Mosley, Thomas H.

Abstract INTRODUCTION Associations of arterial stiffness, measured through pulse wave velocity (PWV), with incident dementia may be driven by age‐related structural changes to the arterial wall or by elevated blood pressure. METHODS Dementia‐free White or Black participants in the community‐based Atherosclerosis Risk in Communities (ARIC) cohort study with measures of PWV were examined. The associations of carotid‐femoral PWV (cfPWV) and total, structural, and load‐dependent PWV with dementia were estimated using Poisson regression models and Cox proportional hazards models. Dementia cases were defined by physician‐adjudicated review, telephone interviews, hospitalization records, and death certificates. RESULTS Of 4818 participants included in the study population (mean age: 75 years; 41% male, 21% Black), 1067 (22%) developed dementia over a median follow‐up of 9.0 years. Higher cfPWV, total PWV, structural PWV, and load‐dependent PWV were associated with greater dementia risk. DISCUSSION Both structural and pressure‐related arterial stiffness mechanisms may underlie the link between PWV and dementia.

Abstract INTRODUCTION Prospective studies of blood‐based biomarkers reflecting pathogenic processes, other than Alzheimer‐specific pathologies, that contribute to dementia in diverse cohorts are lacking. METHODS We jointly fitted linear mixed‐effect models and proportional hazards models to examine associations of midlife glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble cluster of differentiation‐14 (sCD14), neurofilament light chain (NfL), total tau (t‐tau), and ubiquitin C‐terminal hydrolase L1 (UCHL1) levels in serum (collected in 1993 to 1995) with cognitive decline and incident dementia (ascertained over 29 years through 2022) in the community‐based Atherosclerosis Risk in Communities Study. sCD14 and YKL‐40 were measured in 3082 participants and the other four biomarkers in 1766 participants. RESULTS Higher serum GFAP, YKL‐40, sCD14, and NfL were associated with faster cognitive decline and elevated dementia rate (e.g., 1 standard deviation [SD] higher log‐base2 YKL‐40 was associated with −0.11SD faster 25‐year cognitive decline (95% confidence interval [CI]: −0.15,−0.07) and 45% higher dementia hazard (hazard ratio [HR]: 1.45 [95% CI: 1.25, 1.68]). Higher t‐tau and UCHL1 were also associated with faster cognitive decline. DISCUSSION Midlife blood biomarkers reflecting glial and neuronal dysfunction and neuroinflammation are associated with early cognitive impairment.

Objective We investigated potential racial disparities in the effects of audiometric hearing loss and its treatment on dementia and mortality among 3,602 older adults aged 68–89 years, 22% of whom were self-identified Black race. Methods Adjudicated all-cause dementia was determined using neurocognitive test data, proxy reports, and surveillance of hospital records and death certificates. Audiometric hearing loss, defined as the better-ear averaged pure-tone threshold (0.5–4 kHz), was categorized using clinical cutpoints. Multivariable-adjusted Cox proportional hazards models included hearing loss–race interaction terms. Results Dementia risk associated with moderate-to-severe hearing loss did not differ by race [Black participants: hazard ratio (HR): 1.66; 95% confidence interval (CI): 1.05, 2.61; White participants: HR: 1.71; 95% CI: 1.16, 2.51; P -interaction = 0.92]. However, moderate-to-severe hearing loss was associated with a 2.3-fold increase in mortality among Black participants only (95% CI: 1.17, 4.60). Conclusions Our findings emphasize the importance of including minoritized populations in hearing treatment research to build an evidence base for policy development and clinical decision-making. Hearing loss affects the health of both Black and White Americans. Racial disparities in hearing healthcare should be addressed to advance health equity for all older adults.

BACKGROUND: Cerebral microbleeds (CMBs) are associated with dementia, but the impact of specific microbleed patterns (with distinct pathophysiologies) is unclear. Lobar CMBs commonly result from cerebral amyloid angiopathy (sometimes with cortical superficial siderosis [cSS]), while subcortical microbleeds indicate a hypertensive cause. This study investigates the association of CMB presence, patterns, and frequency with dementia risk. METHODS: Participants from the ARIC-NCS (Atherosclerosis Risk in Communities-Neurocognitive Study), a community-based longitudinal cohort, with a 3T research magnetic resonance imaging scan at visit 5 (2011–2013) and without prior intracerebral hemorrhage or dementia were included. CMB and cSS presence and location were evaluated using a T2* gradient-recalled echo sequence. Each individual’s pattern of CMBs was classified as no CMBs, subcortical only, mixed (subcortical and lobar±cSS), lobar±cSS only, or cSS. Dementia adjudication was determined by blinded review of cognitive testing, informant interviews, and hospital discharge codes or death certificates (from follow-up visits and ongoing surveillance). Cox proportional hazards models assessed associations between CMBs and incident dementia through 2020, adjusted for demographics, vascular risk factors, and white matter hyperintensities. RESULTS: Among 1583 participants (mean age, 76 years; 24.7% cumulative dementia incidence over a median of 23.6 follow-up years), 361 had CMBs. Compared with individuals without CMBs, those with mixed (hazard ratio, 1.99 [95% CI, 1.40–2.83]) or lobar±cSS (hazard ratio, 1.96 [95% CI, 1.30–2.97]) CMB patterns had increased dementia risk, whereas individuals with a subcortical-only pattern did not (hazard ratio, 1.04 [95% CI, 0.78–1.39]). cSS presence (n=21; versus absence) showed an increased risk of dementia (hazard ratio, 2.57 [95% CI, 1.36–4.89]). Greater numbers of microbleeds across all CMB subtypes exhibited an increased risk of dementia. CONCLUSIONS: Lobar and mixed CMB patterns and increasing numbers of CMBs are associated with incident dementia. Certain CMB patterns have differential associations with dementia, but severe enough disease burden, regardless of CMB distribution, is associated with increased dementia risk.

Abstract INTRODUCTION Understanding comorbidities’ combined impacts on dementia risk may offer a more comprehensive understanding of individuals’ risk. Using machine‐learning, we grouped individuals with similar midlife risk profiles into clusters and explored associations with dementia risk. METHODS Participants without dementia at baseline (1987–1989) from the prospective Atherosclerosis Risk in Communities (ARIC) study were included (ages 45–64 years; N = 15,250). Using unsupervised hierarchical cluster analysis, nine clusters were created and defined based on 14 midlife morbidities. The associations with incident dementia ( N = 3272 cases, median follow‐up 25 years) and deaths ( N = 9099) were evaluated using time‐to‐event regression models. RESULTS Compared with the healthiest cluster (Cluster 1), Clusters 2 (smoking) (hazard ratio [HR](95% confidence interval [CI]) = 1.62 (1.08, 2.43)), 5 (obesity, diabetes, hypertension, and hypertriglyceridemia) (HR(95%CI) = 1.91 (1.35,2.70)), and 7/8 (atrial fibrillation/heart failure) (HR(95%CI) = 2.69 (1.59,4.57)) were associated with dementia. Accounting for competing risk of death in the Fine‐Gray subdistribution model negated the cluster‐dementia association. DISCUSSION Midlife morbidity clusters are important for dementia and mortality risk.

Abstract Background Decreased kidney function, indicated by a lower estimated glomerular filtration rate (eGFR), may affect interpretation of Alzheimer's disease (AD) blood biomarkers, including phosphorylated tau ( p ‐tau) and amyloid‐beta (Aβ) peptides, due to altered clearance. However, there is limited data available to determine the influence of eGFR on these biomarkers and whether it differs by biomarker or assay type, especially in racially diverse studies of community‐based older adults. Methods We used data from 557 participants in the Mayo Clinic Study of Aging (Rochester, MN n = 182; age 79±8 years; 36.3% Female, White participants) and the UMMC MIND Center‐Mayo Clinic Study of Aging (Jackson, MS n = 375; age 69±8 years; 73% Female 27% Black participants). eGFR was determined using the 2021 CKD‐EPI Creatinine equation. Plasma biomarkers were measured using the Lumipulse immunoassays for p ‐tau217, Aβ42, and Aβ40 (Fujirebio Diagnostics; n = 420); or the mass spectrometry‐based PrecivityAD2 assay (C2N Diagnostics; n = 253) for p ‐tau217, np‐tau217, Aβ42, and Aβ40. Common ratio values were calculated. Aβ42/40 measures were inverted so higher values are worse for all biomarkers. Log base‐2 transformed regression analysis related eGFR to each single analyte and ratio; coefficients (95% CI) reflect estimated doubling in biomarker per doubling in eGFR. Group specific [MN White ( n = 182), MS White ( n = 224), MS Black ( n = 151) participants] estimates are reported, as the distribution of social determinants of health can vary across populations and locations. Results Lower eGFR was associated with higher (worse) AD‐plasma biomarkers, and group stratified estimates were mostly consistent (Figure 1). Ratios of biomarkers diminished but did not entirely alleviate associations with eGFR. For example, MN White participants’ C2N p ‐tau217 association of ‐1.47 (‐1.94, ‐1.00), was attenuated to ‐0.67 (‐1.11, ‐0.22), when using p ‐tau217/np‐tau217. Conclusions Kidney function may be associated with AD‐plasma biomarker values, even with common ratio corrections. There was not strong evidence for highly differential associations of eGFR by race/site categories, though sample sizes are currently limited. The implications for diagnosis and risk classification need to be explored further to support health equity. Optimal consideration of comorbidities on blood biomarker concentrations must continue to be informed by investigation in large, racially and ethnically diverse, community‐based studies.

Abstract Background Plasma biomarkers of Alzheimer's disease (AD) pathology and neurodegeneration provide a non‐invasive method to assess brain pathology associated with dementia and cognitive decline. However, it remains unclear whether these biomarkers are differentially associated with changes in specific cognitive domains or how they relate to subsequent cognitive change in participants with or without cognitive impairment. Methods Plasma biomarkers were assayed in a subset of ARIC participants using Quanterix SiMoA technology on stored specimens collected in midlife (visit 3: 1993‐95, mean age: 59) and late‐life (visit 5: 2011‐13, mean age: 77). Biomarkers included amyloid‐β 42 to amyloid‐β 40 (Aβ42:Aβ40) ratio, phosphorylated tau at threonine 181 ( p ‐Tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Factor scores for global cognition and cognitive domains (memory, language, executive function) were calculated from ten neuropsychological tests administered at visits 5 (2011‐13), 6 (2016‐17), 7 (2018‐19), 8 (2020), and 9 (2021‐22). Linear mixed effects models with multiple imputation of pre‐death cognitive change estimated the association between biomarkers in midlife and late‐life, and biomarker change from midlife to late‐life, with 5‐year change in late‐life global and domain‐specific cognition, adjusting for demographics, lifestyle and cardiovascular risk factors, and APOE‐ε4 status. Exploratory analyses examined effect modification of the biomarker‐global cognition associations by visit 5 adjudicated cognitive impairment. Results Among 1515 participants with plasma biomarkers (60.7% female, 25.5% identified as Black), 39% had late‐life cognitive impairment (Table 1). Higher midlife NfL and GFAP were associated with faster 5‐year declines in global cognition and language during late‐life (Table 2). Only midlife NfL was associated with faster late‐life memory decline. No midlife biomarkers were associated with executive function. In late‐life, lower Aβ42:Aβ40 and higher p ‐Tau 181, NfL, and GFAP were associated with faster declines in global cognition, memory, and language. Midlife to late‐life changes in p ‐Tau 181, NfL, and GFAP were associated with declines in global cognition and language. No consistent effect modification by cognitive impairment was observed (Figure 1). Conclusions Plasma biomarkers of AD pathology, neuronal injury, and astrogliosis, measured at different life epochs (midlife vs. late‐life) show distinct association patterns with subsequent changes in cognitive function across domains.

Abstract Background Plasma biomarkers show promise as a noninvasive method for measuring Alzheimer's disease pathology and neurodegeneration throughout the lifecourse. However, the relationship between longitudinal changes in these biomarkers and late‐life brain morphology in community‐dwelling populations requires further investigation. Method Between 2011 and 2013, 1,977 participants from the Atherosclerosis Risk in Communities Study received an adjudicated cognitive diagnosis and underwent 3 Tesla magnetic resonance imaging scans. Whole‐brain cortical thickness was quantified by Freesurfer. Stored plasma samples collected in midlife (1993‐95, mean age 59.0 years) and late‐life (2011‐13, mean age 76.8 years) from a subsample of 1,515 participants were assayed in 2022 using Quanterix SiMoA. The assay quantified amyloid‐β (Aβ)42/40, phosphorylated tau at threonine 181 ( p ‐Tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Linear regression models estimated the association of plasma biomarkers from midlife, late‐life, and the change from midlife to late‐life with cortical thickness in late‐life. Interactions and effect modification by age were examined in exploratory analyses. Result The sample (Table 1) included 920 (60.7%) women, 387 (25.5%) Black participants, 513 (33.9%) participants with mild cognitive impairment, and 85 (5.6%) participants with dementia. The average age in late‐life was 76.8 (5.3 SD) years and the average cortical thickness was 2.27 (0.11 SD) millimeters. Cortical thickness was lower in individuals with adjudicated mild cognitive impairment or dementia compared to individuals without cognitive impairment (2.25 mm versus 2.29 mm, p <0.0001). In models adjusted for demographics, lifestyle factors, cardiovascular factors, and the presence of APOE ε4 alleles, higher midlife measures of p ‐Tau181 and increases from midlife to late‐life in NfL and GFAP were associated with lower cortical thickness in late‐life (Table 2). Concurrent measures of plasma biomarkers in late‐life were associated with lower cortical thickness (Table 2) and exhibited a stronger association among participants ≥75 years compared to <75 years (Table 3). Conclusion Plasma biomarkers of Alzheimer's disease pathology and neurodegeneration obtained in midlife and late‐life were associated with late‐life differences in cortical thickness. Additional longitudinal research is needed to determine whether plasma biomarkers predict cortical thinning over time and may serve as an early indicator of accelerated brain atrophy.