA; Nasreddine et al. 2005 ). To assess memory decline we used the Test de Aprendizaje Verbal España-Complutense (TAVEC, the Spanish version of the California Verbal Learning Test, CVLT; Delis et al. 1987 ; Spanish adaptation by Benedet and Alejandre 1998 ) in the CompAS and the Rey Auditory Verbal Learning Test (RAVLT; Schmidt 1996 ; Québec French adaptation by Lavoie et al. 2018 ) in the CIMA-Q. For the harmonization process, equivalent measures of Total Immediate Recall, Short Delay Free Recall, and Long Delay Free Recall were obtained from both studies. For the purposes of this study, dependent variables were the common measures from TAVEC and RAVLT. Both instruments assess verbal episodic memory performance based on learning and recall of word lists, and their administration is quite similar. The list of words to be recalled is presented orally in 5 consecutive trials immediately after each essay; the participant should say the words he/she remembers. The sum of the five consecutive learning trials is the total immediate recall measure. A single trial is then performed with an interference list of words, after which the participant is asked again from the words of the original list, obtaining the short delay free recall measure. Finally, the number of words remembered from the original list is asked again after a delay of 20 minutes, obtaining the long delay free recall measure. 2.4. Statistical Analysis The data were analyzed using the SPSS statistical software package, version 29.0 (SPSS, Chicago, IL, USA), for descriptive analysis and group comparisons. Descriptive statistics were calculated for all variables, and between cohort-studies (CompAS and CIMA-Q) and inter-group (CU, SCD) differences were tested in the sociodemographic and health measures considered. One factor ANOVAs (age, years of schooling, comorbidity) and Chi-square test (Sex, Profession, Memory familiar antecedents and CR in quartiles) were performed to test group differences and the percentages of participants belonging to each of the two groups were compared using cross-tabulations (p<.05 and p<.001). One factor ANOVAs for all neuropsychological measures considered were performed to test between study and between groups differences (p<.05 and p<.001). We also conducted post hoc Bonferroni correction (p<.003) to reduce the probability of type I error (Holland and Copenhaver 1987 ). Descriptive statistics, using mean and standard deviation were calculated for each progression group (CU-S, SCD-S, CU-P, SCD-P) for all memory measures of total immediate recall, short delay free recall and long delay free recall using harmonized memory measures from the CVLT and the RAVLT tests. Changes over time were assessed by comparing baseline and follow-up performance within and between each group. To evaluate longitudinal memory trends, a Multivariate General Linear Model Repeated Measures (3 × 4 design) was conducted by considering the time (T0, T1, and T2) as the within-subject factor and progression groups (CU-S, SCD-S, CU-P, SCD-P) as the between-subject factors for memory measures of total immediate recall, short delay free recall, and long delay free recall as dependent variables. ANCOVAs with schooling, age, and comorbidity (variables corresponding to the between-study differences found) as covariates for controlling group differences in those variables were used to analyze differences in memory trends between CU and SCD groups that worsen and those that remain stable over time. The alpha value was established at .05 for all analyses, and the partial eta squared ( η p 2 ) value was reported as an estimate of effect size in the ANCOVAs. Between-group tests were conducted to identify the main effects of time, progression groups, and covariates on memory performance. Pairwise Bonferroni post-hoc tests were applied to avoid the risk of incurring Type I error associated with multiple comparisons. The estimated marginal means represented in the figures correspond to the changes in memory performance trends across groups and the follow-up period adjusted for the covariates for each of the memory measures. 3. Results The sample descriptive scores for between-group (CU, SCD) and between-study (CompAS; CIMA-Q) differences in sociodemographic, health, and cognitive measures at baseline (T0) are shown in Table 2 . Table 2 Between-group (CU, SCD) and between-study (CompAS, CIMA-Q) differences in sociodemographic, health, and cognitive measures Between-Group Between-Studies CompAS CIMA-Q CU SCD Age -- -- (2) CIMA-Q>CompAS*** (2) CIMA-Q>CompAS*** Schooling (years) (2) CU > SCD** -- -- (2) CIMA-Q>CompAS*** Profession -- -- (3) CIMA-Q>CompAS*** (3) CIMA-Q>CompAS*** Complaints (1) (2) SCD > CU*** (2) SCD > CU*** -- -- CCI (1) -- (2) SCD > CU* (2) CIMA-Q>CompAS*** (2) CIMA-Q>CompAS*** GDS-15 (1) (2) SCD > CU** (2) SCD > CU** -- -- NPI-Q (1) -- -- (2) CompAS>CIMA-Q* (2) CompAS>CIMA-Q* CAMCOG-R/MoCA (1) (2) CU > SCD* -- (2) CompAS>CIMA-Q*** -- --INSERT Table 2 -- SCD participants in the CIMA-Q and CompAS studies reported more depressive symptoms and subjective cognitive complaints compared to control group participants. However, SCD participants in CompAS had a lower education level than the CU group, while in the CIMA-Q study showed greater comorbidity. Between study differences showed that CIMA-Q participants (both CU and SCD) were older, presented greater comorbidity, and achieved greater professional attainment. SCD participants from the CIMA-Q also had significantly higher education. The CompAS participants (both CU and SCD) reported significantly more neuropsychiatric symptoms. CU participants from the CompAS reported better cognitive performance (see Table 2 ). The mean and standard deviations of episodic memory scores for each of the diagnostic groups (CU-S, SCD-S, CU-P, SCD-P) and evaluation times (T0, T1 and T2) are included in Table 3 . Table 3 Mean and standard deviations (in parentheses) of the stable and worsening groups across longitudinal measurements in episodic memory measures Measure Group T0 T1 T2 Total immediate recall CU-S 54.10 (9.49) 54.95 (10.06) 54.47 (10.40) SCD-S 52.06 (8.92) 51.48 (9.25) 51.89 (11.27) CU-P 51.44 (8.70) 52.41 (10.57) 51.06 (13.06) SCD-P 43.87 (9.32) 41.37 (10.78) 38.12 (13.33) Total 51.68 (9.58) 51.58 (10.65) 50.99 (12.46) Short delay free recall CU-S 11.70 (2.64) 11.63 (2.70) 11.94 (2.91) SCD-S 10.65 (2.44) 10.71 (3.29) 10.88 (3.46) CU-P 10.51 (2.61) 10.20 (3.10) 9.82 (4.21) SCD-P 9.08 (2.53) 7.87 (3.71) 6.58 (3.84) Total 10.80 (2.65) 10.61 (3.30) 10.57 (3.80) Long delay free recall CU-S 12.25 (2.52) 12.39 (2.54) 12.22 (2.73) SCD-S 11.18 (2.57) 11.22 (2.89) 11.25 (3.20) CU-P 11.20 (2.61) 12.00 (2.86) 10.55 (4.07) SCD-P 9.37 (2.84) 7.54 (3.57) 6.75 (4.25) Total 11.33 (2.72) 11.29 (3.20) 10.93 (3.70) --INSERT Table 3 -- 3.1. Longitudinal differences in total immediate recall performance in Stable and Worsening CU and SCD Groups For the total immediate recall variable, the model indicated a significant main effect of the progression group factor [ F (3, 190) = 8.735, p < .001, η p 2 = .121, observed power = .994]. Significant effects were found also for the covariates Age [ F (1, 190) = 55.077, p< .001, η p 2 = .225, observed power = 1.000] and Schooling [ F (1, 190) = 18.904, p< .001, η p 2 = .090, observed power = .991]. Intra-subject tests showed significant effects for time [ F (2, 189) = 6.377, p= .002, η p 2 = .063, observed power = 0.898] and interactions between time and age [ F (2, 189) = 10.704, p< .001, η p 2 = .102, observed power = .989] and time and comorbidity [ F (2, 189) = 4.183, p= .017, η p 2 = .042, observed power = .731]. There was no time x group interaction. The Bonferroni´s pairwise comparison for the progression group factor [ F (3, 190) = 8.735, p <.001, η p 2 = .121, observed power = .994] showed significant lower scores in SCD-P compared to stable groups (CU-S, SCD-S). Despite of interaction between the progression group and time factors did not achieve signification, Bonferroni’s pairwise comparison showed a significant decrease from T0 to T2 only in the SCD-P group [ F (2, 189) = 3.456, p= .034, η p 2 = .035, observed power = .642] and significant lower scores in SCD-P compared to SCD-S at T0 [ F (3, 190) = 4.567, p= .004, η p 2 = .067, observed power = .882], T1 [ F (3, 190) = 6.010, p< .001, η p 2 = .087, observed power = .956] and T2 [ F (3, 190) = 8.096, p< .001, η p 2 = .113, observed power = .991], extending the group differences to the CU-S in this last follow-up (see Fig. 2 ). 3.2. Longitudinal differences in short delay free recall performance in Stable and Worsening CU and SCD Groups Between-subject tests for short delay free recall showed a significant main effect of progression group [ F (3, 190) = 8.898, p< .001, η p 2 = .123, observed power = .995] pointing out lower scores in SCD-P than in the stable groups (CU-S, SCD-S). Significant effects were found for the covariates Age [ F (1, 190) = 53.006, p< .001, η p 2 = .218, observed power = 1.000] and Schooling [ F (1, 190) = 10.649, p= .001, η p 2 = .053, observed power = .901]. Intra-subject tests showed significant effects for time [ F (2, 189) = 8.277, p< .001, η p 2 = .081, observed power = 0.960] and interactions between time and age [ F (2, 189) = 11.588, p< .001, η p 2 = .109, observed power = .993]. A significant interaction between time and progression group were observed [ F (6, 380) = 2.607, p= .017, η p 2 = .040, observed power = .854] that was specified through Bonferroni´s pairwise comparisons as follows: a) significantly lower scores of SCD-P compared to the stable groups (SCD-S, CU-S) at T1[ F (3, 190) = 4.673, p= .004, η p 2 = .069, observed power = .890] and at T2 [ F (3, 190) = 10.747, p< .001, η p 2 = .145, observed power = .999], but not at T0 [ F (3, 190) = 2.832, p= .113, η p 2 = .043, observed power = .673]; and b) a significant decrease in the T2 compared to T0 only in the SCD-P group [ F (2, 189) = 7.600, p< .001, η p 2 = .074, observed power = .943] (see Fig. 2 ). 3.3. Longitudinal differences in long delay free recall performance in Stable and Worsening CU and SCD Groups Between-subject tests for long delay free recall showed a significant main effect of progression group [ F (3, 189) = 11.712, p< .001, η p 2 = .157, observed power = 1.000] due to lower scores in SCD-P than in the stable groups (CU-S, SCD-S) and also CU-P group. Significant effects were found for the covariates Age [ F (1, 189) = 52.952, p< .001, η p 2 = .219, observed power = 1.000] and Schooling [ F (1, 189) = 9.049, p= .003, η p 2 = .046, observed power = .849]. Intra-subject tests showed significant effects for time [ F (2, 189) = 8.256, p< .001, η p 2 = .081, observed power = 0.959] and interactions between time and age [ F (2, 188) = 12.872, p< .001, η p 2 = .120, observed power = .997], time and comorbidity [ F (2, 188) = 7.454, p< .001, η p 2 = .073, observed power = .939]. A significant interaction between time and progression group were observed [ F (6, 378) = 3.894, p< .001, η p 2 = .058, observed power = .968] that was specified through Bonferroni´s pairwise comparisons as follows: a) significantly lower scores in the SCD-P compared to the three other groups at T1 [ F (3, 189) = 9.658, p< .001, η p 2 = .133, observed power = .977] and at T2 [ F (3, 189) = 11.665, p< .001, η p 2 = .156, observed power = 1.000] but not at T0 [ F (3, 189) = 3.523, p = .083, η p 2 = .053, observed power = .777]; and b) significant lower scores in T2 and T1 than in T0 only for the SCD-P group [ F (2, 188) = 10.677, p< .001, η p 2 = .102, observed power = .989] (see Fig. 2 ). --INSERT FIGURE 2 -- 4. Discussion This study aimed to analyze the longitudinal differences in episodic memory performance among CU and SCD participants who remained stable or showed diagnostic progression to MCI, using harmonized data from two methodologically similar study cohorts. Regarding diagnostic progression, our findings indicated that most of the CU (70.1%) and SCD participants (70.5%) remained stable over 48–70 months follow-ups, 17.5% of CU progressed to SCD, 12.3% to MCI, and 21.8% of SCD progressed to MCI. These results are in line with meta-analytic evidence showing that while SCD is associated with increased risk of future decline, most participants remain cognitively stable over several years, with conversion rates increasing from 11% over 5 years to 14% in longer follow-ups over 6–7 years (Mitchell et al. 2014 ). Almost all CU participants in CIMA-Q remained stable (94.4%), whereas stability was lower in CompAS (64.5%). In contrast, SCD stability over the follow ups was very similar across both cohorts (73.3% in CompAS vs. 68.9% in CIMA-Q). Diagnostic progression was also very similar across both cohorts, with 17.5% of CU participants progressing to SCD and 17.7% of CU and SCD participants progressing to MCI in CompAS, compared with 17.3% of total sample progressing to MCI in CIMA-Q over the 48–70-month follow-up. In line with these findings, a recent meta-analysis of five cross-cultural studies reported a 17.2% progression rate from SCD to MCI, with follow-up durations ranging from 24 to 216 months (Tallman et al. 2025 ). The observed differences remained significant even after controlling for age, schooling, and comorbidity, covariates included due to baseline differences between the two cohorts. These findings may be due to the differences between the two cohorts such as recruitment sources or exclusion criteria. Overall, as expected, our results show that significantly lower memory scores were generally observed in the SCD-P group compared to the stable groups (SCD-S, CU-S) across the follow-ups in total immediate recall and short delay free recall and extended to the CU-P group in long delay free recall. These findings are consistent with the previous longitudinal studies showing that the presence of CU or SCD participants who show diagnostic worsening during follow-ups predicts a more accelerated decline on episodic memory measures of immediate and delayed verbal recall compared to those who remain stable (Koppara et al. 2015 ; Pereiro et al. 2021 ). The significant declines in episodic memory scores accompanied diagnostic changes and increases over the follow-ups, particularly in the short and long delayed measures, which shows that analysing the slope of decline over time is a more sensitive indicator than the baseline score in SCD participants at risk of progression to MCI or dementia (Bessi et al. 2018 ; Koppara et al. 2015 ; Rabin et al. 2017 ). Significant declines were observed in both short and long delayed recall measures at T1 in SCD-P group, further worsening at T2, suggesting that delay measures are concurrent to the diagnostic worsening over the follow ups (Bilgel et al. 2014 ; Rabin et al. 2009 ). Both short and long delay free recall are measures of consolidation processes, although they differ in a greater or lesser delay in information retrieval, which can be a significant predictor of conversion to AD in healthy participants (Rabin et al. 2009 ; Tierney et al. 2005 ). However, no significant baseline differences were observed in short and long delay free recall, suggesting that these measures have a limited predictive power in the early stages in identifying participants at risk, however can be better predictors once the change has occurred in the later stages of disease progression (Bilgel et al. 2014 ; Koppara et al. 2015 ). In our study, significant decline in both delayed recall measures in SCD-P participants emerged in T1 and increased at T2, which is consistent with studies that show that subtle memory decline in SCD participants at follow-ups is associated with a higher risk of progression towards dementia (Bilgel et al. 2014 ; Koppara et al. 2015 ; Rabin et al. 2009 ). Our results suggest that long delay free recall was the only measure in which significant decline was also observed in the CU-P group, suggesting that long delay recall may be a more sensitive but less specific indicator than immediate free recall or short delay free recall for differentiating between CU and SCD participants at risk of progression. Studies have shown that long delay recall tasks reflect more memory demanding processes like retention and delayed-retrieval effects (dependent on entorhinal and hippocampal systems) can be more sensitive to subtle decline that may occur with both pathological as well as normal aging (Wearn et al. 2020 ) which makes it a less specific marker of progression compared to immediate or short delay recall (Bilgel et al. 2014 ; Lemos et al. 2016 ). Unlike the delayed recall measures, in total immediate recall, significant lower scores were observed in SCD-P compared to SCD-S already at baseline. However, time and progression group interaction does not achieved significance suggesting similar decline slopes across follows ups in all groups. Longitudinal differences were only found in pairwise comparisons between SCD-P and SCD-S and therefore, this result should be interpreted with caution. Total immediate recall is the sum of words recalled across the five initial learning trials so it reflects encoding rather than consolidation process as in delayed measures like short delay free recall and long delay free recall (Rabin et al. 2009 ), making total immediate recall not as sensitive as delay recall measures for predicting cognitive decline (Bilgel et al. 2014 ; Lemos et al. 2016 ). Significant differentiation of SCD-P and SCD-S groups at baseline jointly with the potentially higher longitudinal decline could suggests immediate recall as candidate to be early predictive marker of future objective cognitive decline (Lemos et al. 2016 ) as well as in identification of SCD at risk (Bilgel et al. 2014 ; Koppara et al. 2015 ). In addition, test-related factors such as reduced practice effects may partly explain the long delay free recall decline observed even in CU-P participants, since it has been shown that CU participants show some improvement across repeated testing (Machulda et al. 2013 ). However, our results show that these practice effects were overshadowed by subtle memory decline in the SCD-P group, with only the most demanding variables such as long delay free recall also showing decline in CU-P group. In contrast, CU-S and SCD-S participants showed improvement at baseline and during follow-ups. Reduced practice effects on the Spanish version of CVLT have previously been described in participants with SCD and MCI to be predictive of cognitive decline (Campos-Magdaleno et al. 2017 ), and our findings extend this evidence by showing similar patterns in both CU-P and SCD-P groups. Future research should aim to replicate these findings in larger sample, as our unequal sample size across cohorts as well as high attrition rate (55.3%) may introduce bias of the results. Moreover, the small number of participants who showed worsening trajectories could reduce statistical power. Another limitation concerns the interpretation of the total immediate recall results. Additionally, we applied Bonferroni correction to control for multiple comparisons which is highly conservative and may have reduced the sensitivity of the measures to detect early group differences. Finally, the current study does not include information on biomarkers in blood and cerebrospinal fluid or structural or functional neuroimaging markers. Future studies should include these measures for a better understanding of how episodic memory measures improve the identification of subtle memory decline in a trajectory from preclinical to prodromal stages of dementia. 5. Conclusion In conclusion, our findings show that significant difference in episodic memory were already observed as early as baseline in total immediate recall and progressively worsening over the follow-ups across all three memory measures in CU and SCD participants who showed diagnostic worsening. Lower scores in total immediate recall measure at baseline could be an indication of potential value for identifying early subtle cognitive decline in at-risk SCD participants. Importantly, long delay free recall was the most sensitive measure, where decline was observed not only in SCD-P but also in CU-P participants. Immediate memory might be more discriminative as early risk marker, but not intense enough as delay measures to detect worsening in at-risk SCD or differentiate it from at-risk CU group. Overall, these results support the utility of episodic memory decline, especially total immediate recall for improving early identification of participants in the preclinical stages of dementia who are at risk of future cognitive decline. Declarations Competing interests: The authors declare no competing interests. Funding: This work was financially supported through FEDER founds (‘A way to make Europe’) by the Spanish AEI (Doi: 10.13039/501100011033; Refs. PID2020-114521RB-C21 and PID2023-151659OB-C21) and by the Galician Government (Consellería de Cultura, Educación e Ordenación Universitaria; axudas para a consolidación e estruturación de unidades de investigación competitivas do Sistema Universitario de Galicia ED431C 2025/14; GI-1807-USC). The CIMA-Q project is supported by various funding sources, including the FRQS-Pfizer Innovation Program (grant number 27239), the FRQS-Cohorte (grant 2020-VIVO-279261), the Fondation Courtois (Neuromod project), the Consortium canadien en neurodégénérescence associée au vieil lissement (grant number 137794), the Réseau Québécois de Recherche sur le Vieillissement, and the Fondation Famille Lemaire. This publication was also supported by Grants to the co-author Sylvie Belleville from the Canadian Institutes of Health Research (grant number MOP81302); Natural Sciences and Engineering Research Council of Canada (NSERC), and Canada Research Chair in Cognitive Neuroscience of Aging and Brain Plasticity. Author Contribution Data curation: Sonali Arora, María Campos-Magdaleno, Lucía Pérez-Blanco, Samira Mellah; Conceptualization: Sonali Arora, Sylvie Belleville, Arturo X. Pereiro; Validation: Sonali Arora, Samira Mellah, Arturo X. Pereiro; Investigation: Sonali Arora, María Campos-Magdaleno, Lucía Pérez-Blanco, Sylvie Belleville, Arturo X. Pereiro; Methodology: Sonali Arora, María Campos-Magdaleno Visualization: Sonali Arora; Resources: Samira Mellah, Sylvie Belleville; Writing – original draft: Sonali Arora; Writing – review and editing: Sonali Arora, Lucía Pérez-Blanco, Samira Mellah, Sylvie Belleville, Arturo X. Pereiro; Funding acquisition: Arturo X. Pereiro; Project administration: Arturo X. Pereiro; Supervision: Arturo X. Pereiro. Acknowledgements: None Data Availability The datasets generated during and/or analysed during the current study are available from the first and the corresponding author on reasonable request. 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Alzheimers Res Ther 12:119. https://doi.org/10.1186/s13195-020-00693-4 Zhao Q, Lv Y, Zhou Y, Hong Z, Guo Q (2012) Short-term delayed recall of auditory verbal learning test is equivalent to long-term delayed recall for identifying amnestic mild cognitive impairment. PLoS ONE 7:e51157. https://doi.org/10.1371/journal.pone.0051157 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers invited by journal 06 May, 2026 Editor assigned by journal 24 Mar, 2026 Submission checks completed at journal 22 Feb, 2026 First submitted to journal 21 Feb, 2026 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. 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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-8933401","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":637000635,"identity":"6cb76e0a-6501-4b5f-af5e-c345b9a6b8b7","order_by":0,"name":"Sonali Arora","email":"","orcid":"","institution":"Instituto de Psicoloxía (IPsiUS), Universidade de Santiago de Compostela","correspondingAuthor":false,"prefix":"","firstName":"Sonali","middleName":"","lastName":"Arora","suffix":""},{"id":637000636,"identity":"54f4e695-0e09-4819-b501-d20e8671817f","order_by":1,"name":"María Campos-Magdaleno","email":"","orcid":"","institution":"Instituto de Psicoloxía (IPsiUS), Universidade de Santiago de Compostela","correspondingAuthor":false,"prefix":"","firstName":"María","middleName":"","lastName":"Campos-Magdaleno","suffix":""},{"id":637000637,"identity":"7e8acbb9-f01e-4960-8b04-ecf111e740ed","order_by":2,"name":"Lucía Pérez-Blanco","email":"","orcid":"","institution":"Instituto de Psicoloxía (IPsiUS), Universidade de Santiago de Compostela","correspondingAuthor":false,"prefix":"","firstName":"Lucía","middleName":"","lastName":"Pérez-Blanco","suffix":""},{"id":637000638,"identity":"499b046c-ae65-4428-bce7-d020c2eee6c9","order_by":3,"name":"Samira Mellah","email":"","orcid":"","institution":"Institut universitaire de gériatrie de Montréal","correspondingAuthor":false,"prefix":"","firstName":"Samira","middleName":"","lastName":"Mellah","suffix":""},{"id":637000639,"identity":"a941512a-9c4f-444e-b2a3-e23056bd5a7c","order_by":4,"name":"Sylvie Belleville","email":"","orcid":"","institution":"Institut universitaire de gériatrie de Montréal","correspondingAuthor":false,"prefix":"","firstName":"Sylvie","middleName":"","lastName":"Belleville","suffix":""},{"id":637000640,"identity":"68580f84-ae87-48d9-b457-09f922df04f5","order_by":5,"name":"Arturo X. Pereiro","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABA0lEQVRIiWNgGAWjYCgAHgYG5gME1DBjaGFLIE0LSJcBXg38s88fk66oOCwn397A9uDjHhsZ8/aeb5I/ahjk5Buwa5E4l8wmeeZMmrHBmQPshjOepfHInDm7TZrnGIOxwQEc1pxhZpNsbLNJ3CCRwCbNc+Awj4RE7jZpxgaGxA04dMhDtEgkzp//gE36z4H/QC05zyR/NjDUz8fhMAOYLQ03GNikGQ4cAGlhk+BtYEhgwOEwwzPMxpYNYL8kthv2HEjmkeA5ZmzNc0zCcAMOLXJnGB/ebACH2OFjD34csLOXYG9+ePNHjY08rhBDAoxtyDwJgupBgI0oVaNgFIyCUTDyAAAN3FFgqS0s8QAAAABJRU5ErkJggg==","orcid":"","institution":"Instituto de Psicoloxía (IPsiUS), Universidade de Santiago de Compostela","correspondingAuthor":true,"prefix":"","firstName":"Arturo","middleName":"X.","lastName":"Pereiro","suffix":""},{"id":637000641,"identity":"2c6c308e-a7c8-4378-9ab8-cba184499493","order_by":6,"name":"CIMA- Q","email":"","orcid":"","institution":"Institut universitaire de gériatrie de Montréal","correspondingAuthor":false,"prefix":"","firstName":"CIMA-","middleName":"","lastName":"Q","suffix":""}],"badges":[],"createdAt":"2026-02-21 12:23:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8933401/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8933401/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109337783,"identity":"8ae8f850-0c82-4676-9a2b-953f4725422a","added_by":"auto","created_at":"2026-05-15 17:47:02","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":196187,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eFlowchart of the grouping process according to the stability and diagnostic progression for the total sample\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNote:\u003c/em\u003e CU = Cognitively Unimpaired; SCD = Subjective Cognitive Decline; MCI = Mild Cognitive Impairment; T0 (baseline measurement); T1 (1st follow-up 18-24 months after T0); T2 (2nd follow-up 48-70 months after T0).\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-8933401/v1/8560c7ce8345eda0625fa4cb.png"},{"id":109337782,"identity":"538a9834-9db1-4e10-ba63-e862b230add9","added_by":"auto","created_at":"2026-05-15 17:47:02","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":155588,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eEstimated marginal means in total immediate recall (Chart A), short delay free recall (Chart B), and long delay free recall scores (Chart C) considering CU and SCD stable and worsening groups and longitudinal measurements, with age, schooling, and comorbidity as covariates\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eNote:\u003c/em\u003e Error bars: 95% CI; T0 (baseline measurement); T1 (1\u003csup\u003est\u003c/sup\u003e follow-up 18-24 months after T0); T2 (2\u003csup\u003end\u003c/sup\u003e follow-up 48-70 months after T0); CU-S= CU who remain stable; SCD-S= SCD who remain stable; CU-P= CU who progress to SCD/MCI; SCD-P= SCD who progress to MCI.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-8933401/v1/afceb26bc97babc2d54413af.png"},{"id":109337785,"identity":"103a29cd-a2bc-496b-8b66-d61a0ba192fe","added_by":"auto","created_at":"2026-05-15 17:47:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":610053,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8933401/v1/15ce0006-3f00-4d84-9185-eca424963e7c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Longitudinal Trajectories of Episodic Memory in Older Adults in Preclinical stages depending on whether they remain Stable or Progress to Mild Cognitive Impairment: Evidence from the CompAS and CIMA-Q cohorts","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eSubjective cognitive decline (SCD) refers to a condition characterized by the presence of cognitive complaints and a persistent feeling of cognitive decline compared to previously normal functioning, in the absence of any objective cognitive impairment on neuropsychological tests and unrelated to an acute event (Jessen et al. \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2014\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). According to the National Institute on Aging and Alzheimer\u0026rsquo;s Association (NIA-AA) diagnostic framework, including its updated 2024 revision (Jack et al. \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2018\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2024\u003c/span\u003e), SCD falls between the normative aging decline (i.e., Cognitively Unimpaired, CU) and prodromic (i.e., Mild Cognitive Impairment, MCI) stages of the continuum the age-associated cognitive decline (Sperling et al. \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e2011\u003c/span\u003e). To address some of the challenges related to the standardization of SCD (Molinuevo et al. \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e2017\u003c/span\u003e), a flexible criterion for classification was proposed by the International Working Group of AD researchers in 2014 called the SCD Initiative that provided a conceptual framework and consensus terminology for SCD diagnosis in preclinical AD (Jessen et al. \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). However, it is just a provisional diagnosis as SCD lacks a gold standard measurement criterion and can be influenced by factors that affect its prevalence and predictive value (Jessen et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Slot et al. \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e2019\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eEpidemiologically, the criteria for diagnosing SCD are not yet well-established or agreed upon as definitions, age ranges, inclusion/exclusion criteria, and measurement tools vary considerably across studies (Parnetti et al. \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Rabin et al. \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). This lack of consensus results in wide-ranging prevalence across studies. For example, a recent meta-analysis of 16 international population-based cohort studies from 15 countries found that SCD prevalence ranges between 7.8\u0026ndash;52.7% in individuals over 60 (R\u0026ouml;hr et al. \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). Moreover, SCD is an unspecific symptom as it can be a result of the normative as well as pathological aging process and can be influenced by sociodemographic variables like age, education, health variables like comorbidity, and depression and anxiety (Arora et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2024\u003c/span\u003e; Crumley et al. \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Tank et al. \u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e2024\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSome studies suggest that subtle decline in memory performance, especially episodic memory, is a common feature in SCD individuals and could predict progression from SCD to objective cognitive decline (Bessi et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Jessen et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Jester et al. \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). This requires examining memory of people with SCD using longitudinal design (Mitchell et al. \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). Longitudinal studies and meta-analysis suggest that greater memory decline over time in SCD individuals is associated with an increased risk of future objective cognitive decline and dementia (Bessi et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Rabin et al. \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Tallman et al. \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). However, evidence also suggests that baseline memory performance may already be slightly lower on sensitive memory tasks in SCD individuals compared to cognitively healthy controls (Morrison and Oliver \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2023\u003c/span\u003e), even though at this stage it may be largely compensated (Arora et al. \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2026\u003c/span\u003e; Erk et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2011\u003c/span\u003e) or affected by factors related to repeated testing (Campos-Magdaleno et al. \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2017\u003c/span\u003e; Machulda et al. \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). For example, a study on a longitudinal German cohort over an 8-year follow-up period showed that baseline performance in the SCD group was lower and declined more steeply in immediate and delayed verbal episodic memory recall compared to the control group in predicting future memory decline (Koppara et al. \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). Similarly, a Spanish population-based study found that individuals with SCD showed significantly lower performance at baseline on episodic memory and executive function tasks compared to non-SCD participants, in predicting cognitive decline (S\u0026aacute;nchez et al. 2018). In line with these findings, a recent six-year longitudinal study from Montreal, found that older adults with SCD already showed subtle baseline declines across several cognitive domains, including episodic and semantic memory, compared to those without SCD, and showed accelerated decline over the follow-ups in predicting progression to future cognitive impairment (Morrison and Oliver \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Similarly, a Spanish three-year longitudinal study identified a subgroup with SCD participants who showed difficulties in cognitive domains of language and working memory at baseline, and this subgroup also showed a larger risk of progression over-the follow up to MCI and dementia relative to SCD with no impairment (Pic\u0026oacute;n et al. \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e2019\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eHowever, evidence is mixed, and it remains unclear whether baseline performance or longitudinal changes in episodic memory are more informative in anticipating future clinical stability or progression (Koppara et al. \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Morrison and Oliver \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Identifying subtle cognitive changes during earlier stages, such as CU and SCD to MCI stage may hold greater clinical relevance for early detection and intervention. Besides, longitudinal cross-cultural studies using harmonized methods across cohorts remain scarce, despite being recommended for SCD research (Jessen et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2020\u003c/span\u003e; Rabin et al. \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). We aim to explore baseline and longitudinal differences in episodic memory trends between CU and SCD participants who remain stable or progress to MCI in samples from two methodologically similar study cohorts: The CompAS and the CIMA-Q studies, respectively carried out in Spain and Canada.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Cohort Information\u003c/h2\u003e \u003cp\u003eThe data for this study was selected for cross-cultural collaborative research using harmonized datasets from two longitudinal cohorts on aging research: the Compostela Aging Study (CompAS; Juncos-Rabad\u0026aacute;n et al. \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2014\u003c/span\u003e) based in Galicia, Spain, and the Consortium for the Early Identification of Alzheimer's Disease-Quebec (CIMA-Q; Belleville et al. \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2019\u003c/span\u003e) based in the province of Quebec, Canada.\u003c/p\u003e \u003cp\u003eThe CompAS cohort is an ongoing longitudinal study initiated in 2008, focusing on the detection of cognitive impairment in middle-aged and older community-dwelling adults (\u0026gt;\u0026thinsp;50 years) attending primary care centers in Galicia (an autonomous region in northwestern Spain) (Juncos-Rabad\u0026aacute;n et al. \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). The CIMA-Q longitudinal study is composed of community-dwelling adults aged 65 and over from Montreal, Sherbrooke, and Quebec City in Canada (Belleville et al. \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). In both cohorts, participants included are cognitively unimpaired and with SCD.\u003c/p\u003e \u003cp\u003eThe data used in this manuscript were obtained in part through the Consortium for the Early Identification of Alzheimer\u0026rsquo;s Disease - Qu\u0026eacute;bec (CIMA-Q). The primary objective of CIMA-Q is the longitudinal characterization of an observational cohort of more than 350 aging women and men who are cognitively healthy, with subjective cognitive impairments, with mild cognitive impairments or with a dementia resulting from a probable AD. CIMA-Q gathers clinical, cognitive, biological, radiological and pathological data from these participants in order to (1) establish early AD diagnosis; (2) make a cohort with specific characteristics available to the scientific community; (3) identify new therapeutic targets enabling to prevent or slow cognitive decline and AD; and (4) support new clinical studies of these targets (Belleville et al, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2019\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Study design and participants\u003c/h2\u003e \u003cp\u003eA sample of 216 participants without objective cognitive impairment (mean age: 66.66\u0026thinsp;\u0026plusmn;\u0026thinsp;8.28), who completed at least two follow-ups, were selected from the CompAS (n\u0026thinsp;=\u0026thinsp;124) and CIMA-Q (n\u0026thinsp;=\u0026thinsp;92) cohort studies. Participant met the following exclusion criteria: prior diagnosis of dementia, psychiatric or neurological disorders, severe illness, sensory deficits (e.g., deafness of blindness), substance abuse, or if they were undergoing chemotherapy. Additionally, CIMA-Q participants were excluded if they planned to move out of Quebec within three years, had a Patient Health Questionnaire-9 (Kroenke et al. \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2001\u003c/span\u003e) score of 20 or higher, or any condition that could compromise their participation in the study. All participants completed clinical and neuropsychological assessments at baseline (T0) and at follow-ups assessments: T1 conducted 18\u0026ndash;24 months after baseline and T2 conducted 48\u0026ndash;70 months after baseline in the CompAS; and T1 and T2, conducted approximately 24 and 48 months after baseline in the CIMA-Q. Mean follow-up across both cohorts was 21.53 months for T1 and 56.57 months for T2. All participants gave written informed consent prior to participation in the study. Ethics approval was granted by the Galician Clinical Research Ethics Committee (Xunta de Galicia, Spain) and the Committee of the Institut universitaire de g\u0026eacute;riatrie de Montr\u0026eacute;al (IUGM), both in accordance with the ethical standards outlined in the Declaration of Helsinki as revised in Fortaleza, Brazil, in 2013.\u003c/p\u003e \u003cp\u003eTrained psychologists or psychometrician carried out extensive clinical and cognitive assessments of the participants, who were classified as CU or SCD at a special meeting held by the research team. To identify SCD, participants of both studies fulfilled the SCD-I criteria (Jessen et al. \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2014\u003c/span\u003e) which consisted of reporting cognitive concerns and the absence of objective cognitive impairment (applying the appropriate age and education adjustments). In addition, a psychometric criterion was applied: SCD participants had to report cognitive complaints above the 5th percentile (age-adjusted) on total scores of the complaint\u0026rsquo;s questionnaire, which has been found to be a valid measure of subjective cognitive complaints for improving the prediction of progression to MCI and dementia (Pereiro et al. \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2021\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAlternatively, participants were categorized as CU if their cognitive objective performance was under the normal range (considering adjustments), and cognitive complaints scores did not exceed the proposed cut-off (see Instruments subsection).\u003c/p\u003e \u003cp\u003eTo assess cognitive worsening in the follow-up evaluations, MCI criteria was considered. The MCI diagnosis was made according to the standard criteria established by the National Institute on Aging and the Alzheimer\u0026rsquo;s Association (NIA-AA; Albert et al. \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2011\u003c/span\u003e) based on Petersen (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e2004\u003c/span\u003e) standards: presence of cognitive complaints, an objective impairment 1\u0026ndash;2 standard deviations below the expected for their age and educational level, and preserved instrumental activities of daily living or minimally affected (see Instrument subsection). To avoid circularity, independent memory tests were used for the diagnostic criteria and for the dependent variable measuring memory decline in our analyses.\u003c/p\u003e \u003cp\u003eThe participants were grouped based on the change of their diagnostic status at any time between baseline (T0) and follow-ups (T1 and T2): stability (no change in diagnosis), progression (diagnostic worsening), or reversion (diagnostic improvement) (see the flowchart of the grouping process in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The definition of stability vs progression was made on the diagnostic criteria and independent of the dependent variable used in the study. The diagnosis at baseline was conservatively adjusted when diagnosis at the first follow-up (18\u0026ndash;24 months after baseline) showed an unexpected cognitive recovery (i.e., from MCI to SCD and/or CU; from SCD to CU) (Pereiro et al. \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Stable groups included CU participants who did not change diagnostic criteria (CU-S: 68 participants) and SCD participants who remained stable (SCD-S: 84 participants). The worsening groups included CU participants who progressed to SCD/MCI (CU-P, 29 participants) and SCD participants who progressed to MCI (SCD-P, 2 participants). Among the SCD participants, 9 (4.16%) reverted to a CU at the follow-ups and were excluded from the main analyses. In the CompAS cohort, 13 participants (10.48%) progressed to dementia and in the CIMA-Q cohort, 5 participants (5.43%) progressed to dementia at the second follow up, but these participants were excluded from the main analyses as this was not the objective of the study.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e--INSERT FIGURE \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e--\u003c/p\u003e \u003cp\u003eDescriptive statistics and diagnostic changes by cohort are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cem\u003eDescriptive statistics (proportions, Mean, SD) and diagnostic progression for the total sample and by study (CompAS and CIMA-Q)\u003c/em\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eTotal\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eCompAS\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eCIMA-Q\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eN\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e216\u003c/p\u003e \u003cp\u003e(CU\u0026thinsp;=\u0026thinsp;97, SCD\u0026thinsp;=\u0026thinsp;119)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e124\u003c/p\u003e \u003cp\u003e(CU\u0026thinsp;=\u0026thinsp;79, SCD\u0026thinsp;=\u0026thinsp;45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e92\u003c/p\u003e \u003cp\u003e(CU\u0026thinsp;=\u0026thinsp;18, SCD\u0026thinsp;=\u0026thinsp;74)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge M(SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67.09 (8.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63.15 (8.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e72.40 (4.62)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSex (% women)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74.5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e77.4%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e70.6%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCU-S\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68 (70.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51 (64.55% of CU)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e17 (94.44% of CU)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSCD-S\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e84 (70.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (73.33% of SCD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51 (68.91% of SCD)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCU-P\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (29.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28 (35.44% of CU)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1 (5.55% of CU)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSCD-P\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (21.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11(24.44% of SCD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15 (20.27% of SCD)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003e\u003cem\u003eNote\u003c/em\u003e: CU-S: CU who remained stable; SCD-S\u0026thinsp;=\u0026thinsp;SCD who remained stable; CU-P\u0026thinsp;=\u0026thinsp;CU who progress to SCD/MCI; SCD-P\u0026thinsp;=\u0026thinsp;SCD who progress to MCI.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e--INSERT Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e--\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Instruments and harmonization procedure\u003c/h2\u003e \u003cp\u003eAt baseline, the participants completed a comprehensive neuropsychological battery including sociodemographic, affective, neuropsychiatric, health, and cognitive tests and measures. Sociodemographic variables were collected using an ad hoc questionnaire, including age, sex, years of schooling, and professional attainment in both studies and were used to characterize between group differences. Professional attainment was standardized across studies by unifying four categories. We used Cognitive Reserve Index questionnaire (CRIq; Nucci et al. \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2012\u003c/span\u003e) in the CompAS and Cognitive Reserve Questionnaire (CRQ, adapted in French by Eduardo Cisneros; Rami et al. \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e2011\u003c/span\u003e) used in CIMA-Q which defined the four categories as (1) Unskilled worker or homemaker (e.g., farmer, gardener, baby-sitter); (2) Skilled manual worker (e.g., tailor, hairdresser, military); (3) Skilled non-manual worker (e.g., teacher, musician, commercial agent); (4) Mid-level professional (e.g., doctor, psychologist, lawyer); and (5) Executive or management work (e.g., researcher, surgeon, CEO).\u003c/p\u003e \u003cp\u003eDepressive symptomatology was assessed using the short form of the Geriatric Depression Scale (GDS-15, Sheikh and Yesavage \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e1986\u003c/span\u003e, Spanish validation by Mart\u0026iacute;nez de la Iglesia et al. 2002). Health was assessed using the Charlson Comorbidity Index (CCI; Charlson et al. \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e1987\u003c/span\u003e), which quantifies the individual's burden of disease from the patient's medical history. The severity and stress of neuropsychiatric symptoms were measured using the Neuropsychiatric Inventory Questionnaire (NPI-Q; Kaufer et al. \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2000\u003c/span\u003e; Spanish validation by Boada et al. \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2002\u003c/span\u003e). These measures were assessed at baseline and included in the analyses to study the between-group differences in CU and SCD participants.\u003c/p\u003e \u003cp\u003eFor this study, cognitive complaints were measured using the Memory Failures of Everyday questionnaire (MFE; Sunderland et al. \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e1984\u003c/span\u003e; Spanish adaptation by Montejo Carrasco et al. \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e2012\u003c/span\u003e) from the CompAS and a short version of the \u003cem\u003eQuestionnaire D\u0026rsquo;auto-\u0026eacute;valuation de la M\u0026eacute;moire\u003c/em\u003e (Cl\u0026eacute;ment et al. \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2008\u003c/span\u003e) from the CIMA-Q study. For the harmonization process, equivalent items (two related to conversation, and three related to movies and reading) from both instruments were identified and matched. The items were: (1) \u0026ldquo;Do you have difficulty following a conversation going on with one person because you forget what has just been said?\u0026rdquo; (MFE item 16, QAM item 1); (2) \u0026ldquo;During a conversation, do you repeat many times the same thing because you forgot that you have just said it?\u0026rdquo; (MFE item 28, QAM item 3); (3) \u0026ldquo;Do you have difficulty in reading because you forget what you have just read, which obliges you to read the text again?\u0026rdquo; (MFE item 17, QAM item 7); (4) \u0026ldquo;Do you have difficulty in remembering what you have read a few days before?\u0026rdquo; (MFE item 9, QAM item 8); and (5) \u0026ldquo;Do you have difficulty in following a movie or a TV program because you forget what just happened?\u0026rdquo; (MFE item 3, QAM item 9). To harmonize the scales, QAM responses (Likert 1\u0026ndash;6; 1\u0026thinsp;=\u0026thinsp;never, 6\u0026thinsp;=\u0026thinsp;always) were recoded to match the MFE scale (0\u0026ndash;2; 0\u0026thinsp;=\u0026thinsp;never/ rarely, 1\u0026thinsp;=\u0026thinsp;sometimes, 2\u0026thinsp;=\u0026thinsp;always), such that scores 1\u0026ndash;2 were coded as 0, 3\u0026ndash;4 as 1, and 5\u0026ndash;6 as 2. A total cognitive complaints score was calculated by summing the harmonized items across both studies.\u003c/p\u003e \u003cp\u003eFor this study, we measured general cognition using data from the Cambridge Cognitive Assessment Revised (CAMCOG-R; Roth et al. \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e1986\u003c/span\u003e). Spanish age and education norms (Pereiro et al. \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2015\u003c/span\u003e) to obtain a total score and to evaluate cognitive performance by domains (orientation, language, memory, attention/calculation, praxis, abstract thinking, perception, and executive functions) in the CompAS cohort. For the CIMA-Q cohort, we used the Montreal Cognitive Assessment to measure general cognition (MoCA; Nasreddine et al. \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e2005\u003c/span\u003e). To assess memory decline we used the Test de Aprendizaje Verbal Espa\u0026ntilde;a-Complutense (TAVEC, the Spanish version of the California Verbal Learning Test, CVLT; Delis et al. \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e1987\u003c/span\u003e; Spanish adaptation by Benedet and Alejandre \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e1998\u003c/span\u003e) in the CompAS and the Rey Auditory Verbal Learning Test (RAVLT; Schmidt \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e1996\u003c/span\u003e; Qu\u0026eacute;bec French adaptation by Lavoie et al. \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) in the CIMA-Q. For the harmonization process, equivalent measures of Total Immediate Recall, Short Delay Free Recall, and Long Delay Free Recall were obtained from both studies.\u003c/p\u003e \u003cp\u003eFor the purposes of this study, dependent variables were the common measures from TAVEC and RAVLT. Both instruments assess verbal episodic memory performance based on learning and recall of word lists, and their administration is quite similar. The list of words to be recalled is presented orally in 5 consecutive trials immediately after each essay; the participant should say the words he/she remembers. The sum of the five consecutive learning trials is the total immediate recall measure. A single trial is then performed with an interference list of words, after which the participant is asked again from the words of the original list, obtaining the short delay free recall measure. Finally, the number of words remembered from the original list is asked again after a delay of 20 minutes, obtaining the long delay free recall measure.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Statistical Analysis\u003c/h2\u003e \u003cp\u003eThe data were analyzed using the SPSS statistical software package, version 29.0 (SPSS, Chicago, IL, USA), for descriptive analysis and group comparisons.\u003c/p\u003e \u003cp\u003eDescriptive statistics were calculated for all variables, and between cohort-studies (CompAS and CIMA-Q) and inter-group (CU, SCD) differences were tested in the sociodemographic and health measures considered. One factor ANOVAs (age, years of schooling, comorbidity) and Chi-square test (Sex, Profession, Memory familiar antecedents and CR in quartiles) were performed to test group differences and the percentages of participants belonging to each of the two groups were compared using cross-tabulations (p\u0026lt;.05 and p\u0026lt;.001). One factor ANOVAs for all neuropsychological measures considered were performed to test between study and between groups differences (p\u0026lt;.05 and p\u0026lt;.001). We also conducted post hoc Bonferroni correction (p\u0026lt;.003) to reduce the probability of type I error (Holland and Copenhaver \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e1987\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDescriptive statistics, using mean and standard deviation were calculated for each progression group (CU-S, SCD-S, CU-P, SCD-P) for all memory measures of total immediate recall, short delay free recall and long delay free recall using harmonized memory measures from the CVLT and the RAVLT tests. Changes over time were assessed by comparing baseline and follow-up performance within and between each group.\u003c/p\u003e \u003cp\u003eTo evaluate longitudinal memory trends, a Multivariate General Linear Model Repeated Measures (3 \u0026times; 4 design) was conducted by considering the time (T0, T1, and T2) as the within-subject factor and progression groups (CU-S, SCD-S, CU-P, SCD-P) as the between-subject factors for memory measures of total immediate recall, short delay free recall, and long delay free recall as dependent variables. ANCOVAs with schooling, age, and comorbidity (variables corresponding to the between-study differences found) as covariates for controlling group differences in those variables were used to analyze differences in memory trends between CU and SCD groups that worsen and those that remain stable over time. The alpha value was established at .05 for all analyses, and the partial eta squared (\u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e) value was reported as an estimate of effect size in the ANCOVAs. Between-group tests were conducted to identify the main effects of time, progression groups, and covariates on memory performance. Pairwise Bonferroni post-hoc tests were applied to avoid the risk of incurring Type I error associated with multiple comparisons. The estimated marginal means represented in the figures correspond to the changes in memory performance trends across groups and the follow-up period adjusted for the covariates for each of the memory measures.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eThe sample descriptive scores for between-group (CU, SCD) and between-study (CompAS; CIMA-Q) differences in sociodemographic, health, and cognitive measures at baseline (T0) are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cem\u003eBetween-group (CU, SCD) and between-study (CompAS, CIMA-Q) differences in sociodemographic, health, and cognitive measures\u003c/em\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eBetween-Group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eBetween-Studies\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cem\u003eCompAS\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cem\u003eCIMA-Q\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eCU\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cem\u003eSCD\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003csup\u003e(2)\u003c/sup\u003e CIMA-Q\u0026gt;CompAS***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003csup\u003e(2)\u003c/sup\u003e CIMA-Q\u0026gt;CompAS***\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSchooling\u003c/p\u003e \u003cp\u003e(years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003csup\u003e(2)\u003c/sup\u003e CU\u0026thinsp;\u0026gt;\u0026thinsp;SCD**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003csup\u003e(2)\u003c/sup\u003e CIMA-Q\u0026gt;CompAS***\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProfession\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003csup\u003e(3)\u003c/sup\u003e CIMA-Q\u0026gt;CompAS***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003csup\u003e(3)\u003c/sup\u003e CIMA-Q\u0026gt;CompAS***\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eComplaints\u003csup\u003e(1)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003csup\u003e(2)\u003c/sup\u003e SCD\u0026thinsp;\u0026gt;\u0026thinsp;CU***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003e(2)\u003c/sup\u003e SCD\u0026thinsp;\u0026gt;\u0026thinsp;CU***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCCI\u003csup\u003e(1)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003e(2)\u003c/sup\u003e SCD\u0026thinsp;\u0026gt;\u0026thinsp;CU*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003csup\u003e(2)\u003c/sup\u003e CIMA-Q\u0026gt;CompAS***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003csup\u003e(2)\u003c/sup\u003e CIMA-Q\u0026gt;CompAS***\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGDS-15\u003csup\u003e(1)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003csup\u003e(2)\u003c/sup\u003e SCD\u0026thinsp;\u0026gt;\u0026thinsp;CU**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003csup\u003e(2)\u003c/sup\u003e SCD\u0026thinsp;\u0026gt;\u0026thinsp;CU**\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNPI-Q\u003csup\u003e(1)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003csup\u003e(2)\u003c/sup\u003e CompAS\u0026gt;CIMA-Q*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003csup\u003e(2)\u003c/sup\u003e CompAS\u0026gt;CIMA-Q*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCAMCOG-R/MoCA\u003csup\u003e(1)\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003csup\u003e(2)\u003c/sup\u003e CU\u0026thinsp;\u0026gt;\u0026thinsp;SCD*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003csup\u003e(2)\u003c/sup\u003e CompAS\u0026gt;CIMA-Q***\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e--\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e--INSERT Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e--\u003c/p\u003e \u003cp\u003eSCD participants in the CIMA-Q and CompAS studies reported more depressive symptoms and subjective cognitive complaints compared to control group participants. However, SCD participants in CompAS had a lower education level than the CU group, while in the CIMA-Q study showed greater comorbidity.\u003c/p\u003e \u003cp\u003eBetween study differences showed that CIMA-Q participants (both CU and SCD) were older, presented greater comorbidity, and achieved greater professional attainment. SCD participants from the CIMA-Q also had significantly higher education. The CompAS participants (both CU and SCD) reported significantly more neuropsychiatric symptoms. CU participants from the CompAS reported better cognitive performance (see Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe mean and standard deviations of episodic memory scores for each of the diagnostic groups (CU-S, SCD-S, CU-P, SCD-P) and evaluation times (T0, T1 and T2) are included in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cem\u003eMean and standard deviations (in parentheses) of the stable and worsening groups across longitudinal measurements in episodic memory measures\u003c/em\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMeasure\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eT0\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eT1\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eT2\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eTotal immediate recall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCU-S\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e54.10 (9.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e54.95 (10.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e54.47 (10.40)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSCD-S\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e52.06 (8.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e51.48 (9.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e51.89 (11.27)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCU-P\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e51.44 (8.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e52.41 (10.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e51.06 (13.06)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSCD-P\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e43.87 (9.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e41.37 (10.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e38.12 (13.33)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e51.68 (9.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e51.58 (10.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e50.99 (12.46)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eShort delay free recall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCU-S\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.70 (2.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11.63 (2.70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11.94 (2.91)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSCD-S\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10.65 (2.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.71 (3.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10.88 (3.46)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCU-P\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10.51 (2.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.20 (3.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9.82 (4.21)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSCD-P\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9.08 (2.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.87 (3.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.58 (3.84)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10.80 (2.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.61 (3.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10.57 (3.80)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eLong delay free recall\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCU-S\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e12.25 (2.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.39 (2.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12.22 (2.73)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSCD-S\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.18 (2.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11.22 (2.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e11.25 (3.20)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCU-P\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.20 (2.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.00 (2.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10.55 (4.07)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSCD-P\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9.37 (2.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e7.54 (3.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.75 (4.25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.33 (2.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e11.29 (3.20)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10.93 (3.70)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e--INSERT Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e--\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Longitudinal differences in total immediate recall performance in Stable and Worsening CU and SCD Groups\u003c/h2\u003e \u003cp\u003eFor the total immediate recall variable, the model indicated a significant main effect of the progression group factor [\u003cem\u003eF\u003c/em\u003e (3, 190)\u0026thinsp;=\u0026thinsp;8.735, p\u003cem\u003e\u0026lt;\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.121, observed power = .994]. Significant effects were found also for the covariates Age [\u003cem\u003eF\u003c/em\u003e (1, 190)\u0026thinsp;=\u0026thinsp;55.077, \u003cem\u003ep\u0026lt;\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.225, observed power\u0026thinsp;=\u0026thinsp;1.000] and Schooling [\u003cem\u003eF\u003c/em\u003e (1, 190)\u0026thinsp;=\u0026thinsp;18.904, \u003cem\u003ep\u0026lt;\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.090, observed power = .991]. Intra-subject tests showed significant effects for time [\u003cem\u003eF\u003c/em\u003e (2, 189)\u0026thinsp;=\u0026thinsp;6.377, \u003cem\u003ep=\u003c/em\u003e .002, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.063, observed power\u0026thinsp;=\u0026thinsp;0.898] and interactions between time and age [\u003cem\u003eF\u003c/em\u003e (2, 189)\u0026thinsp;=\u0026thinsp;10.704, \u003cem\u003ep\u0026lt;\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.102, observed power = .989] and time and comorbidity [\u003cem\u003eF\u003c/em\u003e (2, 189)\u0026thinsp;=\u0026thinsp;4.183, \u003cem\u003ep=\u003c/em\u003e .017, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.042, observed power = .731]. There was no time x group interaction.\u003c/p\u003e \u003cp\u003eThe Bonferroni\u0026acute;s pairwise comparison for the progression group factor [\u003cem\u003eF\u003c/em\u003e (3, 190)\u0026thinsp;=\u0026thinsp;8.735, \u003cem\u003ep\u003c/em\u003e\u0026lt;.001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.121, observed power = .994] showed significant lower scores in SCD-P compared to stable groups (CU-S, SCD-S).\u003c/p\u003e \u003cp\u003eDespite of interaction between the progression group and time factors did not achieve signification, Bonferroni\u0026rsquo;s pairwise comparison showed a significant decrease from T0 to T2 only in the SCD-P group [\u003cem\u003eF\u003c/em\u003e (2, 189)\u0026thinsp;=\u0026thinsp;3.456, \u003cem\u003ep=\u003c/em\u003e .034, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.035, observed power = .642] and significant lower scores in SCD-P compared to SCD-S at T0 [\u003cem\u003eF\u003c/em\u003e (3, 190)\u0026thinsp;=\u0026thinsp;4.567, \u003cem\u003ep=\u003c/em\u003e .004, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.067, observed power = .882], T1 [\u003cem\u003eF\u003c/em\u003e (3, 190)\u0026thinsp;=\u0026thinsp;6.010, \u003cem\u003ep\u0026lt;\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.087, observed power = .956] and T2 [\u003cem\u003eF\u003c/em\u003e (3, 190)\u0026thinsp;=\u0026thinsp;8.096, \u003cem\u003ep\u0026lt;\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.113, observed power = .991], extending the group differences to the CU-S in this last follow-up (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003e3.2. Longitudinal differences in short delay free recall performance in Stable and Worsening CU and SCD Groups\u003c/b\u003e \u003c/p\u003e \u003cp\u003eBetween-subject tests for short delay free recall showed a significant main effect of progression group [\u003cem\u003eF\u003c/em\u003e (3, 190)\u0026thinsp;=\u0026thinsp;8.898, \u003cem\u003ep\u0026lt;\u003c/em\u003e.001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.123, observed power = .995] pointing out lower scores in SCD-P than in the stable groups (CU-S, SCD-S). Significant effects were found for the covariates Age [\u003cem\u003eF\u003c/em\u003e (1, 190)\u0026thinsp;=\u0026thinsp;53.006, \u003cem\u003ep\u0026lt;\u003c/em\u003e.001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.218, observed power\u0026thinsp;=\u0026thinsp;1.000] and Schooling [\u003cem\u003eF\u003c/em\u003e (1, 190)\u0026thinsp;=\u0026thinsp;10.649, \u003cem\u003ep=\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.053, observed power = .901]. Intra-subject tests showed significant effects for time [\u003cem\u003eF\u003c/em\u003e (2, 189)\u0026thinsp;=\u0026thinsp;8.277, \u003cem\u003ep\u0026lt;\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.081, observed power\u0026thinsp;=\u0026thinsp;0.960] and interactions between time and age [\u003cem\u003eF\u003c/em\u003e (2, 189)\u0026thinsp;=\u0026thinsp;11.588, \u003cem\u003ep\u0026lt;\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.109, observed power = .993]. A significant interaction between time and progression group were observed [\u003cem\u003eF\u003c/em\u003e (6, 380)\u0026thinsp;=\u0026thinsp;2.607, \u003cem\u003ep=\u003c/em\u003e .017, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.040, observed power = .854] that was specified through Bonferroni\u0026acute;s pairwise comparisons as follows: a) significantly lower scores of SCD-P compared to the stable groups (SCD-S, CU-S) at T1[\u003cem\u003eF\u003c/em\u003e (3, 190)\u0026thinsp;=\u0026thinsp;4.673, \u003cem\u003ep=\u003c/em\u003e .004, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.069, observed power = .890] and at T2 [\u003cem\u003eF\u003c/em\u003e (3, 190)\u0026thinsp;=\u0026thinsp;10.747, \u003cem\u003ep\u0026lt;\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.145, observed power = .999], but not at T0 [\u003cem\u003eF\u003c/em\u003e (3, 190)\u0026thinsp;=\u0026thinsp;2.832, \u003cem\u003ep=\u003c/em\u003e .113, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.043, observed power = .673]; and b) a significant decrease in the T2 compared to T0 only in the SCD-P group [\u003cem\u003eF\u003c/em\u003e (2, 189)\u0026thinsp;=\u0026thinsp;7.600, \u003cem\u003ep\u0026lt;\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.074, observed power = .943] (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cb\u003e3.3. Longitudinal differences in long delay free recall performance in Stable and Worsening CU and SCD Groups\u003c/b\u003e \u003c/p\u003e \u003cp\u003eBetween-subject tests for long delay free recall showed a significant main effect of progression group [\u003cem\u003eF\u003c/em\u003e (3, 189)\u0026thinsp;=\u0026thinsp;11.712, \u003cem\u003ep\u0026lt;\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.157, observed power\u0026thinsp;=\u0026thinsp;1.000] due to lower scores in SCD-P than in the stable groups (CU-S, SCD-S) and also CU-P group. Significant effects were found for the covariates Age [\u003cem\u003eF\u003c/em\u003e (1, 189)\u0026thinsp;=\u0026thinsp;52.952, \u003cem\u003ep\u0026lt;\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.219, observed power\u0026thinsp;=\u0026thinsp;1.000] and Schooling [\u003cem\u003eF\u003c/em\u003e (1, 189)\u0026thinsp;=\u0026thinsp;9.049, \u003cem\u003ep=\u003c/em\u003e .003, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.046, observed power = .849]. Intra-subject tests showed significant effects for time [\u003cem\u003eF\u003c/em\u003e (2, 189)\u0026thinsp;=\u0026thinsp;8.256, \u003cem\u003ep\u0026lt;\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.081, observed power\u0026thinsp;=\u0026thinsp;0.959] and interactions between time and age [\u003cem\u003eF\u003c/em\u003e (2, 188)\u0026thinsp;=\u0026thinsp;12.872, \u003cem\u003ep\u0026lt;\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.120, observed power = .997], time and comorbidity [\u003cem\u003eF\u003c/em\u003e (2, 188)\u0026thinsp;=\u0026thinsp;7.454, \u003cem\u003ep\u0026lt;\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.073, observed power = .939]. A significant interaction between time and progression group were observed [\u003cem\u003eF\u003c/em\u003e (6, 378)\u0026thinsp;=\u0026thinsp;3.894, \u003cem\u003ep\u0026lt;\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.058, observed power = .968] that was specified through Bonferroni\u0026acute;s pairwise comparisons as follows: a) significantly lower scores in the SCD-P compared to the three other groups at T1 [\u003cem\u003eF\u003c/em\u003e (3, 189)\u0026thinsp;=\u0026thinsp;9.658, \u003cem\u003ep\u0026lt;\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.133, observed power = .977] and at T2 [\u003cem\u003eF\u003c/em\u003e (3, 189)\u0026thinsp;=\u0026thinsp;11.665, \u003cem\u003ep\u0026lt;\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.156, observed power\u0026thinsp;=\u0026thinsp;1.000] but not at T0 [\u003cem\u003eF\u003c/em\u003e (3, 189)\u0026thinsp;=\u0026thinsp;3.523, \u003cem\u003ep\u003c/em\u003e= .083, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.053, observed power = .777]; and b) significant lower scores in T2 and T1 than in T0 only for the SCD-P group [\u003cem\u003eF\u003c/em\u003e (2, 188)\u0026thinsp;=\u0026thinsp;10.677, \u003cem\u003ep\u0026lt;\u003c/em\u003e .001, \u003cem\u003eη\u003c/em\u003e\u003csub\u003e\u003cem\u003ep\u003c/em\u003e\u003c/sub\u003e\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;.102, observed power = .989] (see Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e--INSERT FIGURE \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e--\u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eThis study aimed to analyze the longitudinal differences in episodic memory performance among CU and SCD participants who remained stable or showed diagnostic progression to MCI, using harmonized data from two methodologically similar study cohorts. Regarding diagnostic progression, our findings indicated that most of the CU (70.1%) and SCD participants (70.5%) remained stable over 48\u0026ndash;70 months follow-ups, 17.5% of CU progressed to SCD, 12.3% to MCI, and 21.8% of SCD progressed to MCI. These results are in line with meta-analytic evidence showing that while SCD is associated with increased risk of future decline, most participants remain cognitively stable over several years, with conversion rates increasing from 11% over 5 years to 14% in longer follow-ups over 6\u0026ndash;7 years (Mitchell et al. \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). Almost all CU participants in CIMA-Q remained stable (94.4%), whereas stability was lower in CompAS (64.5%). In contrast, SCD stability over the follow ups was very similar across both cohorts (73.3% in CompAS vs. 68.9% in CIMA-Q). Diagnostic progression was also very similar across both cohorts, with 17.5% of CU participants progressing to SCD and 17.7% of CU and SCD participants progressing to MCI in CompAS, compared with 17.3% of total sample progressing to MCI in CIMA-Q over the 48\u0026ndash;70-month follow-up. In line with these findings, a recent meta-analysis of five cross-cultural studies reported a 17.2% progression rate from SCD to MCI, with follow-up durations ranging from 24 to 216 months (Tallman et al. \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e2025\u003c/span\u003e). The observed differences remained significant even after controlling for age, schooling, and comorbidity, covariates included due to baseline differences between the two cohorts. These findings may be due to the differences between the two cohorts such as recruitment sources or exclusion criteria.\u003c/p\u003e \u003cp\u003eOverall, as expected, our results show that significantly lower memory scores were generally observed in the SCD-P group compared to the stable groups (SCD-S, CU-S) across the follow-ups in total immediate recall and short delay free recall and extended to the CU-P group in long delay free recall. These findings are consistent with the previous longitudinal studies showing that the presence of CU or SCD participants who show diagnostic worsening during follow-ups predicts a more accelerated decline on episodic memory measures of immediate and delayed verbal recall compared to those who remain stable (Koppara et al. \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Pereiro et al. \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). The significant declines in episodic memory scores accompanied diagnostic changes and increases over the follow-ups, particularly in the short and long delayed measures, which shows that analysing the slope of decline over time is a more sensitive indicator than the baseline score in SCD participants at risk of progression to MCI or dementia (Bessi et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Koppara et al. \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Rabin et al. \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e2017\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSignificant declines were observed in both short and long delayed recall measures at T1 in SCD-P group, further worsening at T2, suggesting that delay measures are concurrent to the diagnostic worsening over the follow ups (Bilgel et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Rabin et al. \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2009\u003c/span\u003e). Both short and long delay free recall are measures of consolidation processes, although they differ in a greater or lesser delay in information retrieval, which can be a significant predictor of conversion to AD in healthy participants (Rabin et al. \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Tierney et al. \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e2005\u003c/span\u003e). However, no significant baseline differences were observed in short and long delay free recall, suggesting that these measures have a limited predictive power in the early stages in identifying participants at risk, however can be better predictors once the change has occurred in the later stages of disease progression (Bilgel et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Koppara et al. \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2015\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn our study, significant decline in both delayed recall measures in SCD-P participants emerged in T1 and increased at T2, which is consistent with studies that show that subtle memory decline in SCD participants at follow-ups is associated with a higher risk of progression towards dementia (Bilgel et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Koppara et al. \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Rabin et al. \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2009\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOur results suggest that long delay free recall was the only measure in which significant decline was also observed in the CU-P group, suggesting that long delay recall may be a more sensitive but less specific indicator than immediate free recall or short delay free recall for differentiating between CU and SCD participants at risk of progression. Studies have shown that long delay recall tasks reflect more memory demanding processes like retention and delayed-retrieval effects (dependent on entorhinal and hippocampal systems) can be more sensitive to subtle decline that may occur with both pathological as well as normal aging (Wearn et al. \u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e2020\u003c/span\u003e) which makes it a less specific marker of progression compared to immediate or short delay recall (Bilgel et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Lemos et al. \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2016\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eUnlike the delayed recall measures, in total immediate recall, significant lower scores were observed in SCD-P compared to SCD-S already at baseline. However, time and progression group interaction does not achieved significance suggesting similar decline slopes across follows ups in all groups. Longitudinal differences were only found in pairwise comparisons between SCD-P and SCD-S and therefore, this result should be interpreted with caution. Total immediate recall is the sum of words recalled across the five initial learning trials so it reflects encoding rather than consolidation process as in delayed measures like short delay free recall and long delay free recall (Rabin et al. \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e2009\u003c/span\u003e), making total immediate recall not as sensitive as delay recall measures for predicting cognitive decline (Bilgel et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Lemos et al. \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Significant differentiation of SCD-P and SCD-S groups at baseline jointly with the potentially higher longitudinal decline could suggests immediate recall as candidate to be early predictive marker of future objective cognitive decline (Lemos et al. \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2016\u003c/span\u003e) as well as in identification of SCD at risk (Bilgel et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2014\u003c/span\u003e; Koppara et al. \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2015\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn addition, test-related factors such as reduced practice effects may partly explain the long delay free recall decline observed even in CU-P participants, since it has been shown that CU participants show some improvement across repeated testing (Machulda et al. \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2013\u003c/span\u003e). However, our results show that these practice effects were overshadowed by subtle memory decline in the SCD-P group, with only the most demanding variables such as long delay free recall also showing decline in CU-P group. In contrast, CU-S and SCD-S participants showed improvement at baseline and during follow-ups. Reduced practice effects on the Spanish version of CVLT have previously been described in participants with SCD and MCI to be predictive of cognitive decline (Campos-Magdaleno et al. \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2017\u003c/span\u003e), and our findings extend this evidence by showing similar patterns in both CU-P and SCD-P groups.\u003c/p\u003e \u003cp\u003eFuture research should aim to replicate these findings in larger sample, as our unequal sample size across cohorts as well as high attrition rate (55.3%) may introduce bias of the results. Moreover, the small number of participants who showed worsening trajectories could reduce statistical power. Another limitation concerns the interpretation of the total immediate recall results. Additionally, we applied Bonferroni correction to control for multiple comparisons which is highly conservative and may have reduced the sensitivity of the measures to detect early group differences.\u003c/p\u003e \u003cp\u003eFinally, the current study does not include information on biomarkers in blood and cerebrospinal fluid or structural or functional neuroimaging markers. Future studies should include these measures for a better understanding of how episodic memory measures improve the identification of subtle memory decline in a trajectory from preclinical to prodromal stages of dementia.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eIn conclusion, our findings show that significant difference in episodic memory were already observed as early as baseline in total immediate recall and progressively worsening over the follow-ups across all three memory measures in CU and SCD participants who showed diagnostic worsening. Lower scores in total immediate recall measure at baseline could be an indication of potential value for identifying early subtle cognitive decline in at-risk SCD participants. Importantly, long delay free recall was the most sensitive measure, where decline was observed not only in SCD-P but also in CU-P participants. Immediate memory might be more discriminative as early risk marker, but not intense enough as delay measures to detect worsening in at-risk SCD or differentiate it from at-risk CU group. Overall, these results support the utility of episodic memory decline, especially total immediate recall for improving early identification of participants in the preclinical stages of dementia who are at risk of future cognitive decline.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003ch2\u003eFunding:\u003c/h2\u003e\n\u003cp\u003eThis work was financially supported through FEDER founds (\u0026lsquo;A way to make Europe\u0026rsquo;) by the Spanish AEI (Doi: 10.13039/501100011033; Refs. PID2020-114521RB-C21 and PID2023-151659OB-C21) and by the Galician Government (Conseller\u0026iacute;a de Cultura, Educaci\u0026oacute;n e Ordenaci\u0026oacute;n Universitaria; axudas para a consolidaci\u0026oacute;n e estruturaci\u0026oacute;n de unidades de investigaci\u0026oacute;n competitivas do Sistema Universitario de Galicia ED431C 2025/14; GI-1807-USC).\u003c/p\u003e\n\u003cp\u003eThe CIMA-Q project is supported by various funding sources, including the FRQS-Pfizer Innovation Program (grant number 27239), the FRQS-Cohorte (grant 2020-VIVO-279261), the Fondation Courtois (Neuromod project), the Consortium canadien en neurod\u0026eacute;g\u0026eacute;n\u0026eacute;rescence associ\u0026eacute;e au vieil lissement (grant number 137794), the R\u0026eacute;seau Qu\u0026eacute;b\u0026eacute;cois de Recherche sur le Vieillissement, and the Fondation Famille Lemaire. This publication was also supported by Grants to the co-author Sylvie Belleville from the Canadian Institutes of Health Research (grant number MOP81302); Natural Sciences and Engineering Research Council of Canada (NSERC), and Canada Research Chair in Cognitive Neuroscience of Aging and Brain Plasticity.\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eData curation: Sonali Arora, Mar\u0026iacute;a Campos-Magdaleno, Luc\u0026iacute;a P\u0026eacute;rez-Blanco, Samira Mellah; Conceptualization: Sonali Arora, Sylvie Belleville, Arturo X. Pereiro; Validation: Sonali Arora, Samira Mellah, Arturo X. Pereiro; Investigation: Sonali Arora, Mar\u0026iacute;a Campos-Magdaleno, Luc\u0026iacute;a P\u0026eacute;rez-Blanco, Sylvie Belleville, Arturo X. Pereiro; Methodology: Sonali Arora, Mar\u0026iacute;a Campos-Magdaleno Visualization: Sonali Arora; Resources: Samira Mellah, Sylvie Belleville; Writing \u0026ndash; original draft: Sonali Arora; Writing \u0026ndash; review and editing: Sonali Arora, Luc\u0026iacute;a P\u0026eacute;rez-Blanco, Samira Mellah, Sylvie Belleville, Arturo X. Pereiro; Funding acquisition: Arturo X. Pereiro; Project administration: Arturo X. Pereiro; Supervision: Arturo X. Pereiro.\u003c/p\u003e\n\u003ch2\u003eAcknowledgements:\u003c/h2\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the first and the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAlbert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, Gamst A, Holtzman DM, Jagust WJ, Petersen RC, Snyder PJ, Carrillo MC, Thies B, Phelps CH (2011) The diagnosis of mild cognitive impairment due to Alzheimer\u0026rsquo;s disease: Recommendations from the National Institute on Aging-Alzheimer\u0026rsquo;s Association workgroups on diagnostic guidelines for Alzheimer\u0026rsquo;s disease. 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PLoS ONE 7:e51157. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1371/journal.pone.0051157\u003c/span\u003e\u003cspan address=\"10.1371/journal.pone.0051157\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-ageing","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejoa","sideBox":"Learn more about [European Journal of Ageing](http://link.springer.com/journal/10433)","snPcode":"10433","submissionUrl":"https://submission.nature.com/new-submission/10433/3","title":"European Journal of Ageing","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Subjective Cognitive Decline (SCD), episodic memory, immediate recall, longitudinal design, Cognitively Unimpaired (CU), older adults","lastPublishedDoi":"10.21203/rs.3.rs-8933401/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8933401/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSubjective Cognitive Decline (SCD) refers to self-perceived decline in the absence of objective cognitive impairment, but whether longitudinal decline differentiates stable and progressing Cognitively Unimpaired (CU) and SCD individuals remains unclear. We aimed to analyse longitudinal differences in memory trends in stable and progressing CU and SCD participants to Mild Cognitive Impairment (MCI) from two methodologically similar cohorts, Compostela Aging Study (CompAS) and Consortium for the Early Identification of Alzheimer's Disease (CIMA-Q). 216 participants (67.09\u0026thinsp;\u0026plusmn;\u0026thinsp;8.29 years) without objective cognitive impairment were classified into four groups considering baseline diagnosis and progression at two follow-ups: CU-S (CU who remained stable), SCD-S (SCD who remained stable), CU-P (CU who progressed to SCD/MCI), and SCD-P (SCD who progressed to MCI). Memory was assessed using immediate, short-, and long-delay free recall measures. Longitudinal memory trends were evaluated considering time as within-subject factor, group as between-subject factor, and schooling, age, and comorbidity as covariates. Longitudinal episodic memory declines were larger in CU-P in long-delay and, particularly, in SCD-P in all three memory measures compared to stables. For immediate memory, slope decline was similar in SCD-P, but the group effect also indicated lower performance in SCD-P at baseline. Long-delay measure was able to differentiate longitudinal memory decline between SCD-P and CU-P groups. Our results suggest that longitudinal change in delay measures is concurrent with diagnostic change in at-risk SCD participants. Immediate memory might be more discriminative as early risk marker, but not intense enough to detect worsening in at-risk SCD or differentiate it from at-risk CU group.\u003c/p\u003e","manuscriptTitle":"Longitudinal Trajectories of Episodic Memory in Older Adults in Preclinical stages depending on whether they remain Stable or Progress to Mild Cognitive Impairment: Evidence from the CompAS and CIMA-Q cohorts","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-15 17:46:58","doi":"10.21203/rs.3.rs-8933401/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewersInvited","content":"","date":"2026-05-06T08:13:04+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-24T10:13:01+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-23T02:55:42+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Ageing","date":"2026-02-21T12:16:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-ageing","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejoa","sideBox":"Learn more about [European Journal of Ageing](http://link.springer.com/journal/10433)","snPcode":"10433","submissionUrl":"https://submission.nature.com/new-submission/10433/3","title":"European Journal of Ageing","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"846b2ab6-02cd-49be-991b-898ca18ffb46","owner":[],"postedDate":"May 15th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewersInvited","content":"20","date":"2026-05-06T08:13:04+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-15T17:46:58+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-15 17:46:58","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8933401","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8933401","identity":"rs-8933401","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}