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Background The contribution of atrial cardiopathy to dementia risk is uncharacterized. We aimed to evaluate the association of atrial cardiopathy with incident dementia and potential mediation by atrial fibrillation (AF) and stroke. Methods and Results We conducted a prospective cohort analysis of participants in the ARIC (Atherosclerosis Risk in Communities) study attending visit 5 (2011–2013). We used Cox regression to determine the association between atrial cardiopathy and risk of dementia. Structural equation modeling methods were used to determine potential mediation by AF and/or stroke. Atrial cardiopathy was defined if ≥1 of the following at visit 5: P‐wave terminal force >5000 mV·ms in ECG lead V1, NT‐proBNP (N‐terminal pro–brain natriuretic peptide) >250 pg/mL or left atrial volume index ≥34 mL/m 2 by transthoracic echocardiography. We repeated our analysis necessitating ≥2 markers to define atrial cardiopathy. The prevalence of atrial cardiopathy was 34% in the 5078 participants (mean age 75 years, 59% female, 21% Black adults), with 763 participants developing dementia. Atrial cardiopathy was significantly associated with dementia (adjusted HR, 1.35 [95% CI, 1.16–1.58]), with strengthening of the effect estimate when necessitating ≥2 biomarkers (adjusted HR, 1.54 [95% CI, 1.25–1.89]). There was an increased risk of dementia among those with atrial cardiopathy when excluding those with AF (adjusted HR, 1.31 [95% CI, 1.12–1.55]) or stroke (adjusted HR, 1.28 [95% CI, 1.09–1.52]). The proportion of the effect mediated by AF was 4% ( P =0.005), and 9% was mediated by stroke ( P =0.048). Conclusions Atrial cardiopathy was significantly associated with an increased risk of dementia, with only a small percent mediation of the effect by AF or stroke.

Background: Olfactory identification (OI) impairment appears early in the course of Alzheimer’s disease dementia (AD), prior to detectable cognitive impairment. However, the neuroanatomical correlates of impaired OI in cognitively normal older adults (CN) and persons with mild cognitive impairment (MCI) are not fully understood. Objective: We examined the neuroanatomic correlates of OI impairment in older adults from the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Methods: Our sample included 1,600 older adults without dementia who completed clinical assessment and structural brain imaging from 2011 to 2013. We characterized OI impairment using the 12-item Sniffin’ Sticks odor identification test (score ≤6). We used voxel-based morphometry (VBM) and region of interest (ROI) analyses to examine the neuroanatomic correlates of impaired OI in CN and MCI, after adjusting for potential confounders. Analyses were also separately stratified by race and sex. Results: In CN, OI impairment was associated with smaller amygdala gray matter (GM) volume ( p < 0.05). In MCI, OI impairment was associated with smaller GM volumes of the olfactory cortex, amygdala, entorhinal cortex, hippocampus, and insula (ps < 0.05). Differential associations were observed by sex in MCI; OI impairment was associated with lower insular GM volumes among men but not among women (p-interaction = 0.04). There were no meaningful interactions by race. Conclusion: The brain regions associated with OI impairment in individuals without dementia are specifically those regions known to be the primary targets of AD pathogenic processes. These findings highlight the potential utility of olfactory assessment in the identification and stratification of older adults at risk for AD.

Objective 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. Methods 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. Results 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). Interpretation 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

AbstractBackgroundPhysical frailty is associated with increased risk for dementia and other neurologic sequelae. However, the neurobiological changes underlying frailty and frailty risk remain unknown. We examined the association of cerebral white matter structure with current and future frailty.MethodsAtherosclerosis Risk in Communities Study Neurocognitive Study participants who underwent 3T brain MRI were included. Frailty status was classified according to the Fried criteria. Cerebral white matter integrity was defined using white matter hyperintensity (WMH) volume and microstructure, measured using diffusion tensor imaging fractional anisotropy (FA) and mean diffusivity (MD). Multivariable linear regression was used to relate baseline frailty to white matter structure; multivariable logistic regression was used to relate baseline white matter to frailty risk among participants nonfrail at baseline.ResultsIn the cross-sectional analysis (N = 1 754; mean age: 76 years), frailty was associated with greater WMH volume, lower FA, and greater MD. These associations remained consistent after excluding participants with a history of stroke or dementia. Among participants nonfrail at baseline who completed follow-up frailty assessment (N = 1 379; 6.6-year follow-up period), each standard deviation increase in WMH volume was associated with 1.46 higher odds of frailty at follow-up. Composite FA and MD measures were not associated with future frailty; however, secondary analyses found several significant white matter tract-specific associations with frailty risk.ConclusionThe current study demonstrates a robust association of WMH volume with current and future frailty. Although measures of white matter microstructure were altered in frail individuals, these measures were not generally associated with progression from nonfrail to frail status.

AbstractIntroductionSlower mobility is associated with mild cognitive impairment (MCI) and dementia. We examined the interaction of endurance with gait speed on prevalent MCI and dementia.MethodsCross‐sectional multinomial regression in the ARIC cohort (n = 2844 participants; 71 to 94 years; 44% men; 18% Black persons) with cognitive status (normal/MCI/dementia), 4 m gait speed, and endurance (2 minute walk [2MW]).ResultsFaster gait speed (up to but not above 1 m/s) and better 2MW were separately associated with lower dementia risk. Good performance in both (2MW = 200 m, gait speed = 1.2 m/s) was associated with 99% lower dementia (Relative Prevalence Ratio [RPR] = 0.01 [95% CI: 0.0 to 0.06]) and 73% lower MCI, RPR = 0.27 (0.15 to 0.48) compared to poor performance in both (2MW = 100 m, gait speed = 0.8 m/s). Models incorporating a gait speed‐by‐2MW interaction term outperformed gait speed‐only models (P < .001).DiscussionGait speed relationships with dementia diminish at faster gait speeds. Combining endurance with gait speed may yield more sensitive markers of MCI and dementia than gait speed alone.

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.

AbstractBackgroundPrior evidence has suggested associations between hearing loss and smaller brain volumes particularly in the temporal lobe where the primary auditory cortex is located, probably due to changes in cortical organization associated with reduced auditory stimulation. Evidence regarding associations of central auditory processing with brain volumes is relatively limited. The study aims to investigate cross‐sectional associations of central auditory processing with brain volumes in older adults.MethodWe studied 587 cognitively normal (Mini‐Mental State Exam ≥23 if high school degree or less and ≥25 if above high school degree) older adults (mean age: 77±4 years, 56% female, 17% black), including 426 with hearing loss from the Aging and Cognitive Health Evaluation in Elders (ACHIEVE) baseline (2018‐19), which is an ancillary randomized controlled trial of the Atherosclerosis Risk in Communities (ARIC) Study and 161 with normal hearing, comparable age and cognitive status from the ARIC Visit 6/7 (2016‐17/2018‐19). Brain volumes were measured by magnetic resonance imaging (MRI) scans and were transformed to z‐scores. Central auditory processing was measured by the Quick Speech‐in‐Noise (QuickSIN) test. Total scores range from 0 to 30 with lower scores indicating worse speech‐in‐noise performance. Multivariable‐adjusted linear regression was used to estimate cross‐sectional differences in standardized brain volumes associated with differences in QuickSIN score. Models adjusted for age, sex, race, education, cohort, body mass index, smoking, hypertension, diabetes, stroke, intracranial volume, and pure‐tone average.ResultEvery 5‐point decrease in QuickSIN score (worse performance) was associated with smaller volumes of the temporal lobe (‐0.07SD, 95% CI: ‐0.13, ‐0.01). QuickSIN score was also associated with subregions of the temporal lobe related to auditory processing, memory and emotion, including amygdala (‐0.13SD, 95% CI: ‐0.21, ‐0.04), middle (‐0.08SD, 95% CI: ‐0.15, ‐0.00) and superior temporal gyri (‐0.08SD, 95% CI: ‐0.15, ‐0.01).ConclusionPoorer central auditory processing was associated with smaller temporal lobe volumes, including but not limited to subregions important for auditory processing. The ongoing collection of ACHIEVE data with longitudinal MRI data will facilitate understanding of association between hearing loss and brain atrophy as well as the potential promising effects of hearing treatment in mitigating brain aging.

AbstractBackgroundImaging‐based markers of cerebrovascular disease are associated with adverse health events, including incident dementia. However, only infarcts ≥3mm are typically considered in clinical and research settings. Recent evidence demonstrates that smaller infarcts in individuals during mid‐life, particularly when co‐occurring with larger infarcts, may be clinically relevant to cognitive decline, incident stroke, and stroke mortality. We aimed to determine if there was a similar compounding of risk for incident dementia among those with both smaller and larger infarcts at midlife.MethodThe ARIC study is a multi‐site longitudinal cohort study which began in 1987. At visit 3 (1993‐95), brain 1.5T MRI scans were completed in 1881 participants with self‐reported Black/White race and no history of stroke (Mean age=62.9±4.9, 40% Male, 50% Black). Infarcts were identified on T2 and proton density weighted images, with smaller infarcts defined as those <3mm and larger infarcts defined as ≥3mm. All participants were followed prospectively for incident dementia using a combination of medical record surveillance, telephone interviews, in‐person assessments, and expert adjudicated dementia status at three in‐person exams (2011‐2013, 2015‐17, 2018‐19). Cox regression was used to determine the association between infarct group [none(referent), smaller only, larger only, both] and incident dementia adjusted for age, sex, education, site‐race, APOE4, and competing risk of mortality.ResultAmong 1881 participants, 539 incident dementia cases were identified over 25 years of follow‐up. 1611 participants were infarct‐free, 50 participants had only smaller infarcts, 185 had only larger infarcts, and 35 participants had both. Compared to those with no infarcts, participants with both smaller and larger infarcts were over 2.5 times more likely to develop dementia [Hazard Ratio(HR)=2.61; 95% Confidence Interval(CI)=1.44, 4.72]. Associations were in similar directions but had wider and indeterminate confidence intervals when comparing the smaller infarcts only (HR=1.22; 95%CI=0.70, 2.13) or larger infarcts only (HR=1.27; 95%CI=0.92, 1.74) to the no infarct group. Of the 35 participants with both smaller and larger infarcts, all but two either died or developed dementia.ConclusionA midlife infarct burden including both smaller and larger lesions may represent a vulnerability to dementia beyond the risk conferred by either smaller or larger infarcts alone.

Abstract Brain imaging-based biomarkers of neuropathology are associated with mobility in older adults, but the relation of regional microstructural integrity to gait speed in the context of a broader neuropathological profile is less understood. We examined cross-sectional associations of microstructural integrity with 4-meter usual-pace gait speed (cm/s) in a subsample of ARIC study participants who completed 3T MRI brain scans with diffusion tensor imaging(2011-13; n=1785; mean age=76.2±5.3, 60% Female, 28% Black). We considered total brain and six regional averages of fractional anisotropy (FA; lower=worse microstructural integrity) and mean diffusivity (MD; higher=worse microstructural integrity): frontal, temporal, parietal, occipital, anterior and posterior corpus callosum. Associations were tested in multivariable linear regression models adjusted for demographics, cardiovascular risk factors, and with and without additional neuropathological indices: total brain volume, white matter hyperintensities, infarcts, and microhemorrhages. When modeled separately, all neuropathology indices were associated with slower gait speed. Every standard deviation(SD) higher total brain FA was associated with +2.56 cm/s gait speed (95%CI: 1.64,3.48) and every SD higher MD was associated with -4.27 cm/s gait speed (-5.34,-3.20). All regional estimates were comparable. When adjusted for all other neuropathology indices, only posterior corpus callosum FA (β=1.72; 0.67,2.77), total MD (β=-1.63; -3.02,-0.25), frontal lobe MD (β=-1.76; -3.03,-0.48), and temporal lobe MD (β=-1.40; -2.78,-0.02) remained significantly associated with gait speed. Microstructural integrity is an informative measure of brain pathology in relation to mobility, with regional measures tied to executive, memory, and somatosensory function being more informative when a broader neuropathological profile is considered.