Windham, B. Gwen

Introduction: Hypertension in midlife, but not late life, is a robust predictor of subsequent dementia. However, the fraction of dementia attributable to hypertension might vary depending on the age of the population considered, and the age through which dementia onset occurs. Here, we investigated associations of hypertension assessed at various ages with incident dementia by age 80 or 90, then estimated population attributable fractions (PAF) for dementia from hypertension categories at each of these age groups. Hypothesis: Given hypertension prevalence increases with age but its relative risk for dementia tends to decrease, we had no prior expectation of the age at which the PAF’s would be highest. We hypothesized, however, that PAFs for incident dementia would be higher when hypertension is measured in midlife age groups versus late-life age groups. Methods: We leveraged 32 years of follow-up data from the Atherosclerosis Risk in Communities study (ARIC), a prospective, community-based cohort that enrolled participants aged 45-64 years from four US communities (Washington County, MD; Forsyth County, NC; Jackson, MS; and selected suburbs of Minneapolis, MI) at ARIC visit 1 (1987-1989). Participants were followed through 2018-2019. We used Cox proportional hazards models to estimate hazard ratios, then quantified PAFs, of dementia by age 80 and 90 from hypertension assessed at ages of 45-54 (ARIC visit 1), 55-64 (ARIC visits 1 and 4), 65-74 (ARIC visits 4 and 5), and 75-84 (ARIC visit 5). Results: Hypertension was assessed among 7,572 participants aged 45-54; 12,033 aged 55-64; and 6,561 aged 65-74. By age 80 the number identified as having incident dementia was 711, 910, and 372, respectively. Relative to normotension, hypertension in each age category was associated with hazard ratios (HRs) greater than 1.0 for dementia from hypertension by age 80. The PAF for dementia by age 80 from hypertension measured at age 45-54 was 15.3% (95% CI = 6.9, 22.3%), 19.1% (95% CI = 9.9, 26.9%) at ages 55-64, and 19.9% (95% CI = -4.4, 38.5%) at ages 65-74. By age 90, the number of incident dementia cases were 958; 2,302; and 1,327, respectively; and, among the 2,086 participants aged 75-84, 400 incident dementia cases. HRs were slightly smaller than those by age 80, while hypertension assessed in the 75-84 age group was not significant. The PAFs for dementia by age 90 from hypertension at age 45-54 was 13.8% (95% CI = 6.6, 20.0%), 12.9% (95% CI = 7.0, 18.2%) at ages 55-64, 10.9% (95% CI = 0.02, 21.0%) at ages 65-74, and non-significant at ages 75-84. Conclusions: Public health interventions targeting hypertension in midlife through early late-life might reduce a sizeable proportion of dementia cases.

Abstract We hypothesized that poorer cerebral perfusion could impair mobility, particularly at lower systolic blood pressure (SBP). Cerebral perfusion was measured via arterial spin-labelled (ASL)-MRI in community-dwelling adults of the Mayo Clinic Study of Aging. Usual-pace gait speed was assessed over 5.6 meters on an electronic mat. Linear regression models estimated cross-sectional gait speed associations with ASL and modifying effects of age and SBP, adjusting for sex and body mass index. Results report differences in gait speed (meter/second) per standard deviation (SD) lower ASL or SBP (mean=139.1 mmHg, SD=19.7 mmHg). Among 479 participants (aged 31-94 years; mean age 67.6 years; 44% women; mean gait speed 1.17m/s), relationships of ASL with gait speed varied by age and SBP (ASL-x-age interaction: p<.007; ASL-x-SBP interaction: p<.007). At age 65, 75 or 85 years and a SBP of 120mmHg, each SD lower ASL was associated with a 0.04 m/s (0.01,0.07), 0.07 m/s (0.04,0.10), and 0.09 m/s (0.05,0.13) slower gait speed at respective ages. At age 65, 75 or 85 years with low ASL (1 SD below the mean), each SD lower SBP was associated with 0.06 (0.02,0.09) m/s, 0.03 (0.01,0.06) m/s or .01 (-0.02,0.04) m/s slower gait speed, respectively. With high ASL (mean ASL+1SD), lower SBP trended towards faster gait at older age, e.g. estimated gait speed was 0.04 m/s (0.00,0.09) faster for each SD lower SBP at age 85years. Poorer cerebral perfusion may contribute to slower gait, particularly with lower SBP. The interrelations of cerebral perfusion, SBP, and age with mobility merit further study.

At visit 3 (1993–1995) of the ARIC Study, 1.5T brain MRI was completed in 1,881 stroke-free participants (Mean age = 62.9±4.9, 50% Black). Cox regression examined associations between infarct group [infarct-free (referent; n = 1,611), smaller only (<3 mm; n = 50), larger only (≥3 mm but <20 mm; n = 185), both (n = 35)] and up to 25-year incident dementia (n = 539). Participants with both infarcts were over 2.5 times more likely to develop dementia [HR = 2.61; 95% CI = 1.44, 4.72]. Smaller only (HR = 1.22; 95% CI = 0.70, 2.13) and larger only (HR = 1.27; 95% CI = 0.92, 1.74) groups showed associations with wide confidence intervals, unsupported statistically. A late midlife infarct profile including smaller and larger infarcts may represent particular vulnerability to dementia risk.

Abstract Background Whether diabetes and adipokine‐driven inflammation explain the association of obesity to cognitive impairment is unknown. Methods Structural equation models estimated the total effects of waist circumference on cognitive outcomes among African American participants cross‐sectionally (index exam) and longitudinally. Total effects were deconstructed into direct pathways of waist circumference to cognitive impairment and indirect mediation pathways through leptin, soluble tumor necrosis factor receptor 2 (sTNFR2), and diabetes. Waist circumference, leptin, and sTNFR2 were standardized. Cognitive impairment was defined as MMSE <21 or a z‐score < −1.5 standard deviation (SD). Incident cognitive impairment was defined among those without cognitive impairment at the index exam as follow‐up MMSE<21, z‐ score < −1.5, MMSE decline >1 point/year, or z‐score decline of >0.1 SD/year. Results Among 1008 participants (70% women, mean age 62.9 years, 14.5% with obesity, 26% with diabetes), 132 (13%) had baseline cognitive impairment. Each SD higher waist circumference was associated with higher odds of cognitive impairment, odds ratio (OR) = 1.63; (95% confidence interval: 1.17, 2.24), with mediating pathways explaining 65% of the total effect (58% from diabetes; 7% from inflammation). At follow‐up (mean 6.8 years), 106 of 535 (19.8%) had developed cognitive impairment. Each SD higher waist circumference was associated with higher odds of developing cognitive impairment (OR = 1.87; 95%CI: 1.18, 2.74); the direct effect of waist circumference explained 37% of the total effect and mediating pathways explained 63% (61% from diabetes; 2% from inflammation), although individual pathways were not statistically supported in the smaller sample. Conclusion Diabetes, and to a lesser degree, adiposity‐driven inflammation, appear to explain a substantial proportion of abdominal adiposity relationships with cognitive impairment. The impact of preventing and treating obesity on cognitive outcomes merits study.

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.

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.

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.

AbstractIntroductionMotoric cognitive risk (MCR), a clinical syndrome characterized by slow gait speed and subjective cognitive complaints, has been associated with dementia risk. The neuropathological features underlying MCR remain poorly understood.MethodsThe Atherosclerosis Risk in Communities (ARIC) community‐based cohort study classified participants using standardized criteria as MCR+/– and mild cognitive impairment (MCI)+/– at study baseline (2011–2013). We examined the 5‐year dementia risk and baseline brain structural/molecular abnormalities associated with MCR+ and MCI+ status.ResultsOf 5023 nondemented participants included, 204 were MCR+ and 1030 were MCI+. Both MCR+ and MCI+ participants demonstrated increased dementia risk. The pattern of structural brain abnormalities associated with MCR+ differed from that of MCI+. Whereas MCI+ was associated with comparatively smaller volumes in brain regions vulnerable to Alzheimer's disease pathology, MCR+ status was associated with smaller volumes in frontoparietal regions and greater white matter abnormalities.DiscussionMCR may represent a predementia syndrome characterized by prominent white matter abnormalities and frontoparietal atrophy.