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Background: Cardiovascular health may be used for prevention of cerebral vascular disease; however, data on the association of cardiovascular health across midlife and late-life with late-life cerebral vascular disease are lacking. Our aim was to examine whether midlife or late-life cardiovascular health as well as changes of cardiovascular health within midlife and between midlife and late-life were associated with prevalence of magnetic resonance imaging markers of cerebral vascular disease at late-life. Methods: Prospective cohort study including 1638 participants from the Atherosclerosis Risk in Communities Study who took part in 2 visits at midlife (mean ages, 53 and 59 years), and a late-life visit (mean age, 76 years). A cardiovascular health Life’s Simple 7 score (range, 0–12/0–14, depending on diet availability) including 6 out of 7 items was calculated at each visit, with weight assigned to each item as poor (0), intermediate (1), or ideal (2). Participants underwent 3T brain magnetic resonance imaging scans in late-life visit. Outcomes were white matter hyperintensity volume, microbleeds, and lacunar, subcortical, and cortical infarcts at late-life. Linear and logistic regression models were used to assess the associations of cardiovascular health in midlife and late-life, and improvement of cardiovascular health within midlife, and from midlife to late-life with magnetic resonance imaging markers of cerebral vascular disease, adjusting for potential confounders. Results: A higher cardiovascular health in midlife, improvement of cardiovascular health within midlife, higher cardiovascular health at late-life, and improvement of cardiovascular health from midlife to late-life were associated with a lower prevalence of cerebral vascular disease markers. For example, improvement in cardiovascular health (per point) from midlife to late-life was associated with smaller white matter hyperintensity volume (β, −0.07 [95% CI, −0.10 to −0.04]) and lower odds of microbleeds (odds ratio, 0.93 [0.90–0.97]), lacunar (odds ratio, 0.93 [0.89–0.97]), subcortical (odds ratio, 0.93 [0.89–0.97]), and cortical infarcts (odds ratio, 0.92 [0.87–0.97]). Conclusions: Improving cardiovascular health within midlife and from midlife to late-life may prevent development of cerebral vascular disease.

We evaluated whether better cardiovascular health at midlife and improvement of cardiovascular health within midlife were associated with dementia risk.Two longitudinal population-based studies were used: Atherosclerosis Risk in Communities (ARIC) (n = 11,460/visits at ages 54 and 60), and Age, Gene/Environment Susceptibility (AGES)-Reykjavik (n = 3907/visit at age 51). A cardiovascular health score (range 0-12/0-14, depending on diet availability) including six/seven items was calculated at each visit, with weight assigned to each item as poor (0), intermediate (1), or ideal (2). Cardiovascular health was defined as low (score 0-4/0-5), intermediate (5-7/6-9), or high (8-12/10-14). Incident dementia was ascertained through linkage to health records and with neuropsychological examinations.Midlife high compared to low cardiovascular health (hazard ratios [HRs]: for ARIC: 0.60 [95% confidence interval: 0.52, 0.69]); for AGES-Reykjavik: 0.83 [0.66, 0.99] and improvement of cardiovascular health score within midlife (HR per one-point increase: ARIC: 0.94 [0.92, 0.96]) were associated with lower dementia risk.Better cardiovascular health at midlife and improvement of cardiovascular health within midlife are associated with lower dementia risk.Cardiovascular health and dementia were studied in two large cohort studies. Better cardiovascular health at midlife relates to lower dementia risk. Improvement of cardiovascular health within midlife relates to lower dementia risk. Promotion of cardiovascular health at midlife can help to reduce dementia risk.

Background: Ethnic differences in cognitive decline have been reported. Whether they can be explained by differences in systolic blood pressure (SBP) is uncertain. Objective: Determine whether cumulative mean SBP levels explain differences in cognitive decline between Hispanic and White individuals. Methods: Pooled cohort study of individual participant data from six cohorts (1971–2017). The present study reports results on SBP and cognition among Hispanic and White individuals. Outcomes were changes in global cognition (GC) (primary), executive function (EF) (secondary), and memory standardized as t-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1 SD difference in cognition. Median follow-up was 7.7 (Q1–Q3, 5.2–20.1) years. Results: We included 24,570 participants free of stroke and dementia: 2,475 Hispanic individuals (median age, cumulative mean SBP at first cognitive assessment, 67 years, 132.5 mmHg; 40.8% men) and 22,095 White individuals (60 years,134 mmHg; 47.3% men). Hispanic individuals had slower declines in GC, EF, and memory than White individuals when all six cohorts were examined. Two cohorts recruited Hispanic individuals by design. In a sensitivity analysis, Hispanic individuals in these cohorts had faster decline in GC, similar decline in EF, and slower decline in memory than White individuals. Higher time-varying cumulative mean SBP was associated with faster declines in GC, EF, and memory in all analyses. After adjusting for time-varying cumulative mean SBP, differences in cognitive slopes between Hispanic and White individuals did not change. Conclusion: We found no evidence that cumulative mean SBP differences explained differences in cognitive decline between Hispanic and White individuals.

We assessed whether carotid intima-media thickness (cIMT) is prospectively associated with amyloid-β (Aβ). 332 nondemented Atherosclerosis Risk in Communities Study participants with carotid ultrasounds (1990–1992) and PET scans (2012–2014) were studied. Participants in the highest (versus lowest) cIMT tertile had 2.17 times the odds of elevated Aβ (95% CI: 1.15–4.11), after demographic and APOE ɛ4 adjustments. An interaction with APOE ɛ4 was observed (p = 0.02). Greater cIMT was associated with elevated Aβ independent of vascular risk factors among those with ≥1 APOE ɛ4 allele, but not in noncarriers. In this cohort, higher cIMT was associated with Aβ deposition 22 years later, particularly among APOE ɛ4 carriers.

BackgroundSubclinical cardiovascular disease (CVD) measures may reflect biological pathways that contribute to increased risk for coronary heart disease (CHD) events, stroke, and dementia beyond conventional risk scores.MethodsThe Multi-Ethnic Study of Atherosclerosis (MESA) followed 6,814 participants (45-84 years of age) from baseline in 2000-2002 to 2018 over 6 clinical examinations and annual follow-up interviews. MESA baseline subclinical CVD procedures included: seated and supine blood pressure, coronary calcium scan, radial artery tonometry, and carotid ultrasound. Baseline subclinical CVD measures were transformed into z-scores before factor analysis to derive composite factor scores. Time to clinical event for all CVD, CHD, stroke and ICD code-based dementia events were modeled using Cox proportional hazards models reported as area under the curve (AUC) with 95% Confidence Intervals (95%CI) at 10 and 15 years of follow-up. All models included all factor scores together and adjustment for conventional risk scores for global CVD, stroke, and dementia.ResultsAfter factor selection, 24 subclinical measures aggregated into four distinct factors representing: blood pressure, arteriosclerosis, atherosclerosis, and cardiac factors. Each factor significantly predicted time to CVD events and dementia at 10 and 15 years independent of each other and conventional risk scores. Subclinical vascular composites of arteriosclerosis and atherosclerosis best predicted time to clinical events of CVD, CHD, stroke, and dementia. These results were consistent across sex and racial and ethnic groups.ConclusionsSubclinical vascular composites of arteriosclerosis and atherosclerosis may be useful biomarkers to inform the vascular pathways contributing to events of CVD, CHD, stroke, and dementia.

Introduction: We and others observed that social distancing enforced early in the COVID-19 pandemic led to an increase in loneliness, a social condition associated with adverse mental and physical health outcomes. Here, we examine longitudinal changes in perceived loneliness over the first two years of the COVD-19 pandemic among older adults participating in the Atherosclerosis Risk in Communities (ARIC) Study. Hypothesis: Perceived loneliness decreased over the course of the pandemic. Methods: The UCLA 3-item Loneliness questionnaire, which assesses lack of companionship, feeling left out, and feeling isolated, to classify level of perceived loneliness, was administered to ARIC participants in March-October 2020 and again in August 2020-March 2022 as part of the Colllaborative Cohort of Cohorts for COVID-19 Research (C4R). Prepandemic measures (Jan-March 2020) were available in a subset. For each item, response categories “hardly ever”, “some of the time” and “often” were scored from 1 to 3, respectively, and added to create a final score ranging from 3 to 9 (higher scores indicating greater loneliness). T-tests were used to compare mean loneliness score values between the measurement periods. Mixed effects linear regression models were fit to examine predictors of change in the loneliness score. Results: Among 2,335 ARIC cohort participants with repeat assessments of loneliness during the COVID-19 pandemic (mean age 82.4 (SD 4.4) years, 64.8% female, 18.5% Black), mean perceived loneliness score decreased from 4.40 (SD 1.51) to 3.78 (SD 1.25) (p-value Conclusion: Despite reporting greater loneliness during the first six months of the COVID-19 pandemic compared to the time prior to the pandemic, older adults reported similar levels of perceived loneliness in the second year of the pandemic compared to pre-pandemic levels. In particular, Black race and and male sex were associated with greater reductions in loneliness over the pandemic period. These results suggest that older adults were psychologically resilient with respect to the extreme social changes associated with the COVID-19 pandemic.

Introduction: Diabetes is associated with both dementia and death. Ignoring the competing risk of mortality may result in overestimation of the lifetime of dementia. Hypothesis: The lifetime cumulative incidence of dementia associated with diabetes will be much lower when taking into account the competing risk of mortality, particularly at the oldest ages. Methods: We conducted a prospective cohort analysis of data from the Atherosclerosis Risk in Communities (ARIC) Study (midlife baseline at visit 2, 1990-1992). Diabetes was defined as a self-reported physician diagnosis, diabetes medication use, or HbA1C of 6.5% or greater. Incident dementia was ascertained via active surveillance involving interviews and adjudication. We conducted survival analysis using age as the time scale with age 50 as the origin and December 31st, 2019 as the administrative censoring date. Dementia risk was analyzed with death treated as a censoring event or as a competing risk. Results: Among 13,381 participants, 1798 (13.4%) had diabetes at baseline (mean age: 56.8 years). Using a standard Cox model, diabetes was associated with an increased hazard of dementia (HR 1.36; 95% CI 1.21, 1.52) and death (HR 1.87; 95% CI 1.76, 1.99). Censoring mortality (ignoring competing risk), diabetes was associated with a higher cumulative incidence of dementia at all ages ( Figure A ). Competing risk models showed a lower risk of dementia than models censoring death. Furthermore, diabetes was associated with a higher risk of dementia only before age 85 but a lower cumulative risk after age 85 due to the large excess risk of mortality ( Figures B and C ). Conclusion Standard methods dramatically overestimate the lifetime risk of dementia in persons with and without diabetes. Competing risk models are critical for accurate absolute risk estimates, particularly in the oldest ages. Interventions which increase life expectancy in patients with diabetes may increase the cumulative risk of dementia in old age.

Introduction: Cardiovascular health may be used for prevention of cerebral vascular disease. We evaluated whether improvement of cardiovascular health within midlife and from midlife to late-life were each associated with lower prevalence of MRI markers of cerebral vascular disease at late-life. Methods: 1,638 participants from the Atherosclerosis Risk in Communities (ARIC) Study took part in two visits at midlife (mean ages 53 at ARIC visit 1 and 59 at visit 3), and a late-life visit (mean age 76). A cardiovascular health Life’s Simple 7 score (range 0-12/0-14, depending on diet availability) including six/seven items was calculated at each visit, with weight assigned to each item as poor (0), intermediate (1), or ideal (2). Participants underwent 3T brain MRI scans in 2011-2013 (late-life visit). Outcomes were white matter hyperintensity volume, microbleeds, and lacunar, subcortical, and cortical infarcts at late-life. Linear and logistic regression models were used to assess the associations of cardiovascular health with MRI markers of cerebral vascular disease. Results: Thirty nine percent of participants had high cardiovascular health at midlife visit 1, 32% at midlife visit 3, and 33% at late-life. Improvement of cardiovascular health within midlife and from midlife to late-life were each associated with a lower prevalence of cerebral vascular disease markers. For example, improvement in cardiovascular health (per point) from midlife to late-life was associated with smaller white matter hyperintensity volume (Beta:-0.07 [95%CI:-0.10,-0.04]), and lower odds of microbleeds (OR:0.93 [0.90,0.97]), lacunar (OR:0.93 [0.89,0.97)], subcortical (OR:0.93 [0.89,0.97])], and cortical infarcts (OR:0.92 [0.87,0.97)] (Figure). Conclusions: Improving cardiovascular health within midlife and from midlife to late-life may prevent development of cerebral vascular disease.

Background and ObjectivesThere are disparities in the prevalence of obesity by race, and the relationship between obesity and cognitive decline is unclear. The objective of this study was to determine whether obesity is independently associated with cognitive decline and whether the association between obesity and cognitive decline differs in Black and White adults. We hypothesized that obesity is associated with greater cognitive decline compared with normal weight and that the effect of obesity on cognitive decline is more pronounced in Black adults compared with their White counterparts.MethodsWe pooled data from 28,867 participants free of stroke and dementia (mean, SD: age 61 [10.7] years at the first cognitive assessment, 55% female, 24% Black, and 29% obese) from 6 cohorts. The primary outcome was the annual change in global cognition. We performed linear mixed-effects models with and without time-varying cumulative mean systolic blood pressure (SBP) and fasting plasma glucose (FPG). Global cognition was set to a t-score metric (mean 50, SD 10) at a participant's first cognitive assessment; a 1-point difference represents a 0.1 SD difference in global cognition across the 6 cohorts. The median follow-up was 6.5 years (25th percentile, 75th percentile: 5.03, 20.15).ResultsObese participants had lower baseline global cognition than normal-weight participants (difference in intercepts, −0.36 [95% CI, −0.46 to −0.17];p< 0.001). This difference in baseline global cognition was attenuated but was borderline significant after accounting for SBP and FPG (adjusted differences in intercepts, −0.19 [95% CI, −0.39 to 0.002];p= 0.05). There was no difference in the rate of decline in global cognition between obese and normal-weight participants (difference in slope, 0.009 points/year [95% CI, −0.009 to 0.03];p= 0.32). After accounting for SBP and FPG, obese participants had a slower decline in global cognition (adjusted difference in slope, 0.03 points/year slower [95% CI, 0.01 to 0.05];p< 0.001). There was no evidence that race modified the association between body mass index and global cognitive decline (p= 0.34).DiscussionThese results suggest that obesity is associated with lower initial cognitive scores and may potentially attenuate declines in cognition after accounting for BP and FPG.

ImportanceFactors associated with the risk of dementia remain to be fully understood. Systemic infections are hypothesized to be such factors and may be targets for prevention and screening.ObjectiveTo investigate the association between hospitalization with infection and incident dementia.Design, Setting, and ParticipantsData from the community-based Atherosclerosis Risk in Communities (ARIC) study, a prospective cohort study, were used. Enrollment occurred at 4 research centers in the US, initiated in 1987 to 1989. The present study includes data up to 2019, for 32 years of follow-up. Data analysis was performed from April 2021 to June 2022.ExposuresHospitalizations with infections were identified via medical record review for selected International Classification of Diseases, Ninth Revision (ICD-9) and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes, from baseline until administrative censoring or dementia diagnosis. Participants were considered unexposed until first hospitalization with infection and exposed thereafter. Selected infection subtypes were also considered.Main Outcomes and MeasuresIncident dementia and time-to-event data were identified through surveillance of ICD-9 and ICD-10 hospitalization and death certificate codes, in-person assessments, and telephone interviews. A sensitivity analysis was conducted excluding cases occurring within 3 years or beyond 20 years from exposure. Data were collected before study hypothesis formulation.ResultsOf the 15 792 ARIC study participants, an analytical cohort of 15 688 participants who were dementia free at baseline and of Black or White race were selected (8658 female [55.2%]; 4210 Black [26.8%]; mean [SD] baseline age, 54.7 [5.8] years). Hospitalization with infection occurred among 5999 participants (38.2%). Dementia was ascertained in 2975 participants (19.0%), at a median (IQR) of 25.1 (22.2-29.1) years after baseline. Dementia rates were 23.6 events per 1000 person-years (95% CI, 22.3-25.0 events per 1000 person-years) among the exposed and 5.7 events per 1000 person-years (95% CI, 5.4-6.0 events per 1000 person-years) among the unexposed. Patients hospitalized with infection were 2.02 (95% CI, 1.88-2.18; P P P APOE-ε genotype.Conclusions and RelevanceHigher rates of dementia were observed among participants who experienced hospitalization with infection. These findings support the hypothesis that infections are factors associated with higher risk of dementias.

Background: Reduced kidney function is related to brain atrophy and higher risk of dementia. It is not known whether kidney impairment is associated with higher levels of circulating amyloid-β and brain amyloid-β deposition, which could contribute to elevated risk of dementia. Objective: To investigate whether kidney impairment is associated with higher levels of circulating amyloid-β and brain amyloid-β deposition. Methods: This cross-sectional study was performed within the community–based Atherosclerosis Risk in Communities (ARIC) Study cohort. We used estimated glomerular filtration rate (eGFR) based on serum creatinine and cystatin C levels and urine albumin-to-creatinine ratio (ACR) to assess kidney function. Amyloid positivity was defined as a standardized uptake value ratios > 1.2 measured with florbetapir positron emission tomography (PET) (n = 340). Plasma amyloid-β1 - 40 and amyloid-β1 - 42 were measured using a fluorimetric bead-based immunoassay (n = 2,569). Results: Independent of demographic and cardiovascular risk factors, a doubling of ACR was associated with 1.10 (95% CI: 1.01,1.20) higher odds of brain amyloid positivity, but not eGFR (odds ratio per 15 ml/min/1.73 m2 lower eGFR: 1.08; 95% CI: 0.95,1.23). A doubling of ACR was associated with a higher level of plasma amyloid-β1 - 40 (standardized difference: 0.12; 95% CI: 0.09,0.14) and higher plasma amyloid-β1 - 42 (0.08; 95% CI: 0.05,0.10). Lower eGFR was associated with higher plasma amyloid-β1 - 40 (0.36; 95% CI: 0.33,0.39) and higher amyloid-β1 - 42 (0.32; 95% CI: 0.29,0.35). Conclusion: Low clearance of amyloid-β and elevated brain amyloid positivity may link impaired kidney function with elevated risk of dementia. kidney function should be considered in interpreting amyloid biomarker results in clinical and research setting.

This scientific commentary refers to ‘Cerebrovascular insulin receptors are defective in Alzheimer’s disease’ by Leclerc et al. (https://doi.org/10.1093/brain/awac309).

ObjectivesEvaluate neurocognitive health and its response to interventions in older, obese patients with heart failure with preserved ejection fraction (HFpEF).BackgroundNeurocognitive dysfunction may be an underrecognized feature of HFpEF that responds to weight-loss interventions.MethodsWe first compared detailed baseline cognitive testing (Uniform Data Set version 3 and Rey Auditory Verbal Learning Test [RAVLT]), and brain volumes and cerebral blood flow (CBF) from 3T magnetic resonance imaging between older patients with HFpEF (n=46) and healthy age-matched controls (HC; n=22). The HFpEF patients were then randomized to a 20-week caloric restriction (CR) intervention with either aerobic-only (CR+AT; n=23) or aerobic+resistance exercise training (CR+AT+RT; n=23), and repeated cognitive testing and neuroimaging post-intervention. Cognitive scores were normalized to national data and transformed toz-scores for global, memory, attention, executive function, visuospatial, and language fluency domains.ResultsCompared to HC, participants with HFpEF had significantly lower baseline global cognitive performance, and lower global, visuospatial processing and language fluency domainz-scores than normative means. Following the diet and exercise intervention, there were significant improvements in global (+0.6 [95% CI: 0.3, 0.8]) and category fluency (+0.2 [95% CI: −0.004, 0.3])z-scores, and in RAVLT immediate (+0.6 [95% CI: 0.1, 1.0] points) and delayed (0.9 [95% CI: 0.2, 1.6] points) recall. Only CR+AT+RT was associated with improved phonemic fluency z-score (+0.4 [95% CI: 0.1, 0.7]). There were no significant intervention effects on brain volumes or CBF.ConclusionsOlder, obese patients with chronic HFpEF have significant cognitive deficits that are ameliorated by diet and exercise interventions.

IntroductionThe burden of Alzheimer’s disease (AD) and AD-related dementias (ADRD) is increasing nationally and globally, with disproportionate impacts on lower-income, lower education and systematically marginalised older adults. Presence of inequalities in neighbourhood factors (eg, social context, physical and built environments) may affect risk of cognitive decline and be key for intervening on AD/ADRD disparities at the population level. However, existing studies are limited by a dearth of longitudinal, detailed neighbourhood measures linked to rich, prospective cohort data. Our main objective is to identify patterns of neighbourhood change related to prevalence of—and disparities in—cognitive decline and dementia.Methods and analysesWe describe the process of collecting, processing and linking extensive neighbourhood data to the Multi-Ethnic Study of Atherosclerosis (MESA), creating a 25+ years dataset. Within the MESA parent study, the MESA Neighborhoods and Aging cohort study will characterise dynamic, longitudinal neighbourhood social and built environment variables relevant to cognition for residential addresses of MESA participants. This includes administering new surveys, expanding residential address histories, calculating new measures derived from spatial data and implementing novel deep learning algorithms on street-level imagery. Applying novel statistical techniques, we will examine associations of neighbourhood environmental characteristics with cognition and clinically relevant AD/ADRD outcomes. We will investigate determinants of disparities in outcomes by socioeconomic position and race/ethnicity and assess the contribution of neighbourhood environments to these disparities. This project will provide new evidence about pathways between neighbourhood environments and cognitive outcomes, with implications for policies to support healthy ageing.Ethics and disseminationThis project was approved by the University of Washington and Drexel University Institutional Review Boards (protocols #00009029 and #00014523, and #180900605). Data will be distributed through the MESA Coordinating Center. Findings will be disseminated in peer-reviewed scientific journals, briefs, presentations and on the participant website.

Background Vascular risk scores are associated with incident dementia. Information regarding their association with cognitive performance and decline in racially/ethnically diverse cohorts is lacking. Method In 4 392 Multi-Ethnic Study of Atherosclerosis participants (aged 60.1 ± 9.4 years; 53% women; 41% White, 11% Chinese American, 26% African American, 21% Hispanic), we compared associations of Exam 1 (2000–2002) Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE), Framingham Stroke Risk Profile (FSRP), and atherosclerotic cardiovascular disease pooled cohort equation (ASCVD-PCE) risk scores with Exam 5 (2010–2012) Cognitive Abilities Screening Instrument (CASI), Digit Symbol Coding (DSC), and Digit Span (DS) cognitive test performance using multivariable linear regression, and examined racial/ethnic interactions. In 1 838 participants with repeat CASI data at Exam 6 (2016–2018), we related risk scores to odds of a 1-SD decline in CASI performance using multivariable logistic regression. Results SD increments in each risk score were associated with worse cognitive performance. CAIDE had stronger associations with CASI performance than the FSRP and ASCVD-PCE, but associations of ASCVD-PCE with the DSC and DS were similar to CAIDE (difference in β [95% CI] = −0.57 [−1.48, 0.34] and −0.21 [−0.43, 0.01], respectively). Race/ethnicity modified associations. For example, associations between CAIDE and CASI were greater in African Americans and Hispanics than in Whites (difference in β = 0.69 [0.02, 1.36] and 1.67 [0.95, 2.39], respectively). Risk scores were comparably associated with decline in CASI performance. Conclusions Antecedent vascular risk scores are associated with cognitive performance and decline in the 4 most common U.S. racial/ethnic groups, but associations differ among risk scores and by race/ethnicity.

Identifying modifiable risk factors that are associated with dementia burden across racial and ethnic groups in the population can yield insights into the potential effectiveness of interventions in preventing dementia and reducing disparities.To calculate the population attributable fraction (PAF) of dementia associated with 12 established modifiable risk factors for all US adults, as well as separately by race and ethnicity.This cross-sectional study used survey data from nationally representative samples of US adults. PAFs were calculated using relative risks and prevalence estimates for 12 risk factors. Relative risks were taken from meta-analyses, as reported in a 2020 systematic review. Prevalence estimates for risk factors were derived from nationally representative cross-sectional survey data collected between 2011 and 2018. Combined PAFs were adjusted for risk factor communality using weights derived from the Atherosclerosis Risk in Communities (ARIC) study (1987-2018). Analyses were conducted May through October 2021.Low education, hearing loss, traumatic brain injury, hypertension, excessive alcohol consumption, obesity, smoking, depression, social isolation, physical inactivity, diabetes, and air pollution.PAF for each dementia risk factor, a combined PAF, and the decrease in the number of prevalent dementia cases in 2020 that would be expected given a 15% proportional decrease in each exposure.Among all US adults, an estimated 41.0% (95% CI, 22.7%-55.9%) of dementia cases were attributable to 12 risk factors. A 15% proportional decrease in each risk factor would reduce dementia prevalence in the population by an estimated 7.3% (95% CI, 3.7%-10.9%). The estimated PAF was greater for Black and Hispanic than it was for White and Asian individuals. The greatest attributable fraction of dementia cases was observed for hypertension (PAF, 20.2%; 95% CI, 6.3%-34.4%), obesity (PAF, 20.9%; 95% CI, 13.0%-28.8%), and physical inactivity (PAF, 20.1%; 95% CI, 9.1%-29.6%). These factors were also highest within each racial and ethnic group, although the proportions varied.A large fraction of dementia cases in the US were associated with potentially modifiable risk factors, especially for Black and Hispanic individuals. Targeting and reducing these risk factors may curb the projected rise in dementia cases over the next several decades.

Midlife vascular risk factors (MVRFs) are associated with incident dementia, as are amyloid β (Aβ) deposition and neurodegeneration. Whether vascular and Alzheimer disease-associated factors contribute to dementia independently or interact synergistically to reduce cognition is poorly understood.Participants in the Atherosclerosis Risk in Communities-Positron Emission Tomography study were followed from 1987-1989 (45-64 years old) through 2016-2017 (74-94 years old), with repeat cognitive assessment and dementia adjudication. In 2011-2013, dementia-free participants underwent brain magnetic resonance imaging (with white matter hyperintensity [WMH] and brain volume measurement) and florbetapir (Aβ) positron emission tomography. The relative contributions of vascular risk and injury (MVRFs, WMH volume), elevated Aβ standardized uptake value ratio (SUVR), and neurodegeneration (smaller temporoparietal brain regions) to incident dementia were evaluated with adjusted Cox models.In 298 individuals, 36 developed dementia (median follow-up = 4.9 years). Midlife hypertension and Aβ each independently predicted dementia risk (hypertension: hazard ratio [HR] = 2.57, 95% confidence interval [CI] = 1.16-5.67; Aβ SUVR [per standard deviation (SD)]: HR = 2.57, 95% CI = 1.72-3.84), but did not interact significantly, whereas late life diabetes (HR = 2.50, 95% CI = 1.18-5.28) and Aβ independently predicted dementia risk. WMHs (per SD: HR = 1.51, 95% CI = 1.03-2.20) and Aβ SUVR (HR = 2.52, 95% CI = 1.83-3.47) independently contributed to incident dementia, but WMHs lost significance when MVRFs were included. Smaller temporoparietal brain regions were associated with incident dementia, independent of Aβ and MVRFs (HR = 2.18, 95% CI = 1.18-4.01).Midlife hypertension and late life Aβ are independently associated with dementia risk, without evidence for synergy on a multiplicative scale. Given the independent contributions of vascular and amyloid mechanisms, multiple pathways should be considered when evaluating interventions to reduce the burden of dementia. ANN NEUROL 2022;92:607-619.

Machine learning methods have been applied to estimate measures of brain aging from neuroimages. However, only rarely have these measures been examined in the context of biologic age. Here, we investigated associations of an MRI-based measure of dementia risk, the Alzheimer’s disease pattern similarity (AD-PS) scores, with measures used to calculate biological age. Participants were those from visit 5 of the Atherosclerosis Risk in Communities Study with cognitive status adjudication, proteomic data, and AD-PS scores available. The AD-PS score estimation is based on previously reported machine learning methods. We evaluated associations of the AD-PS score with all-cause mortality. Sensitivity analyses using only cognitively normal (CN) individuals were performed treating CNS-related causes of death as competing risk. AD-PS score was examined in association with 32 proteins measured, using a Somalogic platform, previously reported to be associated with age. Finally, associations with a deficit accumulation index (DAI) based on a count of 38 health conditions were investigated. All analyses were adjusted for age, race, sex, education, smoking, hypertension, and diabetes. The AD-PS score was significantly associated with all-cause mortality and with levels of 9 of the 32 proteins. Growth/differentiation factor 15 (GDF-15) and pleiotrophin remained significant after accounting for multiple-testing and when restricting the analysis to CN participants. A linear regression model showed a significant association between DAI and AD-PS scores overall. While the AD-PS scores were created as a measure of dementia risk, our analyses suggest that they could also be capturing brain aging.

ImportanceEnlarged perivascular spaces (ePVSs) have been associated with cerebral small-vessel disease (cSVD). Although their etiology may differ based on brain location, study of ePVSs has been limited to specific brain regions; therefore, their risk factors and significance remain uncertain.ObjectiveToperform a whole-brain investigation of ePVSs in a large community-based cohort.Design, Setting, and ParticipantsThis cross-sectional study analyzed data from the Atrial Fibrillation substudy of the population-based Multi-Ethnic Study of Atherosclerosis. Demographic, vascular risk, and cardiovascular disease data were collected from September 2016 to May 2018. Brain magnetic resonance imaging was performed from March 2018 to July 2019. The reported analysis was conducted between August and October 2022. A total of 1026 participants with available brain magnetic resonance imaging data and complete information on demographic characteristics and vascular risk factors were included.Main Outcomes and MeasuresEnlarged perivascular spaces were quantified using a fully automated deep learning algorithm. Quantified ePVS volumes were grouped into 6 anatomic locations: basal ganglia, thalamus, brainstem, frontoparietal, insular, and temporal regions, and were normalized for the respective regional volumes. The association of normalized regional ePVS volumes with demographic characteristics, vascular risk factors, neuroimaging indices, and prevalent cardiovascular disease was explored using generalized linear models.ResultsIn the 1026 participants, mean (SD) age was 72 (8) years; 541 (53%) of the participants were women. Basal ganglia ePVS volume was positively associated with age (β = 3.59 × 10−3; 95% CI, 2.80 × 10−3 to 4.39 × 10−3), systolic blood pressure (β = 8.35 × 10−4; 95% CI, 5.19 × 10−4 to 1.15 × 10−3), use of antihypertensives (β = 3.29 × 10−2; 95% CI, 1.92 × 10−2 to 4.67 × 10−2), and negatively associated with Black race (β = −3.34 × 10−2; 95% CI, −5.08 × 10−2 to −1.59 × 10−2). Thalamic ePVS volume was positively associated with age (β = 5.57 × 10−4; 95% CI, 2.19 × 10−4 to 8.95 × 10−4) and use of antihypertensives (β = 1.19 × 10−2; 95% CI, 6.02 × 10−3 to 1.77 × 10−2). Insular region ePVS volume was positively associated with age (β = 1.18 × 10−3; 95% CI, 7.98 × 10−4 to 1.55 × 10−3). Brainstem ePVS volume was smaller in Black than in White participants (β = −5.34 × 10−3; 95% CI, −8.26 × 10−3 to −2.41 × 10−3). Frontoparietal ePVS volume was positively associated with systolic blood pressure (β = 1.14 × 10−4; 95% CI, 3.38 × 10−5 to 1.95 × 10−4) and negatively associated with age (β = −3.38 × 10−4; 95% CI, −5.40 × 10−4 to −1.36 × 10−4). Temporal region ePVS volume was negatively associated with age (β = −1.61 × 10−2; 95% CI, −2.14 × 10−2 to −1.09 × 10−2), as well as Chinese American (β = −2.35 × 10−1; 95% CI, −3.83 × 10−1 to −8.74 × 10−2) and Hispanic ethnicities (β = −1.73 × 10−1; 95% CI, −2.96 × 10−1 to −4.99 × 10−2).Conclusions and RelevanceIn this cross-sectional study of ePVSs in the whole brain, increased ePVS burden in the basal ganglia and thalamus was a surrogate marker for underlying cSVD, highlighting the clinical importance of ePVSs in these locations.

Imaging markers of cerebrovascular disease and Alzheimer’s disease (AD) are implicated in mobility impairment in older adults, but few studies have examined these relationships longitudinally in a racially-diverse population-based sample. At Visit 5 (2011–13) of the ARIC Study, 1859 participants had usual pace gait speed (cm/s) assessed and brain MRI (mean age = 76.3, 28.5% Black) and PET (n = 343; mean age = 75.9, 42.6% Black) measures including total/regional brain volume (cm(3)), white matter hyperintensities (WMH; cm(3)), infarcts (present/absent), microbleeds (count) and global beta-amyloid (Aβ). Participants returned at Visit 6 (n = 1264, 2016–17) and Visit 7 (n = 1108, 2018–19) for follow-up gait speed assessments. We used linear regression to estimate effects of baseline infarct presence, higher microbleed count, and a one interquartile range (IQR) poorer measures of continuous predictors (−1 IQR total brain volume, temporal-parietal lobe meta region of interest(ROI); +1 IQR WMH volume, global Aβ SUVR) on cross-sectional gait speed and change in gait speed adjusting for age, sex, education, study site, APOE e4, estimated intracranial volume, BMI, and cardiovascular risk factors. Cross-sectionally, slower gait speed outcome was associated with higher WMH volume, −3.38 cm/s (95%CI:−4.71, −2.04), infarct presence, −5.60 cm/s (−7.69, −3.51), microbleed count, −2.20 cm/s (−3.20, −0.91), smaller total brain volume, −9.26 cm/s (−12.1, −6.43), and smaller temporal-parietal lobe ROI −6.28 cm/s (−8.28, −4.28). Longitudinally, faster gait speed outcome decline was associated with higher WMH volume, −0.27 cm/s/year, (−0.51, −0.03) and higher global Aβ SUVR, −0.62 cm/s/year (−1.20, −0.03). Both cerebrovascular and AD pathology may contribute to mobility decline commonly seen with aging.

We investigated associations between neighborhood racial/ethnic segregation and cognitive change.We used data (n = 1712) from the Multi-Ethnic Study of Atherosclerosis. Racial/ethnic segregation was assessed using Getis-Ord (Gi*) z-scores based on American Community Survey Census tract data (higher Gi* = greater spatial clustering of participant's race/ethnicity). Global cognition and processing speed were assessed twice, 6 years apart. Adjusted multilevel linear regression tested associations between Gi* z-scores and cognition. Effect modification by race/ethnicity, income, education, neighborhood socioeconomic status, and neighborhood social support was tested.Participants were on average 67 years old; 43% were White, 11% Chinese, 29% African American/Black, 17% Hispanic; 40% had high neighborhood segregation (Gi*1.96). African American/Black participants with greater neighborhood segregation had greater processing speed decline in stratified analyses, but no interactions were significant.Segregation was associated with greater processing speed declines among African American/Black participants. Additional follow-ups and comprehensive cognitive batteries may further elucidate these findings.A study of neighborhood racial/ethnic segregation and change in cognition. Study was based on a racially and geographically diverse, population-based cohort of older adults. Racial/ethnic segregation (clustering) was measured by the Getis-ord (Gi*) statistic. We saw faster processing speed decline among Black individuals in segregated neighborhoods.

Strategies to prevent or delay Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) are urgently needed. Blood pressure (BP) management is a promising strategy for AD/ADRD prevention and the key element in the primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD), yet the effects of different population level BP control strategies across the life course on AD/ADRD are not known.Large-scale randomized controlled trials are the least biased approach to identifying the effect of BP control on AD/ADRD, yet trials may be infeasible due to the need for prolonged follow-up and very large sample sizes. Thus, simulation analyses leveraging the best available observational data may be the best and most practical approach to answering these questions.In this manuscript, we describe the design principles, implementation details, and population-level validation of a novel population health microsimulation framework, the MIchigan ChROnic Disease SIMulation (MICROSIM), for The Effect of Lower Blood Pressure over the Life Course on Late-life Cognition in Blacks, Hispanics, and Whites (BP COG) study of the effect of BP levels over the life course on cognitive decline and dementia.MICROSIM was designed by applying computer programming best practices to create a novel simulation model. The initial purpose of this extensible, open-source framework is to explore a series of questions related to the impact of different blood pressure management strategies on late-life cognition and all-cause dementia, as well as the effects on race differences in all-cause dementia incidence. Ultimately, though, the framework is designed to be extensible such that a variety of different clinical conditions could be added to the framework.

Background: Higher visit-to-visit variability in fasting glucose (GV) and HbA1c (A1cV), indicating worse glycemic control, is associated with incident dementia in adults with type 2 diabetes (T2D). Few studies have investigated the relationship of GV and A1cV with cognitive decline in the general population. Hypothesis: Higher visit-to-visit GV and A1cV are associated with decline in global cognitive performance. Methods: Fasting glucose (FG) was measured in MESA participants at Exam 1 (2000-02) and each of 5 follow-up exams, and HbA1c was measured at Exam 2 (2002-04), Exam 5 (2010-12), and Exam 6 (2016-18). Global cognitive performance was assessed by the Cognitive Abilities Screening Instrument (CASI; scored 0-100) at Exam 5 and re-administered to a subset at Exam 6. We calculated GV and A1cV as the SD (SD GV ; SD A1c ), coefficient of variation (CV GV ; CV A1c ), and average real variability (ARV GV ; ARV A1c ), and defined global cognitive decline as a ≥1 race/ethnicity-specific SD decrease in CASI score from Exam 5 to Exam 6 (-5.9 to -8.2 points across 4 races/ethnicities). We report the CASI point-change and relative odds of decline (OR) from Exam 5 to Exam 6 (95% CI) associated with continuous log 2 -normalized and highest quartile (Q4 vs. quartiles 1-3 for potential floor effects) of GV and A1cV from inverse probability of censor-weighted linear and logistic regression adjusted for Exam 5 CASI score, age, sex, race/ethnicity, education, vascular risk factors, and APOE ε4 status. Results: A total of 1834 Exam 6 participants (aged 73±8 years; 47% men; 43% White; 7% with T2D at Exam 1; 13% with incident T2D over follow-up) had ≥3 FG measurements and repeat CASI data. The overall 6-year mean (SD) change in CASI was +0.1 (6.6) points. Q4 of SD GV , CV GV , and ARV GV was associated with 0.8 (0.1, 1.5), 0.9 (0.2, 1.6), and 0.7 (0.03, 1.4) point decreases in CASI, respectively, and Q4 of CV GV was associated with higher odds of global cognitive decline (OR = 1.5 [1.1, 2.1]); continuous GV indices were not associated with CASI change. Associations with SD GV and CV GV were driven by participants with incident T2D (interaction P A1c was associated with a 0.5 (0.1, 0.9) point decrease in CASI. However, in participants with incident T2D, 2-fold increments in SD A1c , CV A1c , and ARV A1c were associated with 1.3 (0.2, 2.4), 1.4 (0.2, 2.6), and 1.8 (0.6, 3.0) point decreases in CASI, respectively, and a 2-fold increment in ARV A1c was associated with greater odds of decline (OR = 2.1 [1.1, 3.8]) (interaction P all Conclusions: Poor glycemic control over 14-16 years is associated with modest cognitive decline over the subsequent 6-8 years, particularly among adults at high risk for T2D during mid- to late-life.

Objective: To characterize the direct and indirect association of prediabetes with dementia risk and to examine the age at diabetes onset and subsequent risk of dementia. Methods: At baseline (1990-1992), prediabetes was defined based on HbA1C 5.7-6.4% among people without a history of diagnosed diabetes or medication use for diabetes; diabetes was defined based on self-reported physician diagnosis or diabetes medication use or HbA1C level of 6.5% or greater. Incident diabetes with the same definition during the follow-up was included as a time-varying variable. Incident dementia was ascertained using surveillance, interviews and adjudication. Survival analysis used age as the time scale using an origin at age 50 and left and right censoring. Adjustment models included sex, race, education, APOE, BMI, smoking status, alcohol use, physical activity, total cholesterol, HDL cholesterol and hypertension. Results: Among the 13,388 participants, 2314 (17.3%) had prediabetes and 1798 (13.4%) had diabetes at baseline. Before adjusting for incident diabetes, the adjusted hazard ratios of dementia were 2.35 (95% CI: 1.99, 2.76) and 1.13 (95% CI: 1.02, 1.25) for diabetes and prediabetes compared to no diabetes in the fully adjusted model. After adding incident diabetes, the excess risk of dementia for prediabetes decreased by ~50% and the association was not significant. The relative hazards of dementia were 3.16 (95% CI: 2.15, 4.66), 1.64 (95% CI: 1.36, 1.97), 1.29 (95% CI: 1.14, 1.47) and 1.06 (95% CI: 0.89, 1.28) for diabetes with age onset at < 60, 60-69, 70-79 and 80-93, respectively (Table). Conclusion: Midlife diabetes and prediabetes are associated with excess hazard of dementia and death. Earlier age of onset of diabetes shows a strong dose response with higher dementia hazard. Much of the risk of dementia in pre-diabetes is explained by intervening incidence of clinical diabetes. Dementia prevention efforts would benefit from preventing or delaying the progression of prediabetes to diabetes.

Introduction: Animal studies and emerging population data link liver function and integrity to brain health, although mostly based on cross-sectional estimates. We reported that low liver transaminases are associated with risk of dementia, but prospective studies on liver biomarkers and altered brain morphology are lacking. Methods: We studied 1,596 participants of the Atherosclerosis Risk in Communities (ARIC) Study cohort examined in 1996-98 (mean age: 62 years, 59% female, 27% Black) free of chronic liver disease, cirrhosis, and stroke, and with alanine aminotransferase (ALT) to aspartate aminotransferase (AST) ratio ≤2. Brain magnetic resonance imaging (MRI) scans were performed in 2011-13, at the time of re-examination. Serum transaminases (ALT, AST) and gamma-glutamyl transferase (GGT) at baseline were analyzed as sex-specific quintiles, with the first quintile further subdivided into a th and 10 th -20 th percentiles to allow for nonlinear associations at low biomarker levels. Brain MRI markers were measured with 3 Tesla MRI. Multinomial logistic and linear regressions were used, adjusted for demographics and APOE-ε4. Results: Monotonic associations were observed between higher GGT levels and smaller cortical volume and temporal lobe volume meta regions of interest (Figure) . The lowest GGT levels were associated with smaller volumes of white matter hyperintensities. In contrast, associations of transaminases with brain morphological measures were inconclusive. Conclusions: GGT levels measured in late mid-life are associated vascular sequelae on brain MRI among older adults. As a potent regulator of antioxidant capacity and a predictor of atherosclerosis, GGT may point to vascular pathways that influence brain health. The lack of association between low transaminases and brain MRI findings suggests non-vascular pathways for their association with incident dementia. A deeper understanding of the links between hepatic metabolic dysregulation and brain health is warranted.