Carotid atherosclerosis associated with tau pathology and cognitive function in cognitively intact adults: the CABLE study

Carotid atherosclerosis associated with tau pathology and cognitive function in cognitively intact adults: the CABLE study | 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 Carotid atherosclerosis associated with tau pathology and cognitive function in cognitively intact adults: the CABLE study Ming-Zhan Zhang, Cheng-Kun Sun, Yan-Ming Chen, Quan Hao, Zi-Qi Zhang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4602922/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Carotid atherosclerosis has been implicated in cognitive decline, but the evidence from current studies is insufficient and the detailed mechanism remains unclear. Objective This study aimed to explore the association of carotid atherosclerosis with cognitive function and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers, as well as attempted to investigate the underlying mechanisms. Methods This study included 365 participants with objective normal cognition from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database. Multiple linear regression models were utilized to assess the associations of carotid atherosclerosis (carotid intima-media roughness [CIMR], carotid intima-media thickness [CIMT], carotid plaque, and CIMT level) with CSF AD biomarkers and cognitive function. The mediation analyses were used to explore whether CSF AD biomarkers mediated the carotid atherosclerosis and cognitive function. Result We found that CIMR, carotid plaque, and CIMT level were significantly associated with tau pathology (T-tau and P-tau, P < 0.05); All markers of carotid atherosclerosis were associated with cognitive function (CM-MMSE and MoCA, P < 0.05). Furthermore, mediation analyses revealed that the effect of carotid plaque on cognitive decline was partially mediated by tau pathology (proportion of mediation = 19.7%, P = 0.012). Conclusion This study indicated that carotid atherosclerosis was associated with tau pathology and cognitive function, and tau pathology partially mediated the association between carotid atherosclerosis and cognitive function. Alzheimer's disease Biomarkers Carotid atherosclerosis Cerebrospinal fluid Cognitive function Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Dementia is a prominent cause of death and disability worldwide, imposing a significant burden on health and cere systems around the world [ 1 ]. Alzheimer's disease (AD), as the most common form of dementia, is characterized pathologically by aberrant amyloid deposition, total tau and phosphorylated tau (indicated by Aβ 42/40 ,T-tau and P-tau, respectively), and clinically by cognitive and behavioral impairments [ 2 ]. Currently, there is no effective treatment that can cure AD or slow down its onset and progression [ 3 ]. Significantly, recent studies found that differences in cerebrospinal fluid (CSF) biomarkers between the AD and cognitively normal groups existed several years before the onset ofAD [ 4 , 5 ]. Therefore, it is crucial to identify the potentially modifiable risk factors associated with AD to facikitaye the early prevention of AD. Carotid atherosclerosis is an important contributor in the onset and development of dementia and AD [ 6 – 9 ]. Increasing research suggested that markers reflecting the burden of carotid atherosclerosis including carotid intima-media roughness (CIMR), carotid intima-media thickness (CIMT), and carotid plaque, were associated with cognitive functioning impairment in individuals at risk of AD development [ 10 – 12 ]. Furthermore, a long-term longitudinal cohort study demonstrated that carotid plaque exacerbated cognitive impairment related to AD [ 13 ]. In this context, several researchers proposed that carotid atherosclerosis could be considered as a modifiable risk factor for AD [ 14 – 16 ]. Nevertheless, the precise mechanisms underlying the association between carotid atherosclerosis and AD remain unknown. Few studies have investigated the bio-mechanisms underlying the association of carotid atherosclerosis with cognitive dysfunction, as well as wherther pathological AD biomarkers influenced the relationship between carotid atherosclerosis and cognition. Thus, the primary objectives of this study were to (1) investigate the associations between carotid atherosclerosis and cognitive function; (2) explore the associations between carotid atherosclerosis and CSF AD biomarkers; and (3) examine whether the impact of carotid atherosclerosis on cognitive performance was mediated by AD pathology in 365 participants. Materials and methods The CABLE database The Chinese Alzheimer’s Biomarker and LifestylE (CABLE) study, initiated in 2017, is an ongoing large-scale independent cohort study primarily focusing on risk factors and biomarkers for AD, aiming to facilitate early diagnosis of AD among the Chinese Han population [ 17 ]. All enrolled participants in the CABLE were recruited from Qingdao Municipal Hospital, Shandong Province, China. The CABLE database was conducted in compliance with the Declaration of Helsinki. The study has been approved by the Institutional Review Board of Qingdao Municipal Hospital. Written informed consent was obtained from all the participants. Participants Participants included in the CABLE were Han Chinese aged between 40 and 90 years old. The main exclusion criteria were: (1) central nervous system infections, multiple sclerosis, head trauma, neurodegenerative diseases other than AD (e.g., epilepsy, Parkinson’s Disease), or other major neurological disorders; (2) significant psychological disorders; (3) severe systemic diseases (e.g., malignancy tumors); (4) family history of genetic disorders. Demographic information and medical history were collected through structured questionnaires supplemented by an electronic medical record system. All diagnoses were assessed by two medical professionals with standardized training in cognitive disorders by means of complete performance on neuropsychological tests, combined with CSF biomarkers and magnetic resonance imaging (MRI) examinations. The baseline cognitive status of participants was determined using the China Modified Mini-Mental State Examination (CM-MMSE) and the Montreal Cognitive Assessment (MoCA). Objective cognitive impairment was difined as having a CM-MMSE score ≤ 17 for those without education, a CM-MMSE score ≤ 20 for those with no more than 6 years of education, a CM-MMSE score ≤ 24 for thore with more than 6 years of education. A total of 2334 participants were enrolled in the CABLE study, out of which 1959 participants who did not undergo carotid ultrasound examination or did not provide CSF biomarkers data were excluded. Ultimately, our study included 365 individuals. Markers of carotid atherosclerosis The carotid arteries were assessed by certified and wel-trained medical sonographers using Philips color Doppler ultrasound machines. All participants underwent the examinations in a supine position with their head tilted back to expose their neck. The lengths of bilateral common carotid artery, carotid bifurcation, and internal carotid arteries were examined transversely first and then longitudinally in grayscale and color flow modes. First, the length of the common carotid arteries, the carotid bifurcation, as well as the internal and external carotid arteries beginning were examined transversally; Then longitudinally in lumen-diameter, grayscale and color flow. Ultrasound variables (dynamic range, depth range, power, reject, edge, grey scale, and smoothness) were constant during all the examinations. Our markers of interest include: 1) the presence of CIMR, defined as granulare chogenicity of deep, normally unechoic intimal-medial layer [ 18 , 19 ]; 2) the presence of CIMT, indicated by CIMT ≥ 0.9 mm in one or both bilateral carotid arteries [ 20 ]; 3) the presence of carotid plaque (plaque), indicated by CIMT ≥ 1.5 mm in one or both bilateral carotid arteries [ 21 ]; 4) graded based on CIMT level (level): 0 = 1.4mm [ 22 , 23 ]. CSF AD biomarkers CSF samples were obtained via lumbar puncture by a qualified physician in 10 ml polypropylene tubes and promptly transported to the laboratory for processing within 2 hours. After centrifugation at 2000 × g for 10 min, the samples were divided and stored in an enzyme-free EP (Eppendorf) tubes (AXYGEN; PCR-02-C) at − 80°C. The freeze-thawing cycle was limited to two times or less. CSF levels of Aβ 42 , Aβ 40 , P-tau, and T-tau levels were quantified using the ELISA kits (Innotest β-AMYLOID (1–42) [catalog number: 81583]; β-AMYLOID (1–40) [catalog number: 81585]; PHOSPHO-TAU (181p) [catalog number: 81581]; hTAU-Ag [catalog number: 81579]; Fujirebio, Ghent, Belgium). All measurements were performed in duplicate by professional technicians blinded to clinical information. Within-batch coefficients of variations (CVs) were < 5% ((4.8% for Aβ 42 , 3.6% for Aβ 40 , 2.4% for P-tau, and4.6% for T-tau). Inter-batch CVs were < 20% (9% for Aβ 42 , 3.6% for Aβ 40 , 10.9% for P-tau, and12.2% for T-tau). Among these CSF AD biomarkers, we utilized the Aβ 42/40 ratio instead of the absolute value of Aβ 42 since the ratio could better represent amyloid deposition and diagnostic accuracy [ 24 – 26 ]. APOE-ε4 genotyping The QIAamp® DNA Blood Mini Kit (250) was utilized for extracting DNA from fasting blood samples. Subsequently, the DNA was isolated and stored an enzyme-free EP tube at − 80°C until completion of APOE genotyping for the study. APOE ε4 status was determined by genotyping rs7412 and rs429358 using a restriction fragment-length polymorphisms technique. Participants were categorized as either APOE ε4 non-carriers or APOE ε4 carriers (with at least one copy of the APOE ε4 gene). Statistical analyses In order to describe baseline characteristics of the participants, categorical variables were presented as numbers and percentages, while continuous variables were expressed as means with standard deviations (SD). The characteristics were compared using Chi-square tests (categorical variables) and Mann–Whitney U test (continuous variables). CSF AD biomarker measurements underwent normalization through the Box–Cox transformation and were standardized via z Scale in the case of skewed distributions. Multiple linear regression models were used to explore the associations of carotid atherosclerosis with CSF AD biomarkers and cognitive function after adjusting for age (continuous), sex (categorical), education (continuous), APOE ε4 status (categorical). Moreover, sensitivity analyses were conducted by adding further covariates, including self-report histories of hyperlipidemia (yes or no), high blood pressure (yes or no), and diabetes mellitus (yes or no). Furthermore, subgroup analyses stratified by age, sex and APOE ε4 status were performed. Next, mediation analyses based on Baron and Kenny's method were conducted to examine whether the associations between carotid atherosclerosis and cognition was mediated by AD pathology. Mediation effects would be established if all the criteria are simultaneously satisfied: 1) significant associations between carotid atherosclerosis and CSF AD biomarkers; 2) significant associations between carotid atherosclerosis and cognitive measures; 3) significant associations between CSF AD biomarkers and cognitive measures; and 4) attenuated associations between carotid atherosclerosis and cognitive measures when adding CSF AD biomarkers (the mediators) in the regression model. Additionally, the indirect effect or attenuation was estimated, with significance determined through 10,000 bootstrapped iterations. Each path of the mediator model was corrected for age, sex, education, and APOE ε4 status. All statistical analyses and visualization were performed using IBM SPSS Statistics 26 software and R Studio software (version 4.2.0.). The significance threshold was set at a P < 0.05 (two-tailed). Results Participant characteristics The demographical and clinical characteristics of the participants are summarized in Table 1 . This study enrolled 365 participants from the CABLE database. The study sample had an age range of 40 to 90 years (mean ± SD = 65.82 ± 10.04), an average education level of 9.92 ± 4.59 years, a female percentage of 46.30%, and an APOE ε4 carriers proportion of 15.89%. In terms of cognitive scores, the study sample had an average CM-MMSE score of 26.63 ± 3.87 and an average MoCA score of 21.84 ± 5.52. Table 1 Characteristics of participants from CABLE database. Variable Descriptive statistics Total (N = 365) Age (y) mean (SD) 65.82 (10.04) Sex (Female) N (%) 169 (46.30%) Education (y) mean (SD) 9.92 (4.59) APOE ɛ4 carriers N (%) 47 (15.89%) Aβ 42/40 mean (SD) 0.07 (0.76) P-tau (pg/ml) mean (SD) 42.29 (17.15) T-tau (pg/ml) mean (SD) 233.92 (140.62) CM-MMSE mean (SD) 26.63 (3.87) MoCA mean (SD) 21.84 (5.52) Abbreviation: CN, cognitively normal participants; SCD, participants with subjective cognitive decline; APOE ɛ4, apolipoprotein E ɛ4 gene; Aβ, amyloid-β; P-tau, phosphorylated tau protein; T-tau, total tau protein; CM-MMSE, China-Modified Mini-Mental State Examination; N, number; y, years; SD, standard deviation. Difference in CSF AD biomarkers and cognitive function between participants with and without carotid atherosclerosis Significant differences were observed in CSF levels of P-tau ( P = 0.039) and T-tau ( P = 0.028) (Fig. 1 A and B), as well as scores of CM-MMSE ( P = 0.002) and MoCA ( P < 0.001) (Fig. 2 A and B) between participants with and without CIMR. Similarly, significant differences were found in CSF levels of P-tau ( P = 0.018) and T-tau ( P = 0.045) (Fig. 1 C and D), as well as scores of CM-MMSE ( P = 0.045) and MoCA ( P = 0.005) (Fig. 2 C and D) between participants with and without CIMT. Furthermore, significant differences were observed in CSF levels of P-tau ( P = 0.048) and T-tau ( P = 0.028) (Fig. 1 E and F), as well as scores of CM-MMSE ( P = 0.026) and MoCA ( P < 0.001) (Fig. 2 E and F) between participants with and without carotid plaque. As the CIMT level increased, differences in CSF levels of P-tau ( P = 0.012) and T-tau ( P = 0.019) increased (Fig. 1 G and H), as well as the CM-MMSE ( P = 0.029) and MoCA score ( P = 0.003) decreased (Fig. 2 G and H). However, in terms of these carotid atherosclerosis, no intergroup differences were found in CSF Aβ 42/40 (CIMR: Aβ 42/40 , P = 0.072; CIMT: Aβ 42/40 , P = 0.243; carotid plaque: Aβ 42/40 , P = 0.655; CIMT level increased: Aβ 42/40 , P = 0.324). Associations of carotid atherosclerosis with CSF AD biomarkers and cognitive function In the whole sample of subjects, the presence of CIMR was significantly associated with higher levels of P-tau (β = 0.092, P = 0.014) and T-tau (β = 0.099, P = 0.047), as well as lower scores on CM- MMSE (β = -1.499, P < 0.001) and MoCA (β = -2.519, P = 0.008) (Fig. 3 ; Supplementary table 1 ). Besides, CIMT was significantly associated with lower scores on both CM- MMSE (β = -0.826, P = 0.011) and MoCA (β = -1.631, P = 0.023) (Fig. 3 ; Supplementary table 1 ). Moreover, carotid plaque was significantly associated with higher levels of P-tau (β = 0.052, P = 0.029) and T-tau (β = 0.075, P = 0.018), as well as lower scores on CM- MMSE (β = -0.597, P = 0.034) and MoCA (β = -1.907, P = 0.001) (Fig. 3 ; Supplementary table 1 ). Furthermore, the CIMT level was also significantly associated with higher levels of P-tau (β = 0.041, P = 0.008) and T-tau (β = 0.048, P = 0.022), as well as lower scores on CM- MMSE (β = -0.405, P = 0.014) and MoCA (β = -1.159, P = 0.002) (Fig. 3 ; Supplementary table 1 ). However, the association between CIMR, CIMT, carotid plaque and CIMT level with Aβ 42/40 level ( P > 0.05) was not observed, as well as no significant association between CIMT and tau pathology (P-tau, β = 0.059, P = 0.061; T-tau, β = 0.036, P = 0.399). Subgroup analyses According to age, sex and APOE ε4 status, subgroups analyses were used to identify specific vulnerable population. We found that the aforementioned associations of carotid atherosclerosis with CSF AD biomarkers and cognitive function remained statistically significant: (1) CIMR: in mid-age (CM-MMSE, β = -1.358, P = 0.003), in late-age (P-tau, β = 0.131, P = 0.021; T-tau, β = 0.311, P = 0.008; CM-MMSE, β = -1.962, P = 0.021; MoCA, β = -5.523, P = 0.003), in women (P-tau, β = 0.117, P = 0.023; T-tau, β = 0.168, P = 0.013; CM-MMSE, β = -1.707, P < 0.001; MoCA, β = -3.479, P = 0.001), and in APOE ɛ4 non-carriers (P-tau, β = 0.108, P = 0.013; T-tau, β = 0.118, P = 0.035; CM-MMSE, β = -1.460, P < 0.001; MoCA, β = -3.388, P < 0.001) (Fig. 4 ; Supplementary table 2, 3 and 4); (2) CIMT: in late-age (MoCA, β = -3.394, P = 0.015), in women (CM-MMSE, β = -1.331, P = 0.006; MoCA, β = -3.147, P = 0.002), and in APOE ɛ4 non-carriers (CM-MMSE, β = -0.739, P = 0.043; MoCA, β = -2.164, P = 0.011) (Fig. 4 ; Supplementary table 2, 3 and 4); (3): carotid plaque: in late-age adults (P-tau, β = 0.073, P = 0.025; T-tau, β = 0.157, P < 0.001; MoCA, β = -2.834, P = 0.001), in women (P-tau, β = 0.072, P = 0.038; T-tau, β = 0.106, P = 0.026; MoCA, β = -2.314, P = 0.007), and in APOE ɛ4 non-carriers (P-tau, β = 0.039, P = 0.050; T-tau, β = 0.072, P = 0.040; CM-MMSE, β = -0.678, P = 0.021; MoCA, β = -2.065, P = 0.002) (Fig. 4 ; Supplementary table 2, 3 and 4); (4) CIMT level: in late-age (P-tau, β = 0.054, P = 0.027; T-tau, β = 0.117, P < 0.001; MoCA, β = -2.327, P < 0.001), in women (P-tau, β = 0.053, P = 0.013; T-tau, β = 0.071, P = 0.016; MoCA, β = -1.454, P = 0.003), in APOE ɛ4 carriers (P-tau, β = 0.076, P = 0.039), and in APOE ɛ4 non-carriers (P-tau, β = 0.038, P = 0.029; CM-MMSE, β = -0.444, P = 0.016; MoCA, β = -1.393, P = 0.001) (Fig. 4 ; Supplementary table 2, 3 and 4). Sensitivity analyses In order to be results more credible, additional sensitivity analyses were performed. The above results remained consistent after adjusting for various covariates (Model 1: age, sex, education, APOE ε4 status, and high blood pressure; Model 2: age, sex, education, APOE ε4 status, and diabetes mellitus; and Model 3: age, sex, education, APOE ε4 status, and hyperlipidemia; P < 0.05) (Supplementary table 5, 6 and 7, respectively). Causal mediation analyses These above findings indicated that carotid atherosclerosis was associated with tau pathology and cognitive impairment, so causal mediation analysis was used to explore the underlying mechanisms of cognitive impairment. In the total participants, the associations between carotid plaque and MoCA scores was partially mediated via T-tau (proportion of mediation = 19.7%, P = 0.012) (Fig. 5 A). Furthermore, in women, the above associations remained significant (proportion of mediation = 44.1%, P = 0.008) (Fig. 5 B), as well as we found that T-tau (proportion of mediation = 36.2%, P = 0.010) mediated the association between CIMT level and MoCA scores (Fig. 5 C). Discussion The present study systematically investigates the interrelationships of carotid atherosclerosis (assessment by CIMR, CIMT, carotid plaque, and CIMT level), CSF AD biomarkers and cognitive impairment among participants without objective cognitive impairment. Our findings suggested that: a) there was a statistically significant association between carotid atherosclerosis and cognitive impairment; b) carotid atherosclerosis exhibited a significant association with tau pathology; c) tau pathology partially mediated the effects of carotid atherosclerosis on cognitive dysfunction. These results confirmed the associations between carotid atherosclerosis and cognitive impairment and also supported the hypothesis that carotid atherosclerosis could be a potentially modifiable risk factor for AD. Previous evidence has demonstrated that carotid atherosclerosis preceded the onset of later cognitive impairment and was associated with AD dementia [ 16 ]. Subclinical carotid atherosclerosis manifests as the presence of carotid intima media roughness (CIMR), carotid intima media thickness (CIMT), and carotid plaque [ 27 , 28 ]. In order to refine our study, we categorized CIMT into different level. Our results are consistent with previous research findings from cross-sectionally and longitudinally cohort studies linking carotid atherosclerosis to cognitive functioning [ 29 – 33 ]. The Baltimore Longitudinal Study of Aging found that CIMT was longitudinally associated with an increased risk of accelerated cognitive decline [ 29 ]. Additionally, a Northern Manhattan Study found that carotid plaque was associated with worse cognition [ 31 ], while another study with a follow-up period of 7 years found lower cognitive measurements in participants with carotid plaque [ 30 ]. Furthermore, the Cardiovascular Health Study recruited 4006 stroke-free individuals of old age and observed a positive correlation between CIMT level and cognitive impairment, particularly in those with high-grade (> 75% narrowing of diameter) stenosis [ 33 ]. The Sternstunden der Gesundheit study suggested that the presence of CIMR may serve as a predictor for identifying individuals at risk for developing carotid atherosclerosis [ 12 ]. The Kaohsiung Atherosclerosis Longitudinal Study indicated that indicators related to carotid artery could enhance predictive ability for assessing cognitive dysfunction [ 32 ]. In this study, we not only demonstrated a significant association between carotid atherosclerosis and cognitive impairment, but also identified the mediating effect of tau pathology. Cortical amyloid deposition and tau pathology, which can identify prodromal AD in the MCI stage, have been established as CSF core biomarkers [ 34 – 36 ]. To further explore the mechanism by which carotid atherosclerosis affects cognition remains unclear, this study incorporated AD biomarkers. Our findings revealed that carotid plaque and CIMT level were significantly associated with T-tau and P-tau levels, but no correlation was observed between CIMT and tau pathology. The Malmö Diet and Cancer Study demonstrated that both carotid plaque and heavy CIMT were significantly associated with AD pathology in cognitively unimpaired individuals [ 8 ]. Moreover, the Framingham Heart Study indicated that vascular risk factors may exacerbate tau burden, which is more pronounced in the elderly [ 37 ]. This negative result may be interpreted as the severity of CIMT or confounding effects from other variables. Additionally, it was found that there was a connection between CIMR and the levels of tau-related biomarkers. No association was found between carotid atherosclerosis and amyloid level. The pathological mechanism of AD is still unknown, and one of the suggested is the hypothesis of cerebral hypoperfusion [ 38 ]. Cerebrovascular disease promotes the increase of tau protein levels, which may be caused by increased cerebrovascular resistance and chronic hypoperfusion of the corresponding brain region, resulting in impaired clearance of tau pathological protein [ 39 ]. Furthermore, various animal models suggested that chronic cerebral hypoperfusion leads to greater tau burden and its hyperphosphorylation [ 40 – 42 ]. However, the relationship between longstanding cerebral hypoperfusion and AD pathology remains controversial based on a cross-sectional PET imaging study [ 43 ]. Previous studies have indicated that tau tangles may precede amyloidosis in specific cortical regions related with cognition; alternatively, it can also be argued that the formation of amyloid plaque is a process over an extended period [ 44 – 46 ]. In addition, Costantino Iadecola et al. proposed a hypothesis that tau protein is more sensitive to clearance dysfunction than amyloid, which might explain why carotid atherosclerosis is primarily associated with tau pathology biomarkers in the preclinical stage of AD [ 47 ]. In the future, the mechanism needs to be further validated in long-term longitudinal follow-up studies. Our study identified several subgroup effects that carotid atherosclerosis was closely linked with tau pathology and cognitive impairment in women, old-aged, and APOE ɛ4 non-carriers. In further mediation analysis, we found that the effect of carotid atherosclerosis on cognition was partly mediated by tau pathology, and this finding was also present in the female cohort. The average age of the population in this study was 66 years, and most of the women were postmenopausal. Previous studies have shown that postmenopausal women have decreased levels of sex hormones, leading to an increased risk of atherosclerosis [ 48 , 49 ]. The Baltimore Longitudinal Study of Aging suggested that a greater relevance between carotid atherosclerosis and regional cerebral blood flow was exhibited in the female subgroup compared to male [ 50 ]. This may explain downstream tau deposition and cognitive dysfunction, consistent with the cerebral hypoperfusion hypothesis. Due to its inexpensive and non-invasive characteristics, ultrasound is widely used in the preliminary screening of high-risk population of carotid atherosclerosis [ 51 ]. At present, the drugs and treatments that can significantly improve this disease have been proven in large clinical trials, such as statins, ezetimibe and carotid artery revascularization [ 52 – 54 ]. With the exploration of potential risk factors for AD and significant advances in its cerebrospinal fluid biomarkers in the preclinical stage, primary and secondary prevention is increasingly possible [ 55 ]. Our study had several strengths. The primary strength of our study is the study population with preclinical AD, which makes the study more clinically relevant. Additionally, our study is one of the few to explore the interaction of carotid atherosclerosis, AD biomarkers, and cognition. There are also limitations that should be acknowledged in this study. This was an retrospective and observational study, thus it's impossible to clarify cause and effect. Furthmore, although we found associations of carotid atherosclerosis with tau pathology and cognitive function, the exact underlying mechanism is unclear. Future studies are needed to detect the interventions effects of carotid atherosclerosis management on clinical endpoints such as MCI or AD and explore the mechanisms. Conclusions In conclusion, carotid atherosclerosis was associated with tau pathology and cognitive function, as well as might contribute to AD-related cognitive impairment via affecting tau pathology. Therefore, early management and intervention of carotid atherosclerosis may help prevent or delay the occurrence of AD. Abbreviations P-tau phosphorylated tau protein T-tau total tau protein cimr the carotid intima-media roughness,0 = no,1 = yes cimt the carotid intima–media thickness,0 = no,1 = yes plaque the carotid plaque,0 = no,1 = yes level cimt level,0 = cimt 1.4mm. Declarations Ethics approval and consent to participate The CABLE study was conducted in accordance with the Declaration of Helsinki, and the protocol for this study was approved by the Institutional Ethics Committee of Qingdao Municipal Hospital. Written informed consent was obtained from all study participants directly or from their caregivers. Consent for publication Not applicable. Availability of data and materials The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding This study was supported by grants from the National Natural Science Foundation of China (81971032, 82271475), Taishan Scholars Program of Shandong Province (tsqn20161078), Natural Science Foundation of Shandong Province (ZR2023MH062), and Medical Science Research Guidance Plan of Qingdao (2021-WJZD001). Authors' contributions LT and MST conceptualized the study and revised the manuscript. MZZ and CKS analyzed and interpreted the data, drafting and revision of the manuscript, and prepared the figures. YMC, QH, ZQZ and FG participated in the interpretation of the data and revision of the manuscript. All authors contributed to the writing and revisions of the paper. All authors read and approved the final manuscript. Acknowledgements The authors thank all participants of the present study as well as all members of staff of the CABLE study for their role in data collection. References Wimo A, Seeher K, Cataldi R, Cyhlarova E, Dielemann JL, Frisell O, et al. The worldwide costs of dementia in 2019. Alzheimers Dement. 2023;19 7:2865–73. 10.1002/alz.12901 . Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S, et al. Alzheimer's disease. Lancet. 2016;388 10043:505–17. 10.1016/S0140-6736(15)01124-1 . 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Jama. 2006;296 15:1837; author reply 10.1001/jama.296.15.1837-a . Selkoe DJ. Preventing Alzheimer's disease. Science. 2012;337 6101:1488–92. 10.1126/science.1228541 . Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterial.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4602922","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":323071334,"identity":"e5936f8a-9c2a-4b53-a2c6-b49be563a05b","order_by":0,"name":"Ming-Zhan Zhang","email":"","orcid":"","institution":"Shandong Second Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ming-Zhan","middleName":"","lastName":"Zhang","suffix":""},{"id":323071335,"identity":"afeecfad-0e59-4611-9206-cb892e994db7","order_by":1,"name":"Cheng-Kun Sun","email":"","orcid":"","institution":"Qingdao Municipal Hospital, Dalian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Cheng-Kun","middleName":"","lastName":"Sun","suffix":""},{"id":323071336,"identity":"489f5550-01ab-4f3e-88d5-396de383e090","order_by":2,"name":"Yan-Ming Chen","email":"","orcid":"","institution":"Qingdao University","correspondingAuthor":false,"prefix":"","firstName":"Yan-Ming","middleName":"","lastName":"Chen","suffix":""},{"id":323071337,"identity":"e2f3ff36-200d-4a22-b586-70ca568c594a","order_by":3,"name":"Quan Hao","email":"","orcid":"","institution":"Qingdao University","correspondingAuthor":false,"prefix":"","firstName":"Quan","middleName":"","lastName":"Hao","suffix":""},{"id":323071338,"identity":"ce306624-867e-4ced-8c53-0577c3b9ec78","order_by":4,"name":"Zi-Qi Zhang","email":"","orcid":"","institution":"Shandong Second Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zi-Qi","middleName":"","lastName":"Zhang","suffix":""},{"id":323071339,"identity":"5e244e2d-a18c-4c6e-8e95-e29bb65f86f7","order_by":5,"name":"Fan Guo","email":"","orcid":"","institution":"Qingdao University","correspondingAuthor":false,"prefix":"","firstName":"Fan","middleName":"","lastName":"Guo","suffix":""},{"id":323071340,"identity":"f93142e4-dc27-4fcc-ac49-c92dcf5bd979","order_by":6,"name":"Lan Tan","email":"","orcid":"","institution":"University of Health and Rehabilitation Science","correspondingAuthor":false,"prefix":"","firstName":"Lan","middleName":"","lastName":"Tan","suffix":""},{"id":323071341,"identity":"6a9837ca-38f7-4d92-a6cc-188065860c94","order_by":7,"name":"Meng-Shan Tan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1UlEQVRIiWNgGAWjYDADAwYGxgcJFTWEVfIgaWE2eHDmGGla2CQftjAT1mLPfvboho87au3N2c8eq0hsYGPgb+9OwG8LT17azZlnjifu7MlLu5G4Q4ZB4szZDQQclmN2m7ftWILBgRyzG4ln2BgMJHIJaOF/Y3b7b9sxe4Pzb8wKEtuYidAiAbSFsa2GccONHDMG4rTceGN2s7ftQOKGG2+MJRLOHOMh6Bf2fqAXfrbVAR2WY/jxR0WNHH97L34tUHAYYS0xykGgjliFo2AUjIJRMBIBAGLoTJccNm62AAAAAElFTkSuQmCC","orcid":"","institution":"University of Health and Rehabilitation Science","correspondingAuthor":true,"prefix":"","firstName":"Meng-Shan","middleName":"","lastName":"Tan","suffix":""}],"badges":[],"createdAt":"2024-06-19 03:39:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4602922/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4602922/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":60601807,"identity":"1584d411-9d4e-40d8-9744-56460c901b52","added_by":"auto","created_at":"2024-07-18 16:06:56","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":637037,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDifference in CSF AD biomarkers between participants with and without carotid atherosclerosis were examined by Mann-Whitney \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eU \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003etest or Kruskal-Wallis test\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAbbreviation: P-tau, phosphorylated tau protein; T-tau, total tau protein; cimr, the carotid intima-media roughness, 0 = no, 1 = yes; cimt, the carotid intima–media thickness, 0 = no, 1 = yes; plaque, the carotid plaque, 0 = no, 1 = yes; level, cimt level, 0 = cimt \u0026lt;1.0mm, 1 = 1.0-1.2 mm, 2 = 1.2-1.4 mm, 3 = \u0026gt;1.4mm.\u003c/p\u003e","description":"","filename":"OnlineFig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-4602922/v1/75370f9c001b4f29d9cbdba4.png"},{"id":60601805,"identity":"0dc598c2-998b-4b7d-ac61-cd269e73f06f","added_by":"auto","created_at":"2024-07-18 16:06:56","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":537916,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDifference in cognitive function between participants with and without carotid atherosclerosis were examined by Mann-Whitney \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eU \u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003etest or Kruskal-Wallis test\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAbbreviation: CM-MMSE, China-Modified Mini-Mental State Examination; MoCA, the Montreal Cognitive Assessment; cimr, the carotid intima-media roughness, 0 = no, 1 = yes; cimt, the carotid intima–media thickness, 0 = no, 1 = yes; plaque, the carotid plaque, 0 = no, 1 = yes; level, cimt level, 0 = cimt \u0026lt;1.0mm, 1 = 1.0-1.2 mm, 2 = 1.2-1.4 mm, 3 = \u0026gt;1.4mm.\u003c/p\u003e","description":"","filename":"OnlineFig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-4602922/v1/75dd11f2357e72c116088dcb.png"},{"id":60601806,"identity":"3c78781d-ddfb-4337-9a6e-fd2c3f145b4d","added_by":"auto","created_at":"2024-07-18 16:06:56","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":586027,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAssociations between carotid atherosclerosis with cognition and CSF AD biomarkers.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalyses were adjusted for age, sex, education, and \u003cem\u003eAPOE\u003c/em\u003e ε4 status.\u003c/p\u003e\n\u003cp\u003eAbbreviation: Aβ, amyloid-β; P-tau, phosphorylated tau protein; T-tau, total tau protein; CM-MMSE, China-Modified Mini-Mental State Examination; MoCA, the Montreal Cognitive Assessment; cimr, the carotid intima-media roughness, 0 = no, 1 = yes; cimt, the carotid intima–media thickness, 0 = no, 1 = yes; plaque, the carotid plaque, 0 = no, 1 = yes; level, cimt level, 0 = cimt \u0026lt;1.0mm, 1 = 1.0-1.2 mm, 2 = 1.2-1.4 mm, 3 = \u0026gt;1.4mm.\u003c/p\u003e","description":"","filename":"OnlineFig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-4602922/v1/e2e1c4a4a86efe1b73796ab1.png"},{"id":60602376,"identity":"e24234e5-6b42-4d66-bacb-9ecfc0c30530","added_by":"auto","created_at":"2024-07-18 16:14:56","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":379860,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAssociations between carotid atherosclerosis with cognition and CSF AD biomarkers in subgroups stratified by age, sex, and \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eAPOE\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e ε4 status.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalyses were adjusted for: 1) in age subgroup, sex, education, and \u003cem\u003eAPOE\u003c/em\u003eε4 status; 2) in sex subgroup, age, education, and \u003cem\u003eAPOE\u003c/em\u003e ε4 status; 3) in \u003cem\u003eAPOE\u003c/em\u003e ε4 status subgroup, age, sex, and education.\u003c/p\u003e\n\u003cp\u003eAbbreviation: \u003cem\u003eAPOE \u003c/em\u003eɛ4, apolipoprotein E ɛ4 gene; CSF, cerebrospinal fluid; Aβ, amyloid-β; P-tau, phosphorylated tau protein; T-tau, total tau protein; CM-MMSE, China-Modified Mini-Mental State Examination; MoCA, the Montreal Cognitive Assessment; cimr, the carotid intima-media roughness, 0 = no, 1 = yes; cimt, the carotid intima–media thickness, 0 = no, 1 = yes; plaque, the carotid plaque, 0 = no, 1 = yes; level, cimt level, 0 = cimt \u0026lt;1.0mm, 1 = 1.0-1.2 mm, 2 = 1.2-1.4 mm, 3 = \u0026gt;1.4mm.\u003c/p\u003e\n\u003cp\u003e*, \u003cem\u003eP\u003c/em\u003e \u0026lt;0.05; **, \u003cem\u003eP\u003c/em\u003e \u0026lt;0.01; ***, \u003cem\u003eP\u003c/em\u003e \u0026lt;0.001.\u003c/p\u003e","description":"","filename":"OnlineFig.4.png","url":"https://assets-eu.researchsquare.com/files/rs-4602922/v1/bbbe161a67ab6f2798d8e20b.png"},{"id":60602377,"identity":"c75d7248-d38c-4467-a8d5-c6983bc6bbab","added_by":"auto","created_at":"2024-07-18 16:14:56","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":90722,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCSF AD biomarkers mediation analyses of the associations between carotid atherosclerosis and cognition.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnalyses were adjusted for age, sex, education, and \u003cem\u003eAPOE\u003c/em\u003e ε4 status.\u003c/p\u003e\n\u003cp\u003eAbbreviation: T-tau, total tau protein; MoCA, the Montreal Cognitive Assessment; plaque, the carotid plaque; level, cimt level.\u003c/p\u003e","description":"","filename":"OnlineFig.5.png","url":"https://assets-eu.researchsquare.com/files/rs-4602922/v1/312d4e6cc04c61da832fa078.png"},{"id":60604025,"identity":"108e9581-0a22-48f9-aaf8-274eb5c59bf1","added_by":"auto","created_at":"2024-07-18 16:30:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1487512,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4602922/v1/df70d03c-5f57-4d24-8797-f58505d563ef.pdf"},{"id":60602378,"identity":"4593ccca-f148-48c0-bc80-d32fdb3ad669","added_by":"auto","created_at":"2024-07-18 16:14:56","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":46271,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementarymaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-4602922/v1/c69a23eff941817035d05d17.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Carotid atherosclerosis associated with tau pathology and cognitive function in cognitively intact adults: the CABLE study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDementia is a prominent cause of death and disability worldwide, imposing a significant burden on health and cere systems around the world [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Alzheimer's disease (AD), as the most common form of dementia, is characterized pathologically by aberrant amyloid deposition, total tau and phosphorylated tau (indicated by Aβ\u003csub\u003e42/40\u003c/sub\u003e,T-tau and P-tau, respectively), and clinically by cognitive and behavioral impairments [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Currently, there is no effective treatment that can cure AD or slow down its onset and progression [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Significantly, recent studies found that differences in cerebrospinal fluid (CSF) biomarkers between the AD and cognitively normal groups existed several years before the onset ofAD [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Therefore, it is crucial to identify the potentially modifiable risk factors associated with AD to facikitaye the early prevention of AD.\u003c/p\u003e \u003cp\u003eCarotid atherosclerosis is an important contributor in the onset and development of dementia and AD [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Increasing research suggested that markers reflecting the burden of carotid atherosclerosis including carotid intima-media roughness (CIMR), carotid intima-media thickness (CIMT), and carotid plaque, were associated with cognitive functioning impairment in individuals at risk of AD development [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Furthermore, a long-term longitudinal cohort study demonstrated that carotid plaque exacerbated cognitive impairment related to AD [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In this context, several researchers proposed that carotid atherosclerosis could be considered as a modifiable risk factor for AD [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Nevertheless, the precise mechanisms underlying the association between carotid atherosclerosis and AD remain unknown.\u003c/p\u003e \u003cp\u003eFew studies have investigated the bio-mechanisms underlying the association of carotid atherosclerosis with cognitive dysfunction, as well as wherther pathological AD biomarkers influenced the relationship between carotid atherosclerosis and cognition. Thus, the primary objectives of this study were to (1) investigate the associations between carotid atherosclerosis and cognitive function; (2) explore the associations between carotid atherosclerosis and CSF AD biomarkers; and (3) examine whether the impact of carotid atherosclerosis on cognitive performance was mediated by AD pathology in 365 participants.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eThe CABLE database\u003c/h2\u003e \u003cp\u003eThe Chinese Alzheimer\u0026rsquo;s Biomarker and LifestylE (CABLE) study, initiated in 2017, is an ongoing large-scale independent cohort study primarily focusing on risk factors and biomarkers for AD, aiming to facilitate early diagnosis of AD among the Chinese Han population [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. All enrolled participants in the CABLE were recruited from Qingdao Municipal Hospital, Shandong Province, China. The CABLE database was conducted in compliance with the Declaration of Helsinki. The study has been approved by the Institutional Review Board of Qingdao Municipal Hospital. Written informed consent was obtained from all the participants.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eParticipants\u003c/h2\u003e \u003cp\u003eParticipants included in the CABLE were Han Chinese aged between 40 and 90 years old. The main exclusion criteria were: (1) central nervous system infections, multiple sclerosis, head trauma, neurodegenerative diseases other than AD (e.g., epilepsy, Parkinson\u0026rsquo;s Disease), or other major neurological disorders; (2) significant psychological disorders; (3) severe systemic diseases (e.g., malignancy tumors); (4) family history of genetic disorders. Demographic information and medical history were collected through structured questionnaires supplemented by an electronic medical record system. All diagnoses were assessed by two medical professionals with standardized training in cognitive disorders by means of complete performance on neuropsychological tests, combined with CSF biomarkers and magnetic resonance imaging (MRI) examinations. The baseline cognitive status of participants was determined using the China Modified Mini-Mental State Examination (CM-MMSE) and the Montreal Cognitive Assessment (MoCA). Objective cognitive impairment was difined as having a CM-MMSE score\u0026thinsp;\u0026le;\u0026thinsp;17 for those without education, a CM-MMSE score\u0026thinsp;\u0026le;\u0026thinsp;20 for those with no more than 6 years of education, a CM-MMSE score\u0026thinsp;\u0026le;\u0026thinsp;24 for thore with more than 6 years of education. A total of 2334 participants were enrolled in the CABLE study, out of which 1959 participants who did not undergo carotid ultrasound examination or did not provide CSF biomarkers data were excluded. Ultimately, our study included 365 individuals.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eMarkers of carotid atherosclerosis\u003c/h2\u003e \u003cp\u003eThe carotid arteries were assessed by certified and wel-trained medical sonographers using Philips color Doppler ultrasound machines. All participants underwent the examinations in a supine position with their head tilted back to expose their neck. The lengths of bilateral common carotid artery, carotid bifurcation, and internal carotid arteries were examined transversely first and then longitudinally in grayscale and color flow modes. First, the length of the common carotid arteries, the carotid bifurcation, as well as the internal and external carotid arteries beginning were examined transversally; Then longitudinally in lumen-diameter, grayscale and color flow. Ultrasound variables (dynamic range, depth range, power, reject, edge, grey scale, and smoothness) were constant during all the examinations. Our markers of interest include: 1) the presence of CIMR, defined as granulare chogenicity of deep, normally unechoic intimal-medial layer [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]; 2) the presence of CIMT, indicated by CIMT\u0026thinsp;\u0026ge;\u0026thinsp;0.9 mm in one or both bilateral carotid arteries [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]; 3) the presence of carotid plaque (plaque), indicated by CIMT\u0026thinsp;\u0026ge;\u0026thinsp;1.5 mm in one or both bilateral carotid arteries [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]; 4) graded based on CIMT level (level): 0\u0026thinsp;=\u0026thinsp;\u0026lt;\u0026thinsp;1.0mm, 1\u0026thinsp;=\u0026thinsp;1.0-1.2 mm, 2\u0026thinsp;=\u0026thinsp;1.2\u0026ndash;1.4 mm, 3\u0026thinsp;=\u0026thinsp;\u0026gt;\u0026thinsp;1.4mm [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eCSF AD biomarkers\u003c/h2\u003e \u003cp\u003eCSF samples were obtained via lumbar puncture by a qualified physician in 10 ml polypropylene tubes and promptly transported to the laboratory for processing within 2 hours. After centrifugation at 2000 \u0026times; g for 10 min, the samples were divided and stored in an enzyme-free EP (Eppendorf) tubes (AXYGEN; PCR-02-C) at \u0026minus;\u0026thinsp;80\u0026deg;C. The freeze-thawing cycle was limited to two times or less. CSF levels of Aβ\u003csub\u003e42\u003c/sub\u003e, Aβ\u003csub\u003e40\u003c/sub\u003e, P-tau, and T-tau levels were quantified using the ELISA kits (Innotest β-AMYLOID (1\u0026ndash;42) [catalog number: 81583]; β-AMYLOID (1\u0026ndash;40) [catalog number: 81585]; PHOSPHO-TAU (181p) [catalog number: 81581]; hTAU-Ag [catalog number: 81579]; Fujirebio, Ghent, Belgium). All measurements were performed in duplicate by professional technicians blinded to clinical information. Within-batch coefficients of variations (CVs) were \u0026lt;\u0026thinsp;5% ((4.8% for Aβ\u003csub\u003e42\u003c/sub\u003e, 3.6% for Aβ\u003csub\u003e40\u003c/sub\u003e, 2.4% for P-tau, and4.6% for T-tau). Inter-batch CVs were \u0026lt;\u0026thinsp;20% (9% for Aβ\u003csub\u003e42\u003c/sub\u003e, 3.6% for Aβ\u003csub\u003e40\u003c/sub\u003e, 10.9% for P-tau, and12.2% for T-tau). Among these CSF AD biomarkers, we utilized the Aβ\u003csub\u003e42/40\u003c/sub\u003e ratio instead of the absolute value of Aβ\u003csub\u003e42\u003c/sub\u003e since the ratio could better represent amyloid deposition and diagnostic accuracy [\u003cspan additionalcitationids=\"CR25\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003cb\u003eAPOE-ε4\u003c/b\u003e \u003cb\u003egenotyping\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe QIAamp\u0026reg; DNA Blood Mini Kit (250) was utilized for extracting DNA from fasting blood samples. Subsequently, the DNA was isolated and stored an enzyme-free EP tube at \u0026minus;\u0026thinsp;80\u0026deg;C until completion of \u003cem\u003eAPOE\u003c/em\u003e genotyping for the study. \u003cem\u003eAPOE ε4\u003c/em\u003e status was determined by genotyping rs7412 and rs429358 using a restriction fragment-length polymorphisms technique. Participants were categorized as either \u003cem\u003eAPOE ε4\u003c/em\u003e non-carriers or \u003cem\u003eAPOE ε4\u003c/em\u003e carriers (with at least one copy of the \u003cem\u003eAPOE ε4\u003c/em\u003e gene).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analyses\u003c/h2\u003e \u003cp\u003eIn order to describe baseline characteristics of the participants, categorical variables were presented as numbers and percentages, while continuous variables were expressed as means with standard deviations (SD). The characteristics were compared using Chi-square tests (categorical variables) and Mann\u0026ndash;Whitney U test (continuous variables). CSF AD biomarker measurements underwent normalization through the Box\u0026ndash;Cox transformation and were standardized via z Scale in the case of skewed distributions.\u003c/p\u003e \u003cp\u003eMultiple linear regression models were used to explore the associations of carotid atherosclerosis with CSF AD biomarkers and cognitive function after adjusting for age (continuous), sex (categorical), education (continuous), \u003cem\u003eAPOE ε4\u003c/em\u003e status (categorical). Moreover, sensitivity analyses were conducted by adding further covariates, including self-report histories of hyperlipidemia (yes or no), high blood pressure (yes or no), and diabetes mellitus (yes or no). Furthermore, subgroup analyses stratified by age, sex and \u003cem\u003eAPOE ε4\u003c/em\u003e status were performed.\u003c/p\u003e \u003cp\u003eNext, mediation analyses based on Baron and Kenny's method were conducted to examine whether the associations between carotid atherosclerosis and cognition was mediated by AD pathology. Mediation effects would be established if all the criteria are simultaneously satisfied: 1) significant associations between carotid atherosclerosis and CSF AD biomarkers; 2) significant associations between carotid atherosclerosis and cognitive measures; 3) significant associations between CSF AD biomarkers and cognitive measures; and 4) attenuated associations between carotid atherosclerosis and cognitive measures when adding CSF AD biomarkers (the mediators) in the regression model. Additionally, the indirect effect or attenuation was estimated, with significance determined through 10,000 bootstrapped iterations. Each path of the mediator model was corrected for age, sex, education, and \u003cem\u003eAPOE ε4\u003c/em\u003e status. All statistical analyses and visualization were performed using IBM SPSS Statistics 26 software and R Studio software (version 4.2.0.). The significance threshold was set at a \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05 (two-tailed).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eParticipant characteristics\u003c/h2\u003e \u003cp\u003eThe demographical and clinical characteristics of the participants are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. This study enrolled 365 participants from the CABLE database. The study sample had an age range of 40 to 90 years (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u0026thinsp;=\u0026thinsp;65.82\u0026thinsp;\u0026plusmn;\u0026thinsp;10.04), an average education level of 9.92\u0026thinsp;\u0026plusmn;\u0026thinsp;4.59 years, a female percentage of 46.30%, and an \u003cem\u003eAPOE ε4\u003c/em\u003e carriers proportion of 15.89%. In terms of cognitive scores, the study sample had an average CM-MMSE score of 26.63\u0026thinsp;\u0026plusmn;\u0026thinsp;3.87 and an average MoCA score of 21.84\u0026thinsp;\u0026plusmn;\u0026thinsp;5.52.\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\u003eCharacteristics of participants from CABLE database.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eDescriptive statistics Total (N\u0026thinsp;=\u0026thinsp;365)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAge (y) mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65.82 (10.04)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eSex (Female) N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e169 (46.30%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eEducation (y) mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.92 (4.59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003e\u003cem\u003eAPOE\u003c/em\u003e ɛ4 carriers N (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e47 (15.89%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eAβ\u003csub\u003e42/40\u003c/sub\u003e mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.07 (0.76)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eP-tau (pg/ml) mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42.29 (17.15)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eT-tau (pg/ml) mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e233.92 (140.62)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eCM-MMSE mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.63 (3.87)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eMoCA mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21.84 (5.52)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eAbbreviation: CN, cognitively normal participants; SCD, participants with subjective cognitive decline; \u003cem\u003eAPOE\u003c/em\u003e ɛ4, apolipoprotein E ɛ4 gene; Aβ, amyloid-β; P-tau, phosphorylated tau protein; T-tau, total tau protein; CM-MMSE, China-Modified Mini-Mental State Examination; N, number; y, years; SD, standard deviation.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eDifference in CSF AD biomarkers and cognitive function between participants with and without carotid atherosclerosis\u003c/h2\u003e \u003cp\u003eSignificant differences were observed in CSF levels of P-tau (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.039) and T-tau (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.028) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA and B), as well as scores of CM-MMSE (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.002) and MoCA (\u003cem\u003eP\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA and B) between participants with and without CIMR. Similarly, significant differences were found in CSF levels of P-tau (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.018) and T-tau (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.045) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC and D), as well as scores of CM-MMSE (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.045) and MoCA (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.005) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC and D) between participants with and without CIMT. Furthermore, significant differences were observed in CSF levels of P-tau (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.048) and T-tau (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.028) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE and F), as well as scores of CM-MMSE (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.026) and MoCA (\u003cem\u003eP\u0026thinsp;\u0026lt;\u003c/em\u003e\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eE and F) between participants with and without carotid plaque. As the CIMT level increased, differences in CSF levels of P-tau (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.012) and T-tau (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.019) increased (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eG and H), as well as the CM-MMSE (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.029) and MoCA score (\u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.003) decreased (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eG and H). However, in terms of these carotid atherosclerosis, no intergroup differences were found in CSF Aβ\u003csub\u003e42/40\u003c/sub\u003e (CIMR: Aβ\u003csub\u003e42/40\u003c/sub\u003e, \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.072; CIMT: Aβ\u003csub\u003e42/40\u003c/sub\u003e, \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.243; carotid plaque: Aβ\u003csub\u003e42/40\u003c/sub\u003e, \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.655; CIMT level increased: Aβ\u003csub\u003e42/40\u003c/sub\u003e, \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.324).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eAssociations of carotid atherosclerosis with CSF AD biomarkers and cognitive function\u003c/h2\u003e \u003cp\u003eIn the whole sample of subjects, the presence of CIMR was significantly associated with higher levels of P-tau (β\u0026thinsp;=\u0026thinsp;0.092, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014) and T-tau (β\u0026thinsp;=\u0026thinsp;0.099, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.047), as well as lower scores on CM- MMSE (β = -1.499, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and MoCA (β = -2.519, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e; Supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Besides, CIMT was significantly associated with lower scores on both CM- MMSE (β = -0.826, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011) and MoCA (β = -1.631, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e; Supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Moreover, carotid plaque was significantly associated with higher levels of P-tau (β\u0026thinsp;=\u0026thinsp;0.052, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.029) and T-tau (β\u0026thinsp;=\u0026thinsp;0.075, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.018), as well as lower scores on CM- MMSE (β = -0.597, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.034) and MoCA (β = -1.907, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e; Supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Furthermore, the CIMT level was also significantly associated with higher levels of P-tau (β\u0026thinsp;=\u0026thinsp;0.041, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008) and T-tau (β\u0026thinsp;=\u0026thinsp;0.048, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.022), as well as lower scores on CM- MMSE (β = -0.405, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014) and MoCA (β = -1.159, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e; Supplementary table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). However, the association between CIMR, CIMT, carotid plaque and CIMT level with Aβ\u003csub\u003e42/40\u003c/sub\u003e level (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026gt;\u0026thinsp;0.05) was not observed, as well as no significant association between CIMT and tau pathology (P-tau, β\u0026thinsp;=\u0026thinsp;0.059, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.061; T-tau, β\u0026thinsp;=\u0026thinsp;0.036, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.399).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSubgroup analyses\u003c/h2\u003e \u003cp\u003eAccording to age, sex and \u003cem\u003eAPOE\u003c/em\u003e ε4 status, subgroups analyses were used to identify specific vulnerable population. We found that the aforementioned associations of carotid atherosclerosis with CSF AD biomarkers and cognitive function remained statistically significant: (1) CIMR: in mid-age (CM-MMSE, β = -1.358, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003), in late-age (P-tau, β\u0026thinsp;=\u0026thinsp;0.131, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021; T-tau, β\u0026thinsp;=\u0026thinsp;0.311, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008; CM-MMSE, β = -1.962, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021; MoCA, β = -5.523, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003), in women (P-tau, β\u0026thinsp;=\u0026thinsp;0.117, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023; T-tau, β\u0026thinsp;=\u0026thinsp;0.168, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013; CM-MMSE, β = -1.707, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; MoCA, β = -3.479, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), and in \u003cem\u003eAPOE\u003c/em\u003e ɛ4 non-carriers (P-tau, β\u0026thinsp;=\u0026thinsp;0.108, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013; T-tau, β\u0026thinsp;=\u0026thinsp;0.118, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.035; CM-MMSE, β = -1.460, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; MoCA, β = -3.388, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e; Supplementary table 2, 3 and 4); (2) CIMT: in late-age (MoCA, β = -3.394, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015), in women (CM-MMSE, β = -1.331, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006; MoCA, β = -3.147, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002), and in \u003cem\u003eAPOE\u003c/em\u003e ɛ4 non-carriers (CM-MMSE, β = -0.739, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.043; MoCA, β = -2.164, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e; Supplementary table 2, 3 and 4); (3): carotid plaque: in late-age adults (P-tau, β\u0026thinsp;=\u0026thinsp;0.073, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.025; T-tau, β\u0026thinsp;=\u0026thinsp;0.157, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; MoCA, β = -2.834, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001), in women (P-tau, β\u0026thinsp;=\u0026thinsp;0.072, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.038; T-tau, β\u0026thinsp;=\u0026thinsp;0.106, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.026; MoCA, β = -2.314, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.007), and in \u003cem\u003eAPOE\u003c/em\u003e ɛ4 non-carriers (P-tau, β\u0026thinsp;=\u0026thinsp;0.039, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.050; T-tau, β\u0026thinsp;=\u0026thinsp;0.072, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.040; CM-MMSE, β = -0.678, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021; MoCA, β = -2.065, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e; Supplementary table 2, 3 and 4); (4) CIMT level: in late-age (P-tau, β\u0026thinsp;=\u0026thinsp;0.054, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.027; T-tau, β\u0026thinsp;=\u0026thinsp;0.117, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; MoCA, β = -2.327, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), in women (P-tau, β\u0026thinsp;=\u0026thinsp;0.053, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.013; T-tau, β\u0026thinsp;=\u0026thinsp;0.071, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016; MoCA, β = -1.454, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003), in \u003cem\u003eAPOE\u003c/em\u003e ɛ4 carriers (P-tau, β\u0026thinsp;=\u0026thinsp;0.076, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.039), and in \u003cem\u003eAPOE\u003c/em\u003e ɛ4 non-carriers (P-tau, β\u0026thinsp;=\u0026thinsp;0.038, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.029; CM-MMSE, β = -0.444, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016; MoCA, β = -1.393, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e; Supplementary table 2, 3 and 4).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analyses\u003c/h2\u003e \u003cp\u003eIn order to be results more credible, additional sensitivity analyses were performed. The above results remained consistent after adjusting for various covariates (Model 1: age, sex, education, \u003cem\u003eAPOE\u003c/em\u003e ε4 status, and high blood pressure; Model 2: age, sex, education, \u003cem\u003eAPOE\u003c/em\u003e ε4 status, and diabetes mellitus; and Model 3: age, sex, education, \u003cem\u003eAPOE\u003c/em\u003e ε4 status, and hyperlipidemia; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05) (Supplementary table 5, 6 and 7, respectively).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eCausal mediation analyses\u003c/h2\u003e \u003cp\u003eThese above findings indicated that carotid atherosclerosis was associated with tau pathology and cognitive impairment, so causal mediation analysis was used to explore the underlying mechanisms of cognitive impairment. In the total participants, the associations between carotid plaque and MoCA scores was partially mediated via T-tau (proportion of mediation\u0026thinsp;=\u0026thinsp;19.7%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.012) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eA). Furthermore, in women, the above associations remained significant (proportion of mediation\u0026thinsp;=\u0026thinsp;44.1%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.008) (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eB), as well as we found that T-tau (proportion of mediation\u0026thinsp;=\u0026thinsp;36.2%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.010) mediated the association between CIMT level and MoCA scores (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eC).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe present study systematically investigates the interrelationships of carotid atherosclerosis (assessment by CIMR, CIMT, carotid plaque, and CIMT level), CSF AD biomarkers and cognitive impairment among participants without objective cognitive impairment. Our findings suggested that: a) there was a statistically significant association between carotid atherosclerosis and cognitive impairment; b) carotid atherosclerosis exhibited a significant association with tau pathology; c) tau pathology partially mediated the effects of carotid atherosclerosis on cognitive dysfunction. These results confirmed the associations between carotid atherosclerosis and cognitive impairment and also supported the hypothesis that carotid atherosclerosis could be a potentially modifiable risk factor for AD.\u003c/p\u003e \u003cp\u003ePrevious evidence has demonstrated that carotid atherosclerosis preceded the onset of later cognitive impairment and was associated with AD dementia [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Subclinical carotid atherosclerosis manifests as the presence of carotid intima media roughness (CIMR), carotid intima media thickness (CIMT), and carotid plaque [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In order to refine our study, we categorized CIMT into different level. Our results are consistent with previous research findings from cross-sectionally and longitudinally cohort studies linking carotid atherosclerosis to cognitive functioning [\u003cspan additionalcitationids=\"CR30 CR31 CR32\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. The Baltimore Longitudinal Study of Aging found that CIMT was longitudinally associated with an increased risk of accelerated cognitive decline [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Additionally, a Northern Manhattan Study found that carotid plaque was associated with worse cognition [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], while another study with a follow-up period of 7 years found lower cognitive measurements in participants with carotid plaque [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Furthermore, the Cardiovascular Health Study recruited 4006 stroke-free individuals of old age and observed a positive correlation between CIMT level and cognitive impairment, particularly in those with high-grade (\u0026gt;\u0026thinsp;75% narrowing of diameter) stenosis [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. The Sternstunden der Gesundheit study suggested that the presence of CIMR may serve as a predictor for identifying individuals at risk for developing carotid atherosclerosis [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The Kaohsiung Atherosclerosis Longitudinal Study indicated that indicators related to carotid artery could enhance predictive ability for assessing cognitive dysfunction [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. In this study, we not only demonstrated a significant association between carotid atherosclerosis and cognitive impairment, but also identified the mediating effect of tau pathology.\u003c/p\u003e \u003cp\u003eCortical amyloid deposition and tau pathology, which can identify prodromal AD in the MCI stage, have been established as CSF core biomarkers [\u003cspan additionalcitationids=\"CR35\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. To further explore the mechanism by which carotid atherosclerosis affects cognition remains unclear, this study incorporated AD biomarkers. Our findings revealed that carotid plaque and CIMT level were significantly associated with T-tau and P-tau levels, but no correlation was observed between CIMT and tau pathology. The Malm\u0026ouml; Diet and Cancer Study demonstrated that both carotid plaque and heavy CIMT were significantly associated with AD pathology in cognitively unimpaired individuals [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Moreover, the Framingham Heart Study indicated that vascular risk factors may exacerbate tau burden, which is more pronounced in the elderly [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. This negative result may be interpreted as the severity of CIMT or confounding effects from other variables. Additionally, it was found that there was a connection between CIMR and the levels of tau-related biomarkers. No association was found between carotid atherosclerosis and amyloid level. The pathological mechanism of AD is still unknown, and one of the suggested is the hypothesis of cerebral hypoperfusion [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Cerebrovascular disease promotes the increase of tau protein levels, which may be caused by increased cerebrovascular resistance and chronic hypoperfusion of the corresponding brain region, resulting in impaired clearance of tau pathological protein [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Furthermore, various animal models suggested that chronic cerebral hypoperfusion leads to greater tau burden and its hyperphosphorylation [\u003cspan additionalcitationids=\"CR41\" citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. However, the relationship between longstanding cerebral hypoperfusion and AD pathology remains controversial based on a cross-sectional PET imaging study [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Previous studies have indicated that tau tangles may precede amyloidosis in specific cortical regions related with cognition; alternatively, it can also be argued that the formation of amyloid plaque is a process over an extended period [\u003cspan additionalcitationids=\"CR45\" citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. In addition, Costantino Iadecola et al. proposed a hypothesis that tau protein is more sensitive to clearance dysfunction than amyloid, which might explain why carotid atherosclerosis is primarily associated with tau pathology biomarkers in the preclinical stage of AD [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. In the future, the mechanism needs to be further validated in long-term longitudinal follow-up studies.\u003c/p\u003e \u003cp\u003eOur study identified several subgroup effects that carotid atherosclerosis was closely linked with tau pathology and cognitive impairment in women, old-aged, and \u003cem\u003eAPOE ɛ4\u003c/em\u003e non-carriers. In further mediation analysis, we found that the effect of carotid atherosclerosis on cognition was partly mediated by tau pathology, and this finding was also present in the female cohort. The average age of the population in this study was 66 years, and most of the women were postmenopausal. Previous studies have shown that postmenopausal women have decreased levels of sex hormones, leading to an increased risk of atherosclerosis [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. The Baltimore Longitudinal Study of Aging suggested that a greater relevance between carotid atherosclerosis and regional cerebral blood flow was exhibited in the female subgroup compared to male [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. This may explain downstream tau deposition and cognitive dysfunction, consistent with the cerebral hypoperfusion hypothesis.\u003c/p\u003e \u003cp\u003eDue to its inexpensive and non-invasive characteristics, ultrasound is widely used in the preliminary screening of high-risk population of carotid atherosclerosis [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. At present, the drugs and treatments that can significantly improve this disease have been proven in large clinical trials, such as statins, ezetimibe and carotid artery revascularization [\u003cspan additionalcitationids=\"CR53\" citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. With the exploration of potential risk factors for AD and significant advances in its cerebrospinal fluid biomarkers in the preclinical stage, primary and secondary prevention is increasingly possible [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur study had several strengths. The primary strength of our study is the study population with preclinical AD, which makes the study more clinically relevant. Additionally, our study is one of the few to explore the interaction of carotid atherosclerosis, AD biomarkers, and cognition. There are also limitations that should be acknowledged in this study. This was an retrospective and observational study, thus it's impossible to clarify cause and effect. Furthmore, although we found associations of carotid atherosclerosis with tau pathology and cognitive function, the exact underlying mechanism is unclear. Future studies are needed to detect the interventions effects of carotid atherosclerosis management on clinical endpoints such as MCI or AD and explore the mechanisms.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, carotid atherosclerosis was associated with tau pathology and cognitive function, as well as might contribute to AD-related cognitive impairment via affecting tau pathology. Therefore, early management and intervention of carotid atherosclerosis may help prevent or delay the occurrence of AD.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eP-tau\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ephosphorylated tau protein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eT-tau\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etotal tau protein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ecimr\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ethe carotid intima-media roughness,0\u0026thinsp;=\u0026thinsp;no,1\u0026thinsp;=\u0026thinsp;yes\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ecimt\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ethe carotid intima\u0026ndash;media thickness,0\u0026thinsp;=\u0026thinsp;no,1\u0026thinsp;=\u0026thinsp;yes\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eplaque\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ethe carotid plaque,0\u0026thinsp;=\u0026thinsp;no,1\u0026thinsp;=\u0026thinsp;yes\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003elevel\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ecimt level,0\u0026thinsp;=\u0026thinsp;cimt\u0026thinsp;\u0026lt;\u0026thinsp;1.0mm,1\u0026thinsp;=\u0026thinsp;1.0-1.2 mm,2\u0026thinsp;=\u0026thinsp;1.2\u0026ndash;1.4 mm,3\u0026thinsp;=\u0026thinsp;\u0026gt;\u0026thinsp;1.4mm.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe CABLE study was conducted in accordance with the Declaration of Helsinki, and the protocol for this study was approved by the Institutional Ethics Committee of Qingdao Municipal Hospital. Written informed consent was obtained from all study participants directly or from their caregivers.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by grants from the National Natural Science Foundation of China (81971032, 82271475), Taishan Scholars Program of Shandong Province\u0026nbsp;(tsqn20161078), Natural Science Foundation of Shandong Province (ZR2023MH062), and Medical Science Research Guidance Plan of Qingdao (2021-WJZD001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLT and MST conceptualized the study and revised the manuscript. MZZ and CKS analyzed and interpreted the data, drafting and revision of the manuscript, and prepared the figures. YMC, QH, ZQZ and FG participated in the interpretation of the data and revision of the manuscript. All authors contributed to the writing and revisions of the paper. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank all participants of the present study as well as all members of staff of the CABLE study for their role in data collection.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWimo A, Seeher K, Cataldi R, Cyhlarova E, Dielemann JL, Frisell O, et al. The worldwide costs of dementia in 2019. 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Science. 2012;337 6101:1488\u0026ndash;92. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1126/science.1228541\u003c/span\u003e\u003cspan address=\"10.1126/science.1228541\" 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":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Alzheimer's disease, Biomarkers, Carotid atherosclerosis, Cerebrospinal fluid, Cognitive function","lastPublishedDoi":"10.21203/rs.3.rs-4602922/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4602922/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCarotid atherosclerosis has been implicated in cognitive decline, but the evidence from current studies is insufficient and the detailed mechanism remains unclear.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eThis study aimed to explore the association of carotid atherosclerosis with cognitive function and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers, as well as attempted to investigate the underlying mechanisms.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis study included 365 participants with objective normal cognition from the Chinese Alzheimer\u0026rsquo;s Biomarker and LifestylE (CABLE) database. Multiple linear regression models were utilized to assess the associations of carotid atherosclerosis (carotid intima-media roughness [CIMR], carotid intima-media thickness [CIMT], carotid plaque, and CIMT level) with CSF AD biomarkers and cognitive function. The mediation analyses were used to explore whether CSF AD biomarkers mediated the carotid atherosclerosis and cognitive function.\u003c/p\u003e\u003ch2\u003eResult\u003c/h2\u003e \u003cp\u003eWe found that CIMR, carotid plaque, and CIMT level were significantly associated with tau pathology (T-tau and P-tau, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05); All markers of carotid atherosclerosis were associated with cognitive function (CM-MMSE and MoCA, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Furthermore, mediation analyses revealed that the effect of carotid plaque on cognitive decline was partially mediated by tau pathology (proportion of mediation\u0026thinsp;=\u0026thinsp;19.7%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.012).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis study indicated that carotid atherosclerosis was associated with tau pathology and cognitive function, and tau pathology partially mediated the association between carotid atherosclerosis and cognitive function.\u003c/p\u003e","manuscriptTitle":"Carotid atherosclerosis associated with tau pathology and cognitive function in cognitively intact adults: the CABLE study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-18 16:06:49","doi":"10.21203/rs.3.rs-4602922/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9e361bce-3461-474c-9b49-f8b900a78f70","owner":[],"postedDate":"July 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-18T16:06:51+00:00","versionOfRecord":[],"versionCreatedAt":"2024-07-18 16:06:49","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4602922","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4602922","identity":"rs-4602922","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}