Midlife Risk Factors Research Articles

Abstract 065: Educational Attainment And Dementia Risk: Mediation By Vascular Risk Factors At Mid-life In The Atherosclerosis Risk In Communities (ARIC) Study

Background: Dementia prevention largely focuses on the modification of vascular risk factors and is particularly important among stroke survivors, who have the highest burden of vascular risk factors and are at elevated risk of dementia. Low educational attainment is a risk factor not only for worse vascular profiles at midlife but also for incident dementia. It is unclear to what extent the relationship between education and dementia is mediated through these vascular risk factors. Methods: In a cohort of 14,059 Black and White older adults in four U.S. communities, we assessed the relationship between education and dementia among all participants and, separately, among those with incident stroke. We used causal mediation analysis to assess multiple mediation by midlife hypertension, diabetes, BMI and smoking of the relationship between educational attainment and dementia. Results: Participants with less education had higher prevalence of mid-life risk factors. Lower education was associated with 60% higher risk of dementia and 40% higher risk of post-stroke dementia. About half of the association between education and dementia was mediated through vascular risk factors (Table 1). Conclusion: A substantial proportion of the relationship between education and dementia risk is indeed not mediated through mid-life vascular risk factors. The association between education and dementia was weaker in the high-risk participants who have had an incident stroke, indicating that more proximal causes such as vascular disease prior to the stroke superseded the distal cause of differences in educational attainment. As such, any mediated effect of education on dementia is likely through vascular risk factors earlier on in the life-course. Our findings suggest that dementia prevention efforts must also address disparities in socioeconomic resources as well as other mediating pathways.

Education as a moderator of middle-age cardiovascular risk factor-old-age cognition relationships: testing cognitive reserve hypothesis in epidemiological study.

Backgroundhigher educational attainment and less midlife cardiovascular risk factors are related to better old-age cognition. Whether education moderates the association between cardiovascular risk factors and late-life cognition is not known. We studied if higher education provides resilience against the deteriorative effects of higher middle-age body mass index (BMI) and a combination of midlife cardiovascular risk factors on old-age cognition.Methodsthe study population is the older Finnish Twin Cohort (n = 4,051, mean age [standard deviation, SD] = 45.5 years [6.5]). Cardiovascular risk factors and education were studied at baseline with questionnaires in 1975, 1981 and/or 1990 (participation rates of 89, 84 and 77%, respectively). Cognition was evaluated with telephone interviews (participation rate 67%, mean age [SD] =73.4 [2.9] years, mean follow-up [SD] = 27.8 [6.0] years) in 1999–2017. We studied the main and interactive effects of education and BMI/dementia risk score on late-life cognition with linear regression analysis. The study design was formulated before the pre-defined analyses.Resultsyears of education moderated the association between BMI with old-age cognition (among less educated persons, BMI-cognition association was stronger [B = −0.24 points per BMI unit, 95% CI −0.31, −0.18] than among more educated persons [B = −0.06 points per BMI unit, 95% CI −0.16, 0.03], Pinteraction < 0.01). There was a similar moderating effect of education on dementia risk score consisting of cardiovascular risk factors (P < 0.001).Conclusionsour results support the cognitive reserve hypothesis. Those with higher education may tolerate the deteriorative effects of midlife cardiovascular risk factors on old-age cognition better than those with lower education.

Exposure to Neighborhood-Level Racial Residential Segregation in Young Adulthood to Midlife and Incident Subclinical Atherosclerosis in Black Adults: The Coronary Artery Risk Development in Young Adults Study.

Neighborhood-level racial residential segregation has been linked to several cardiovascular disease risk factors and outcomes in Black adults, but its impact on subclinical atherosclerosis remains unknown. In addition, although the impact of segregation on health may vary over the life course, most studies have examined segregation exposure at a single point in time. This article takes a life course approach by examining associations of exposure to neighborhood-level racial residential segregation in young adulthood and patterns of exposure from young adulthood to midlife with coronary artery calcification (CAC) incidence. We used data on 1125 Black CARDIA study (Coronary Artery Risk Development in Young Adults) participants free of CAC. Residential segregation was assessed using the Gi* statistic and measured when participants were young adults (18-30 years old, in 1985-1986) and as the pattern from young adulthood to midlife (15 years later). Poisson regression with generalized estimating equations models was used to measure CAC incidence. We found participants living in low segregation neighborhoods in young adulthood had 0.52 (rate ratio [95% CI: 0.28-0.98]) times lower risk of developing CAC compared with high segregation after adjusting for young adulthood sociodemographic characteristics and neighborhood poverty. Associations were attenuated and no longer statistically significant with adjustment for midlife CAC risk factors hypothesized to be on the causal pathway (rate ratio: 0.56 [95% CI: 0.29-1.09]). Findings for patterns of segregation over time suggest participants living in low segregation neighborhoods in young adulthood were less likely to develop CAC than those who started out in medium/high segregation neighborhoods, regardless of where they lived in midlife (rate ratio for increase from low to medium/high: 0.42 [95% CI: 0.19-0.95]; rate ratio for continuously low versus continuously medium/high segregation neighborhoods: 0.75 [95% CI: 0.31-1.83]). We found that participants living in more segregated neighborhoods in young adulthood were more likely to develop CAC due at least in part to differences in CAC risk factor burden accumulated over follow-up.

Abstract TP196: A Decade Later: Revisiting The Midlife Stroke Surge Among Women In The United States; Updated Results From The National Health And Nutrition Examination Surveys (NHANES)

Background: Previous data from NHANES 1999-2004 showed that women aged 45-54 years were more than twice as likely as men to report a prior stroke. Little is known about recent sex-specific trends in midlife stroke prevalence and risk factors for stroke. Methods: We assessed age- and sex- specific trends in stroke prevalence among individuals aged 35-64 years (n= 23,936; weighted n= 349,074,769) participating in NHANES across epochs in 6-year intervals (1999-2004, 2005-2010, 2011-2016) using survey weighted counts and proportions to reflect US national estimates. Stroke was self-reported. Survey adjusted logistic regression models compared odds of prior stroke by sex across time for each midlife decade adjusting for sociodemographic and clinical variables. Trends in prevalence of vascular risk factors were assessed over time. Results: In 1999-2004, women aged 45-54 years were over twice as likely as men to report prior stroke (OR 2.4, 95% CI 1.4-4.2, p=0.002). In 2005-2010 and 2011-2016, the differences were no longer significant (OR 1.5, 0.9-2.5, p=0.15 and OR 0.9, 0.5-1.6, p=0.71). There were no sex differences in stroke prevalence for those aged 35-44 and 55-64 years (Table). Among those aged 45-54 years, mean systolic blood pressure (SBP) were comparable between women and men in 1999-2004 (124, SE 0.7 mmHg vs 125, SE 0.6 mmHg, p= 0.27), but women’s mean SBP decreased to 121, SE 0.6 mmHg in 2011-2016, while men’s remained stable at 124, SE 0.6 mmHg. Diabetes prevalence increased in both men (9% to 13%) and women (8% to 10%). Obesity prevalence increased from 31% to 38% in men and 37% to 42% in women. Conclusion: A decade later the midlife stroke prevalence surge among women (vs. men) in the US has abated. However, it is unclear whether this change is due to shifts in incidence or case fatality and opportunities remain to address cardiometabolic risk factors for both sexes.

Sex Differences in the Association Between Midlife Cardiovascular Conditions or Risk Factors With Midlife Cognitive Decline.

The prevalence of midlife cardiovascular conditions and risk factors is higher in men than women. Associations between midlife cardiovascular conditions or risk factors and midlife cognitive decline have been reported, but few studies have assessed sex differences in these associations. We included 1,857 participants enrolled in the population-based Mayo Clinic Study of Aging who were 50 to 69 years of age at baseline. Participants were evaluated every 15 months by a coordinator, including neurologic evaluation and neuropsychological testing. The neuropsychological testing used 9 tests to calculate global cognitive and domain-specific (memory, language, executive function, and visuospatial skills) z scores. Nurse abstractors reviewed participant medical records to determine the presence of cardiovascular conditions (coronary heart disease, arrhythmias, congestive heart failure) and risk factors (hypertension, diabetes, dyslipidemia, obesity, ever smoking). Linear mixed-effect models evaluated the association between baseline cardiovascular conditions or risk factors and global and domain-specific cognitive decline. Multivariable models adjusted for demographics, APOE genotype, depression, and other medical conditions. Interactions between sex and each cardiovascular condition or risk factor were examined, and results were stratified by sex. Overall, 1,465 (78.9%) participants had at least 1 cardiovascular condition or risk factor; the proportion of men was higher than women (767 [83.4%] vs 698 [74.5%], p < 0.0001). Cross-sectionally, coronary heart disease and ever smoking were associated with a lower visuospatial z score in multivariable models. Longitudinally, several cardiovascular conditions and risk factors were associated with declines in global and domain-specific z scores but not visuospatial z scores. Most cardiovascular conditions were more strongly associated with cognition among women: coronary heart disease and other cardiovascular conditions were associated with global cognitive decline only in women (all p < 0.05). In addition, diabetes, dyslipidemia, and coronary heart disease were associated with language z score decline only in women (all p < 0.05). However, congestive heart failure was associated with language z score decline only in men (all p < 0.05). Midlife cardiovascular conditions and risk factors are associated with midlife cognitive decline. Moreover, specific cardiovascular conditions and risk factors have stronger associations with cognitive decline in midlife for women than men despite the higher prevalence of those conditions in men.

Causal structure discovery identifies risk factors and early brain markers related to evolution of white matter hyperintensities

Our goal was to understand the complex relationship between age, sex, midlife risk factors, and early white matter changes measured by diffusion tensor imaging (DTI) and their role in the evolution of longitudinal white matter hyperintensities (WMH). We identified 1564 participants (1396 cognitively unimpaired, 151 mild cognitive impairment and 17 dementia participants) with age ranges of 30–90 years from the population-based sample of Mayo Clinic Study of Aging. We used computational causal structure discovery and regression analyses to evaluate the predictors of WMH and DTI, and to ascertain the mediating effect of DTI on WMH. We further derived causal graphs to understand the complex interrelationships between midlife protective factors, vascular risk factors, diffusion changes, and WMH. Older age, female sex, and hypertension were associated with higher baseline and progression of WMH as well as DTI measures (P ≤ 0.003). The effects of hypertension and sex on WMH were partially mediated by microstructural changes measured on DTI. Higher midlife physical activity was predictive of lower WMH through a direct impact on better white matter tract integrity as well as an indirect effect through reducing the risk of hypertension by lowering BMI. This study identified key risks factors, early brain changes, and pathways that may lead to the evolution of WMH.

Association of neighborhood‐level socioeconomic advantage with cognition and dementia risk factors in an Australian cohort

AbstractBackgroundResiding in areas of low socioeconomic advantage is associated with increased risk of dementia1 and associated brain pathology2,3. Given the long and insidious course of dementia pathologies, it is critical to establish the effect of ‘exposomic’ risk factors in midlife and to understand which groups of people are particularly vulnerable. Therefore, the objective of this study was to examine whether cognitive performance or dementia risk factors differed according to neighborhood‐level socioeconomic advantage in cognitively normal middle‐aged people.MethodsOur sample comprised 4798 participants from the Healthy Brain Project, an online cohort of community‐dwelling Australians aged 40‐70 years. Socioeconomic advantage was computed by matching participants’ residential address to the Australian Bureau of Statistics’ Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD), assigning each participant a decile score (10 being the most advantaged). Scores were related to dementia risk estimated using the CAIDE dementia risk score and cognitive performance measured with the Cogstate Brief Battery (CBB) in linear regression models.ResultsOf the 4798 participants (mean age±SD 56±7 years, 26% male), 2762 (58%) were classified as living within an area of high neighbourhood socioeconomic advantage (IRSAD scores ≥ 8th decile), 1296 resided in rural or regional areas (27%), and 984 identified as “non‐European” (21%). Each decile unit increase in neighborhood socioeconomic advantage was associated with a lower CAIDE dementia risk score (β±SE= ‐0.088±0.024, p &lt;0.001), following adjustments for race and rurality, and with better memory performance (β±SE= 0.084±0.024, p &lt;0.001), following adjustments for age, sex, race, education, and rurality. An interaction was observed with differences in memory performance between levels of neighborhood advantage (comparing scores above and below the 8th decile) being larger at older ages and in people with higher dementia risk scores (Figure 1). There was no association between neighborhood‐level advantage and attention.ConclusionsIn a middle‐aged Australian cohort, higher neighborhood‐level socioeconomic advantage was associated with superior memory and lower dementia risk scores. Efforts to lower dementia risk factors, particularly in relation to reducing the negative impacts of disadvantage, are needed to curtail the growing burden of dementia.

Does clinical data capture modifiable midlife risk factors for Alzheimer’s disease?

AbstractBackgroundThe 2020 Lancet Dementia Commission Report highlighted 5 modifiable midlife risk factors for dementia across multiple datasets: hearing loss, traumatic brain injury (TBI), hypertension, alcohol use, and obesity. We tested associations of these risk factors with Alzheimer’s disease (AD) 10 or more years later within clinical care data from a large health system.MethodWe used University of Pittsburgh Medical Center electronic health record data including diagnoses, demographics, social history, and medications from inpatient, outpatient, and emergency visits. Cases were aged 50‐75 at the time of a first ICD‐9 or 10‐based diagnosis of AD between 2016‐2020. Controls were age‐matched to cases 4:1, selected with replacement; they were free from neurodevelopmental, neurodegenerative, or demyelinating disorders, and had a visit from 2016‐2020. Cases and controls had at least one visit 10+ years prior (“early visit”). Risk factors from the early visit were defined as follows: hearing loss and TBI were based on diagnoses; obesity and hypertension were based on diagnoses or 2 measures of body mass index ≥ 30 or systolic blood pressure (BP) ≥ 140 and diastolic BP ≥ 90, respectively; alcohol use was based on diagnoses or self‐reported use ≥ 21 drinks/week. We tested associations of risk factors with AD using logistic regression models; results are presented as unadjusted odds ratios [95% confidence intervals].ResultParticipants had a mean age of 67 in 2016‐2020; N=2382 cases (56% female, 80% white, 19% Black) and N=9528 controls (58% female, 88% white, 10% Black). All midlife risk factors were associated with significantly increased odds of AD. In order of largest to smallest effect size: TBI, 4.5 [4.1, 5.0]; alcohol use, 3.5 [3.0, 4.0]; hypertension 2.6 [2.4, 2.9]. hearing loss, 1.9 [1.7, 2.1]; and obesity, 1.2 [1.1, 1.4]. Narrower definitions of alcohol use and TBI only slightly altered their respective effect sizes.ConclusionIn agreement with the Lancet Report, we find that these modifiable factors in late‐early to midlife are associated with AD. Information about these risk factors is already captured in clinical electronic health records and should be used to guide dementia risk reduction beginning early in midlife.

Disparities in dementia and AD biomarkers in the ARIC study: The important contribution of social determinants of health

AbstractBackgroundDementia disproportionately impacts people of color in the U.S.. Whether these disparities are due to differences in vascular risk factors, cognitive reserve, or AD pathophysiology remains unclear.MethodBlack and White participants from four U.S. communities were recruited into the Atherosclerosis Risk in Communities (ARIC) study at ages 45‐64. Vascular risk factors were evaluated in midlife and at multiple visits over 30+ years, as were markers of cognitive reserve, with expert classification of dementia. In participants with brain MRI, brain volumes were evaluated in association with dementia. In nondemented participants in the ARIC‐PET ancillary study, florbetapir PET scans were used to quantify brain cortical amyloid; differences in levels by race, vascular risk factors, and white matter hyperintensities (WMH) were evaluated.ResultIn 15744 ARIC participants, dementia was more common in Black vs White participants. Although midlife vascular risk factors were related to dementia, the impact of these risk factors on dementia risk and cortical volumes didn’t differ by race. Lower education was nonsignificantly more strongly associated with dementia in Blacks vs Whites, and an APOE e4 allele was more strongly associated with dementia in Whites. In ARIC‐PET (N=322), vascular risk factors from midlife were associated with PET amyloid, without similar associations for late‐life risk factors; these associations did not significantly differ by race. WMH volume was more strongly associated (cross‐sectionally) with PET amyloid in Blacks vs Whites, but differences were not statistically significantly different. Finally, Blacks had an over two‐fold increased odds of elevated florbetapir PET vs Whites, independent of vascular risk factors, demographics, WMH volume, cognitive status, and APOE genotype.ConclusionConsideration of racial disparities in dementia should consider vascular risk, cognitive reserve, and social determinants of health, across the life course. Vascular risk factors do not appear to differentially impact dementia risk or brain amyloid in Blacks vs Whites, but the greater prevalence of these risk factors in Blacks must be considered. Although the A/T/N framework may clarify underlying biology contributing to Alzheimer’s disease, inclusion of these additional factors is needed to understand and reduce racial disparities in dementia rates.

Association between dementia parental family history and mid-life modifiable risk factors for dementia: a cross-sectional study using propensity score matching within the Lifelines cohort

ObjectiveIndividuals with a parental family history (PFH) of dementia have an increased risk to develop dementia, regardless of genetic risks. The aim of this study is to investigate the association...

Midlife subclinical atherosclerosis and cardiovascular risk factors linked to hypometabolism in Alzheimer’s disease relevant regions

AbstractBackgroundAtherosclerosis has been linked to cognitive decline in late life; however, the impact of cardiovascular risk factors (CVRFs) and subclinical atherosclerosis on brain metabolism at earlier stages remains unexplored.MethodThis study, aimed at determining the association between brain metabolism, subclinical atherosclerosis and CVRFs in midlife, included 547 asymptomatic middle‐aged participants (50±4 years, 82% men) from the Progression of Early Subclinical Atherosclerosis study with evidence of subclinical atherosclerosis. Participants underwent 18F‐fluorodeoxyglucose‐positron emission tomography (FDG‐PET). Global brain FDG uptake and voxel‐wise analyses were used to evaluate the associations of cerebral metabolism with CVRFs and atherosclerotic plaque burden in carotids and femorals assessed by 3D‐vascular ultrasound.ResultGlobal FDG uptake showed an inverse correlation with 30‐year Framingham Risk Score (30y‐FRS) (β=‐0.15, p&lt;0.001). This association was mainly driven by the presence of hypertension (d=0.36, p&lt;0.001). Carotid plaque burden was inversely associated with global brain FDG uptake (β=‐0.16, p&lt;0.001), even after adjusting for 30y‐FRS. Voxel‐wise approaches revealed that the brain areas most strongly affected by hypometabolism in association with 30y‐FRS, hypertension, and carotid plaque burden were parietotemporal regions (angular, supramarginal, and inferior/middle temporal gyri) and the cingulate gyrus.ConclusionIn asymptomatic middle‐aged individuals, cardiovascular risk is associated with brain hypometabolism, with hypertension being the modifiable CVRF showing the strongest association. Subclinical carotid plaque burden is also linked to reduced brain metabolism independently of CVRFs. Cerebral areas showing hypometabolism include mainly those known to be affected in Alzheimer´s disease. These results suggest that the interplay between cardiovascular disease and altered brain metabolism starts early in life, many years before the clinical manifestation. Understanding the extent to which cardiovascular risk factors influence brain´s vulnerability early in the course of atherosclerosis may help to refine preventive strategies and reduce the incidence of dementia in late life.

Embedding audiological screening within memory clinic care pathway for individuals at risk of cognitive decline\u2014patient perspectives

BackgroundWith the evolving knowledge on hearing as a potentially modifiable mid-life risk factor for dementia, identification of people at risk becomes increasingly important. People with mild cognitive impairment (MCI) presenting to specialist memory services represent a key “at-risk” target population for audiological evaluation, but few services have established this pathway. This study sought to examine the patient experience and understanding of this process.MethodsAll patients with MCI attending a tertiary referral memory service referred for audiology review were contacted. A patient survey was delivered over the phone. Outpatient letters and the memory clinic database were reviewed.ResultsTwenty patients with MCI were included in the survey. Eight (8/20, 40%) had self-reported hearing loss. Upon formal audiological assessment seventeen (17/20, 85%) had objective evidence of hearing loss; nine (9/17, 52.9%) with mild-moderate and eight (8/17, 47%) with moderate-severe hearing loss. Only six patients (6/20, 30%) recalled having the rationale behind having a hearing test as part of their memory work-up explained to them. However, the majority (15/20, 75%) felt a hearing test was an important part of their memory assessment. Just seven patients overall (7/20, 35%) identified a link between hearing-loss and cognition. All patients who provided feedback on the service itself made positive comments, although (4/20, 20%) felt they did not get adequate information about the results.ConclusionsA significant proportion of people with MCI had de-novo evidence of hearing impairment upon assessment. Patients are satisfied with incorporating audiological evaluation into a memory clinic assessment, however clear communication around indication, recommendations, and follow-up ensuring compliance is required.

Effects of menopause on cognitive deficits in a mouse model of metabolic disease.

By 2025, it is estimated that nearly 20% of the U.S. population will be post-menopausal women. Menopause accelerates metabolic disease, a major mid-life risk factor for dementia. Indeed, ∼80% of those with dementia have concurrent metabolic disease and nearly all women with dementia are post-menopausal. We hypothesize that menopause will exacerbate the metabolic and cognitive effects of a high fat diet. Using young-adult and middle-aged C57BL/6J female mice (N= 9-15/group), we modeled metabolic disease via chronic administration of high fat (HF; 60%) diet vs. low fat (LF; 10% fat) control diet. We modeled menopause via daily injections of 4-vinylcyclohexene diepoxide (VCD), which results in accelerated ovarian failure vs. vehicle. To confirm menopause, we performed daily vaginal cytology. We performed a glucose tolerance test (GTT) at 2.5 months and 7 months on the diet. We assessed deficits in spatial memory (object place recognition test) and episodic-like memory (novel object recognition test). There was a main effect of menopause in increasing glucose intolerance, and % weight gain. Longer time in menopause was associated with greater visceral fat accumulation in HF-fed mice. Spatial memory and episodic-like memory were impaired by age, high fat diet, and menopause. The spatial memory deficits were worse in middle-aged menopausal mice compared to the young menopausal mice. Our data show that post-menopausal mice have greater metabolic impairment than pre-menopausal mice, regardless of age. However, deficits in spatial memory due to HF diet or menopause increase with age. This is in line with clinical data showing that post-menopausal women are more susceptible to metabolic disease and are at increased risk for cognitive impairment and dementia. Altogether, our data highlight the importance of considering endocrine age distinctly from chronological age in studies of dementia.

The impacts of menopause on a mouse model of co‐morbid metabolic syndrome and Alzheimer’s disease

Alzheimer's disease (AD) is the leading cause of disability and 5th cause of death in people over 65 years of age. Approximately 2/3 of AD patients are women, most of whom are postmenopausal. Menopause is linked with cognitive changes in women: younger age at menopause is associated with worse cognitive outcomes. Moreover, menopause accelerates mid-life risk factors for dementia, by increasing risk for cardiovascular and cerebrovascular disease and metabolic disease which is by itself a risk factor for dementia. We have previously shown that female 3xTg-AD mice are more greatly impacted cognitively and metabolically by a high fat diet when compared to males. We therefore hypothesized that menopause would exacerbate both metabolic and cognitive impairment and pathology in a mouse model of AD. Female App NL-F mice were placed on either low fat (LF; 10% fat) or high fat (HF; 60% fat; metabolic disease model) diet for 7 months. An accelerated ovarian failure model of menopause (4-vinylcyclohexene diepoxide) was used at diet onset and female estrus cycles were monitored to determine menopause onset. Metabolic status was assessed by tracking weight gain and assessing glucose tolerance. Mice were then subjected to a battery of behavioral tests before being euthanized and brains and serum were collected. Menopausal mice tended to be more metabolically impaired (worse glucose tolerance) regardless of diet. Cognitive impairment differences between groups were investigated using several behavioral tests. Neither menopause nor HF diet affected anxiety-like behavior (open field testing), however HF diet decreased general activity levels. Novel object recognition testing demonstrated that menopause, regardless of diet, impaired episodic-like memory. Additionally, HF diet, regardless of menopause, impaired spatial learning (assessed via Barnes maze testing). We are currently evaluating the underlying pathology in the brain that could mediate these cognitive deficits (i.e. Amyloid pathology, white matter damage and neuroinflammation). We hope that this work will highlight the need to model endocrine aging in animal models of dementia and will contribute to further understanding of the interaction between metabolic disease and menopause in the scope of AD.

The cumulative effect of cognitive engagement on cognitive function in middle‐aged adults

AbstractBackgroundEngagement in cognitively stimulating work and activities is proposed to slow cognitive decline and delay dementia. Few studies have considered the cumulative effect of multiple cognitively engaging factors on cognitive function. In middle‐aged adults, this study aimed to determine the individual and combined associations of four cognitive engagement factors (i.e., educational attainment, occupational complexity, social engagement and cognitively stimulating leisure activities) with objectively measured cognitive performance and subjective ratings of cognitive function.MethodA total of 1864 cognitively normal middle‐aged adults (aged 40‐70) enrolled in the Healthy Brain Project, a study with an online remote assessment platform seeking to understand midlife risk factors for dementia. Cognitive engagement factors were measured by online self‐report questionnaires. The Cogstate Brief Battery was used to measure cognitive domains of attention and memory. Subjective ratings of cognitive function were measured using the Cognitive Function Instrument.ResultAfter controlling for age, sex, ethnicity and mood symptomatology, participants with high educational attainment or high occupational complexity performed significantly better on attention and memory tasks and reported less subjective ratings of cognitive concern. Higher participation in cognitively engaging leisure activities was significantly associated with better attention and memory performance, but not with subjective ratings of cognitive function. Social engagement was not associated with any outcome. The magnitude of these effects was small and trivial (Cohen’s d ranging from 0‐0.17). Participants were then classified into five groups based on whether they rated highly in 0‐4 cognitive engagement factors. Compared to participants with no factors, participants scoring highly in 2 or more factors performed significantly better on the memory tasks, with the magnitude of difference moderate (Cohen’s d ranging from 0.30‐0.49).ConclusionThese results suggest a cumulative relationship between high cognitive engagement across several domains of life and better memory performance in cognitively normal middle‐aged adults.

Abstract 13428: Mid-Life and Late-Life Exposure to Traditional Cardiovascular Risk Factors and Zero Coronary Artery Calcium: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Our understanding of traditional atherosclerotic risk factors is largely based on their contributions to adverse atherosclerotic events. However, the relative contributions of mid-life and late-life risk factor exposures to persistent zero coronary artery calcium (CAC=0) in older adulthood, a representative healthy vascular aging phenotype, have not been fully examined. Hypothesis: Both mid-life and late-life risk factors are associated with CAC=0, with stronger results for the former. Methods: Using data from 2,035 community-dwelling participants free of coronary heart disease in the ARIC study, we evaluated traditional modifiable risk factors (i.e., lipids, systolic blood pressure, obesity, smoking, and diabetes) at mid-life (median age 49, visit 1 from 1987-1989) and late-life (median age 73, visit 5 from 2011-2013) and their associations with CAC=0 at visit 7 (median age 80, from 2018-2019), using multivariable logistic regression models adjusted for within-visit factors. Results: There were 204 participants (10.0%) with CAC=0. Compared with participants with any CAC, those with CAC=0 had more favorable values for most traditional risk factors (lower cholesterol, BMI, and systolic blood pressure, higher HDL-C, and not smoking) in both mid-life and late-life, with the exception of fasting glucose ( Table ). The results were similar when we modeled diabetes instead of fasting glucose. Lower total cholesterol in mid-life, but not late-life, was associated with CAC=0. Conclusions: Having favorable modifiable risk factors both at mid-life and late-life were independently associated with CAC=0 in older adults free of clinical coronary heart disease. These results highlight the importance of maintaining a healthy risk factor profile from mid-life, with implications on public health promotion and strategy.

Abstract 14336: Association of Mid-Life Cardiovascular Disease and Late-Life Alzheimer's Disease Pathology: Insights From Heart Score Study

Introduction: Data show an association of CVD risk factors in mid-life with older age dementia. Atherosclerosis (ATH) and arteriosclerosis (ART) are both implicated in incident dementia however their relationship with incident Alzheimer’s disease (AD) remains elusive. We investigated the association of mid-life cardiovascular risk factors and mid-life subclinical CVD (ATH and ART) with late-life AD pathology. Methods: Non-demented participants over the age of 65 from the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study underwent brain PET acquisition (2018-2020) for AD specific amyloid deposition [by Pittsburgh Compound B (PiB)]. Pearson’s correlation and OR (95% CI) using Cox regression for association of cortical PiB retention with mid-life (2003-2005) markers of ATH (coronary artery calcium [CAC] score and carotid intima thickness [CIMT]) and ART (vascular stiffness) were calculated. Results: Among 121 participants in late-life (mean age ~79y), age was significantly correlated to lower cognition ( r =0.19, p=0.03) but gender, race and diabetes were not. Late-life AD pathology was not significantly associated with mid-life CAC (&gt;150) [OR=0.12 (0.01, 2.36); p=0.16] or CIMT [OR=1.80 (0.84, 3.86); p=0.40]. Presence of increased vascular stiffness in mid-life showed a significant association with late-life PiB retention (Table ). Conclusions: In a small number of biracial middle-aged adults, subclinical markers of atherosclerosis did not independently predict increased biomarkers of AD pathology. However, vascular stiffness in mid-life was significantly associated with late-life brain biomarkers of Alzheimer’s disease pathology. Further research can elucidate the role of mid-life athero- and arteriosclerosis in Alzheimer's disease dementia.

A Modified CAIDE Risk Score as a Screening Tool for Cognitive Impairment in Older Adults.

Although an efficacious dementia-risk score system, Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) was derived using midlife risk factors in a population with low educational attainment that does not reflect today's US population, and requires laboratory biomarkers, which are not always available. Develop and validate a modified CAIDE (mCAIDE) system and test its ability to predict presence, severity, and etiology of cognitive impairment in older adults. Population consisted of 449 participants in dementia research (N = 230; community sample; 67.9±10.0 years old, 29.6%male, 13.7±4.1 years education) or receiving dementia clinical services (N = 219; clinical sample; 74.3±9.8 years old, 50.2%male, 15.5±2.6 years education). The mCAIDE, which includes self-reported and performance-based rather than blood-derived measures, was developed in the community sample and tested in the independent clinical sample. Validity against Framingham, Hachinski, and CAIDE risk scores was assessed. Higher mCAIDE quartiles were associated with lower performance on global and domain-specific cognitive tests. Each one-point increase in mCAIDE increased the odds of mild cognitive impairment (MCI) by up to 65%, those of AD by 69%, and those for non-AD dementia by > 85%, with highest scores in cases with vascular etiologies. Being in the highest mCAIDE risk group improved ability to discriminate dementia from MCI and controls and MCI from controls, with a cut-off of ≥7 points offering the highest sensitivity, specificity, and positive and negative predictive values. mCAIDE is a robust indicator of cognitive impairment in community-dwelling seniors, which can discriminate well between dementia severity including MCI versus controls. The mCAIDE may be a valuable tool for case ascertainment in research studies, helping flag primary care patients for cognitive testing, and identify those in need of lifestyle interventions for symptomatic control.

Associations of telomere length at birth with predicted atherosclerotic lesions and cardiovascular disease risk factors in midlife: A 40-year longitudinal study

Background and aimsAdult telomere length (TL) is substantially determined by birth TL, but associations of birth TL with cardiovascular disease (CVD) are unknown. MethodsWe included 144 adult offspring born in 1959–1966 from the Collaborative Perinatal Project, a US birth cohort. Birth TL was measured from banked cord blood with quantitative polymerase chain reaction. Atherosclerotic lesions were predicted by the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) score that was based on blood pressure, lipids, hemoglobin A1c, and body weight at the midlife follow-up in 2003–2008 (average age: 42 years). Information on midlife CVD risk factors including the age at first diagnoses of hypertension, hypercholesterolemia, and diabetes was also collected. We used linear and logistic regression models to analyze associations of birth TL with the continuous PDAY score and categorical CVD risk factors, respectively, adjusting for prenatal confounders. ResultsAt midlife follow-up, 31.2% and 18.7% of participants had ever been diagnosed with hypercholesterolemia and hypertension, respectively, and 8.3% met the criteria for metabolic syndrome. Short birth TL (Quartile 1, Q1) was associated with a higher PDAY score (adjusted β: 1.78, 95% CI: 0.31, 3.25), increased odds of hypercholesterolemia (adjusted odds ratio [OR]: 3.23, 95% CI: 1.28, 8.18) and the presence of any cardiometabolic abnormalities (adjusted OR: 2.54, 95% CI: 1.00, 6.48) as compared to longer birth TL (Q2-Q4) after adjusting for prenatal confounders. ConclusionsPeople born with short TL may be at increased risk of predicted midlife atherosclerotic lesions and hypercholesterolemia. Future studies with larger sample sizes and CVD morbidities are warranted to replicate our findings.

Midlife Vascular Factors and Prevalence of Mild Cognitive Impairment in Late-Life in Mexico.

To estimate the prevalence of mild cognitive impairment (MCI) and its subtypes and investigate the impact of midlife cardiovascular risk factors on late-life MCI among the aging Mexican population. Analyses included a sample of non-demented adults over the age of 55 living in both urban and rural areas of Mexico (N = 1807). MCI diagnosis was assigned based on a comprehensive cognitive assessment assessing the domains of memory, executive functioning, language, and visuospatial ability. The normative sample was selected by means of the robust norms approach. Cognitive impairment was defined by a 1.5-SD cut-off per cognitive domain using normative corrections for age, years of education, and sex. Risk factors included age, education, sex, rurality, depression, insurance status, workforce status, hypertension, diabetes, stroke, and heart disease. The prevalence of amnestic MCI was 5.9%. Other MCI subtypes ranged from 4.2% to 7.7%. MCI with and without memory impairment was associated with older age (OR = 1.01 [1.01, 1.05]; OR = 1.03 [1.01, 1.04], respectively) and residing in rural areas (OR = 1.49 [1.08, 2.06]; OR = 1.35 [1.03, 1.77], respectively). Depression (OR = 1.07 [1.02, 1.12]), diabetes (OR = 1.37 [1.03, 1.82]), and years of education (OR = 0.94 [0.91, 0.97]) were associated with MCI without memory impairment. Midlife CVD increased the odds of MCI in late-life (OR = 1.76 [1.19, 2.59], which was driven by both midlife hypertension and diabetes (OR = 1.70 [1.18, 2.44]; OR = 1.88 [1.19, 2.97], respectively). Older age, depression, low education, rurality, and midlife hypertension and diabetes were associated with higher risk of late-life MCI among older adults in Mexico. Our findings suggest that the causes of cognitive impairment are multifactorial and vary by MCI subtype.