Changes in Alzheimer Disease Blood Biomarkers and Associations With Incident All-Cause Dementia.

Importance: Plasma biomarkers show promise for identifying Alzheimer disease (AD) neuropathology and neurodegeneration, but additional examination among diverse populations and throughout the life course is needed. Objective: To assess temporal plasma biomarker changes and their association with all-cause dementia, overall and among subgroups of community-dwelling adults. Design, Setting, and Participants: In 1525 participants from the US-based Atherosclerosis Risk in Communities (ARIC) study, plasma biomarkers were measured using stored specimens collected in midlife (1993-1995, mean age 58.3 years) and late life (2011-2013, mean age 76.0 years; followed up to 2016-2019, mean age 80.7 years). Midlife risk factors (hypertension, diabetes, lipids, coronary heart disease, cigarette use, and physical activity) were assessed for their associations with change in plasma biomarkers over time. The associations of biomarkers with incident all-cause dementia were evaluated in a subpopulation (n = 1339) who were dementia-free in 2011-2013 and had biomarker measurements in 1993-1995 and 2011-2013. Exposure: Plasma biomarkers of amyloid-ß 42 to amyloid-ß 40 (Aß42:Aß40) ratio, phosphorylated tau at threonine 181 (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were measured using the Quanterix Simoa platform. Main Outcomes and Measures: Incident all-cause dementia was ascertained from January 1, 2012, through December 31, 2019, from neuropsychological assessments, semiannual participant or informant contact, and medical record surveillance. Results: Among 1525 participants (mean age, 58.3 [SD, 5.1] years), 914 participants (59.9%) were women, and 394 participants (25.8%) were Black. A total of 252 participants (16.5%) developed dementia. Decreasing Aß42:Aß40 ratio and increasing p-tau181, NfL, and GFAP were observed from midlife to late life, with more rapid biomarker changes among participants carrying the apolipoprotein E epsilon 4 (APOEε4) allele. Midlife hypertension was associated with a 0.15-SD faster NfL increase and a 0.08-SD faster GFAP increase per decade; estimates for midlife diabetes were a 0.11-SD faster for NfL and 0.15-SD faster for GFAP. Only AD-specific biomarkers in midlife demonstrated long-term associations with late-life dementia (hazard ratio per SD lower Aß42:Aß40 ratio, 1.11; 95% CI, 1.02-1.21; per SD higher p-tau181, 1.15; 95% CI, 1.06-1.25). All plasma biomarkers in late life had statistically significant associations with late-life dementia, with NfL demonstrating the largest association (1.92; 95% CI, 1.72-2.14). Conclusions and Relevance: Plasma biomarkers of AD neuropathology, neuronal injury, and astrogliosis increase with age and are associated with known dementia risk factors. AD-specific biomarkers' association with dementia starts in midlife whereas late-life measures of AD, neuronal injury, and astrogliosis biomarkers are all associated with dementia.

Mid-Life Vascular Risk and Rate of Physical Function Decline Among Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study.

BACKGROUND: Physical function and its decline in older age may be connected to treatable vascular risk factors in mid-life. This study aimed to evaluate whether these factors affect the underlying rate of decline. METHODS: This prospective cohort included 5 481 older adults aged 67-91 in the Atherosclerosis Risk in Communities Study (mean [standard deviation {SD}] age = 75.8 [5.0], 58% women, 21% Black race) without a history of stroke. The main outcome was the rate of Short Physical Performance Battery (SPPB) decline over a median late-life follow-up of 4.8 years. Primary mid-life (aged 45-64) exposures were Visit 1 hypertension (>140/90 mm Hg or treatment), diabetes (>126 mg/dL or treatment), high cholesterol (>240 mg/dL or treatment), and smoking, and number of decades of vascular risk exposure across Visits 1-4. RESULTS: The average adjusted rate of SPPB decline (points per 5 years) for older adults was -0.79 (confidence interval [CI]: -0.87, 0.71) and was accelerated by mid-life hypertension (+57% decline vs normotension: additional decline of -0.47, 95% CI: -0.64, -0.30), diabetes (+73% decline vs no diabetes: additional decline of -0.67, 95% CI: -1.09, -0.24), elevated systolic blood pressure (+17% decline per SD: -0.16, 95% CI: -0.23, -0.10), and elevated fasting blood glucose (+16% decline per SD: -0.015, 95% CI: -0.24, -0.06). Each decade greater mid-life exposure to hypertension (+32% decline: -0.93, 95% CI: -1.25, -0.61) and diabetes (+35% decline: -1.03, 95% CI: -1.68, -0.38) was associated with faster SPPB decline. CONCLUSIONS: Mid-life control of blood pressure and diabetes may offset aging-related functional decline.

Educational Attainment and Dementia: Mediation by Mid-Life Vascular Risk Factors.

INTRODUCTION: Lower education is associated with higher burden of vascular risk factors in mid-life and higher risk of dementia in late life. We aim to understand the causal mechanism through which vascular risk factors potentially mediate the relationship between education and dementia. METHODS: In a cohort of 13,368 Black and White older adults in the Atherosclerosis Risk in Communities Study, we assessed the relationship between education (grade school, high school without graduation, high school graduate or equivalent, college, graduate/professional school) and dementia among all participants and among those with incident stroke. Cox models were adjusted for age, race-center (a variable stratified by race and field center), sex, apolipoprotein E (APOE) ε4 genotype, and family history of cardiovascular disease. Causal mediation models assessed mediation by mid-life systolic blood pressure, fasting blood glucose, body mass index, and smoking. RESULTS: More education was associated with 8 to 44% lower risk of dementia compared to grade school-level education in a dose-response pattern, while the relationship between education and post-stroke dementia was not statistically significant. Up to 25% of the association between education and dementia was mediated through mid-life vascular risk factors, with a smaller percentage mediated for lower levels of education. INTERPRETATION: A substantial proportion of the relationship between education and dementia was mediated through mid-life vascular risk factors. However, risk factor modification is unlikely to fully address the large educational disparities in dementia risk. Prevention efforts must also address disparities in socioeconomic resources leading to divergent early-life education and other structural determinants of mid-life vascular risk factors. ANN NEUROL 2023;94:13-26.

Association of Kidney Function Measures With Signs of Neurodegeneration and Small Vessel Disease on Brain Magnetic Resonance Imaging: The Atherosclerosis Risk in Communities (ARIC) Study.

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) is a risk factor for cognitive decline, but evidence is limited on its etiology and morphological manifestation in the brain. We evaluated the association of estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR) with structural brain abnormalities visible on magnetic resonance imaging (MRI). We also assessed whether this association was altered when different filtration markers were used to estimate GFR. STUDY DESIGN: Cross-sectional study nested in a cohort study. SETTING & PARTICIPANTS: 1,527 participants in the Atherosclerosis Risk in Communities (ARIC) Study. PREDICTORS: Log(UACR) and eGFR based on cystatin C, creatinine, cystatin C and creatinine in combination, or ß2-microglobulin (B2M). OUTCOMES: Brain volume reduction, infarcts, microhemorrhages, white matter lesions. ANALYTICAL APPROACH: Multivariable linear and logistic regression models fit separately for each predictor based on a 1-IQR difference in the predictor value. RESULTS: Each 1-IQR lower eGFR was associated with reduced cortex volume (regression coefficient: -0.07 [95% CI, -0.12 to-0.02]), greater white matter hyperintensity volume (logarithmically transformed; regression coefficient: 0.07 [95% CI, 0.01-0.15]), and lower white matter fractional anisotropy (regression coefficient: -0.08 [95% CI, -0.17 to-0.01]). The results were similar when eGFR was estimated with different equations based on cystatin C, creatinine, a combination of cystatin C and creatinine, or B2M. Higher log(UACR) was similarly associated with these outcomes as well as brain infarcts and microhemorrhages (odds ratios per 1-IQR-fold greater UACR of 1.31 [95% CI, 1.13-1.52] and 1.30 [95% CI, 1.12-1.51], respectively). The degree to which brain volume was lower in regions usually susceptible to Alzheimer disease and LATE (limbic-predominant age-related TDP-43 [Tar DNA binding protein 43] encephalopathy) was similar to that seen in the rest of the cortex. LIMITATIONS: No inference about longitudinal effects due to cross-sectional design. CONCLUSIONS: We found eGFR and UACR are associated with structural brain damage across different domains of etiology, and eGFR- and UACR-related brain atrophy is not selective for regions typically affected by Alzheimer disease and LATE. Hence, Alzheimer disease or LATE may not be leading contributors to neurodegeneration associated with CKD.

Associations among Visual, Auditory, and Olfactory Functions in Community-Based Older Adults: The Atherosclerosis Risk in Communities (ARIC) Study.

Purpose: Objective examination of relationships among visual, hearing, and olfactory function may yield mechanistic insights and inform our understanding of the burden of multiple-sensory impairments. Methods: This cross-sectional study capitalized on continuous measures of visual acuity (VA), contrast sensitivity, pure tone audiometry, Quick Speech-in-Noise (QuickSIN), and Sniffin' Sticks from a subset of ARIC participants at two community sites (EyeDOC Study, 2017-2019). Scales of all measures were aligned such that higher values indicated greater impairment. Intersensory bivariate associations were assessed graphically, and correlations assessed using Kendall's tau. Intersensory associations, independent of age, education, smoking, diabetes, and hypertension, were examined using linear regression. Analyses were stratified by community/race (Washington County/White vs Jackson/Black) and sex (men vs women) to explore community-sex heterogeneity. Results: We included 834 participants (mean age, 79 years); 39% were from Jackson and 63% females. We found weak intersensory correlations (tau generally ≤0.15). In the demographics-adjusted regression models, results were heterogeneous across communities and sex. Worse near VA, contrast sensitivity, and olfaction were associated with worse QuickSIN and worse near VA was associated with worse olfaction in some but not all community/race-sex groups (e.g., Jackson/Black women, 0.1 logMAR worse near VA was associated with 0.27 units increase in QuickSIN [95% confidence interval, 0.10-0.45]). Associations were modestly attenuated by adjustment for the shared risk factors of smoking, diabetes, and hypertension. Conclusions: Visual dysfunction showed little or no association with hearing or olfaction impairments, suggesting a modest role for shared risk factors. Translational Relevance: Visually impaired individuals have only a modestly higher risk of other sensory impairment.

The Neuroanatomic Correlates of Olfactory Identification Impairment in Healthy Older Adults and in Persons with Mild Cognitive Impairment.

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.

Associations of Prior Head Injury With Olfaction in Older Adults: Results From the Atherosclerosis Risk in Communities (ARIC) Study.

Importance: Traumatic brain injury has been associated with short-term olfactory dysfunction, but the association of number of prior head injuries and head injury severity with both subjective and objective long-term olfactory function is less clear. Objective: To investigate the associations of prior head injury, number of prior head injuries, and head injury severity with subjective and psychophysical (objective) olfactory function in older adults and to examine concordance between subjective and objective olfactory function among individuals with and without head injury. Design, Setting, and Participants: This prospective cohort study included 5951 participants who attended Atherosclerosis Risk in Communities (ARIC) Study visit 5 (2011 through 2013). Data analysis was performed between November 2021 and May 2022. Exposures: Head injury was defined by self-report and International Classification of Diseases codes. Main Outcomes and Measures: Self-reported subjective olfactory dysfunction was assessed by the question, "Do you suffer from smell loss or a significantly decreased sense of smell?" Objective olfactory performance was assessed using the 12-item Sniffin' Sticks odor identification test. Results: Overall, the 5951 participants were a mean (SD) age of 75.6 (5.2) years, 3501 (58.8%) were female, 1356 (22.8%) were of Black race, and 1666 (28.0%) had a history of head injury. Participants with prior head injury were more likely than individuals without prior head injury to report subjective olfactory dysfunction (24% vs 20%; difference, 4%; 95% CI, 1% to 6%) and have objective anosmia (15% vs 13%; difference, 2%; 95% CI, 0.1% to 4%) but had lower concordance between subjective and objective assessment (72% vs 77%; difference, -5%; 95% CI, -8% to -3%). In logistic regression models adjusted for sociodemographics and medical comorbidities including cognitive status, participants with a history of prior head injury, particularly individuals with 2 or more prior head injuries and more severe head injuries, were more likely to self-report subjective olfactory dysfunction and were more likely to be found to have objective anosmia compared with participants with no history of head injury. Conclusions and Relevance: Findings of this cohort study provide evidence supporting the association between head injury and olfactory dysfunction, particularly among individuals who experienced multiple prior head injuries and among individuals with more severe head injury. The findings also suggest that individuals with prior head injury were more likely to both under-self-report and over-self-report deficits compared with objective olfactory testing; therefore, it may be important to consider objective olfactory testing in this patient population.

Association Between Acute Kidney Injury and Dementia in the Atherosclerosis Risk in Communities (ARIC) Study.

RATIONALE & OBJECTIVE: Acute kidney injury (AKI) causes biochemical changes in the brain in animal models and is associated with adverse neurological complications in hospitalized patients. This study tested the association between AKI and incident dementia in a community-based cohort. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Adult participants in the Atherosclerosis Risk in Communities (ARIC) study who experienced hospitalized AKI compared with participants hospitalized for other reasons (primary analysis, mean follow-up period 4.3 years) or participants without hospitalized AKI (secondary analysis). PREDICTORS: Incident AKI, defined by ICD codes from hospital records. OUTCOME: Incident dementia, diagnosed based on a combination of neurocognitive testing, informant interviews, ICD codes, and death certificates. ANALYTICAL APPROACH: In the primary analysis, we estimated the propensity for hospitalized AKI and matched these participants with those hospitalized for another reason to examine the association of AKI with subsequent onset of dementia (N = 1,708). In the secondary analysis, we estimated the association between time-varying hospitalized AKI and subsequent onset of dementia using multivariable Cox proportional hazards regression models, adjusted for age, sex, race/center, education, smoking status, body mass index, baseline estimated glomerular filtration rate, baseline urinary albumin-creatinine ratio, systolic blood pressure, coronary heart disease, diabetes, hypertension, apolipoprotein E (APOE) ε4 allele, and C-reactive protein. RESULTS: The mean age in the propensity-matched cohort was 76.1 ± 6.5 (SD) years, and 53.2% of the participants were women. People who were hospitalized with AKI had a higher risk of dementia (HR, 1.25 [95% CI, 1.02-1.52]; P = 0.03) compared with those without a hospitalization for AKI. The associations were slightly stronger in the time-varying analysis (HR, 1.69 [95% CI, 1.48-1.92]; P < 0.001). Other risk factors for dementia included older age, male sex, higher albuminuria, diabetes, current smoker status, and presence of the APOE risk alleles. LIMITATIONS: Observational study, with AKI identified through diagnosis codes. CONCLUSIONS: Participants who experienced a hospitalization for AKI were at increased risk of dementia.

Association of Cigarette Smoking Patterns Over 30 Years With Audiometric Hearing Impairment and Speech-in-Noise Perception: The Atherosclerosis Risk in Communities Study.

IMPORTANCE: The implications of cigarette smoking and smoking cessation for hearing impairment remain unknown. Many studies on this topic have failed to account for attrition among smokers in their findings. OBJECTIVE: To assess the association of cigarette smoking patterns with audiometric and speech-in-noise hearing measures among participants of the Atherosclerosis Risk in Communities Study. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study included participants of the Atherosclerosis Risk in Communities Study from 4 US communities. The analysis includes data from visit 1 (1987-1989) through visit 6 (2016-2017); data were analyzed from March 16 through June 25, 2021. Audiometric hearing and speech-in-noise testing was offered to all participants at visit 6. Participants with incomplete audiometric data or missing data for educational level, body mass index, drinking status, a diabetes or hypertension diagnosis, or occupational noise were excluded. In addition, individuals were excluded if they self-reported as having other than Black or White race and ethnicity, or if they self-reported as having Black race or ethnicity and lived in 2 predominantly White communities. MAIN OUTCOMES AND MEASURES: Smoking behavior was classified from visit 1 (1987-1989) to visit 6 (2016-2017) using group-based trajectory modeling based on self-reported smoking status at each clinic visit. Hearing was assessed at visit 6. An audiometric 4-frequency (0.5, 1, 2, 4 kHz) pure-tone average (PTA) was calculated for the better-hearing ear and modeled as a continuous variable. Speech-in-noise perception was assessed via the Quick Speech-in-Noise Test (QuickSIN) and modeled continuously. Attrition during the 30 years of follow-up was addressed by inverse probability of attrition weighting. RESULTS: A total of 3414 participants aged 72 to 94 years (median [IQR] age, 78.8 [76.0-82.9] years; 2032 [59.5%] women) when hearing was measured at visit 6 (2016-2017) were included in the cohort; 766 (22.4%) self-identified as Black and 2648 (77.6%) as White individuals. Study participants were classified into 3 smoking groups based on smoking behavior: never or former smoking at baseline (n = 2911 [85.3%]), quit smoking during the study period (n = 368 [10.8%]), and persistent smoking (n = 135 [4.0%]). In fully adjusted models, persistent smoking vs never or former smoking was associated with an average 2.69 (95% CI, 0.56-4.81) dB higher PTA (worse hearing) and 1.42 (95% CI, -2.29 to -0.56) lower QuickSIN score (worse performance). Associations were stronger when accounting for informative attrition during the study period (3.53 [95% CI, 1.14-5.93] dB higher PTA; 1.46 [95% CI, -2.52 to -0.41] lower QuickSIN scores). Smoking cessation during the study (vs never or former smoking) was not associated with changes in hearing. CONCLUSIONS AND RELEVANCE: In this cross-sectional study, persistent smoking was associated with worse audiometric hearing and speech-in-noise perception. Hearing measures among participants who quit smoking during the study period did not differ from those for never or former smokers, indicating that smoking cessation (as opposed to persistent smoking) may have benefits for hearing health.

Survival advantage of cohort participation attenuates over time: results from three long-standing community-based studies.

PURPOSE: Cohort participants usually have lower mortality rates than nonparticipants, but it is unclear if this survival advantage decreases or increases as cohort studies age. METHODS: We used a 1975 private census of Washington County, Maryland, to compare mortality among cohort participants to nonparticipants for three cohorts, Campaign Against Cancer and Stroke (CLUE I), Campaign Against Cancer and Heart Disease (CLUE II), and Atherosclerosis Risk In Communities (ARIC) initiated in 1974, 1989, and 1986, respectively. We analyzed mortality risk using time-truncated Cox regression models. RESULTS: Participants had lower mortality risk in the first 10 years of follow-up compared with nonparticipants (fully adjusted average hazard ratio [95% confidence intervals] were 0.72 [0.68, 0.77] in CLUE I, 0.69 [0.65, 0.73] in CLUE II, and 0.74 [0.63, 0.86] in ARIC), which persisted over 20 years of follow-up (0.81 [0.78, 0.84] in CLUE I, 0.87 [0.84, 0.91] in CLUE II, and 0.90 [0.83, 0.97] in ARIC). This lower average hazard for mortality among participants compared with nonparticipants attenuated with longer follow-up (0.99 [0.96, 1.01] after 30+ years in CLUE I, 1.02 [0.99, 1.05] after 30 years in CLUE II, and 0.95 [0.89, 1.00] after 30+ years in ARIC). In ARIC, participants who did not attend visits had higher mortality, but those who did attend visits had similar mortality to the community. CONCLUSIONS: Our results suggest the volunteer selection for mortality in long-standing epidemiologic cohort studies often diminishes as the cohort ages.

Association of Surgical Hospitalization with Brain Amyloid Deposition: The Atherosclerosis Risk in Communities-Positron Emission Tomography (ARIC-PET) Study.

BACKGROUND: As more older adults undergo surgery, it is critical to understand the long-term effects of surgery on brain health, particularly in relation to the development of Alzheimer's disease. This study examined the association of surgical hospitalization with subsequent brain ß-amyloid deposition in nondemented older adults. METHODS: The Atherosclerosis Risk in Communities-Positron Emission Tomography (ARIC-PET) study is a prospective cohort study of 346 participants without dementia who underwent florbetapir PET imaging. Active surveillance of local hospitals and annual participant contact were used to gather hospitalization and surgical information (International Classification of Disease, Ninth Revision, Clinical Modification codes) over the preceding 24-yr period. Brain amyloid measured using florbetapir PET imaging was the primary outcome. Elevated amyloid was defined as a standardized uptake value ratio of more than 1.2. RESULTS: Of the 313 participants included in this analysis (age at PET: 76.0 [SD 5.4]; 56% female), 72% had a prior hospitalization, and 50% had a prior surgical hospitalization. Elevated amyloid occurred in 87 of 156 (56%) participants with previous surgical hospitalization, compared with 45 of 87 (52%) participants who had no previous hospitalization. Participants with previous surgical hospitalizations did not show an increased odds of elevated brain amyloid (odds ratio, 1.32; 95% CI, 0.72 to 2.40; P = 0.370) after adjusting for confounders (primary analysis). Results were similar using the reference group of all participants without previous surgery (hospitalized and nonhospitalized; odds ratio, 1.58; 95% CI, 0.96 to 2.58; P = 0.070). In a prespecified secondary analysis, participants with previous surgical hospitalization did demonstrate increased odds of elevated amyloid when compared with participants hospitalized without surgery (odds ratio, 2.10; 95% CI, 1.09 to 4.05; P = 0.026). However, these results were attenuated and nonsignificant when alternative thresholds for amyloid-positive status were used. CONCLUSIONS: The results do not support an association between surgical hospitalization and elevated brain amyloid.

Albuminuria and Estimated GFR as Risk Factors for Dementia in Midlife and Older Age: Findings From the ARIC Study.

RATIONALE & OBJECTIVE: Evidence is limited on how estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio (UACR) relate to dementia at different ages. We evaluated eGFR and UACR in midlife and older age as risk factors for dementia. Additionally, we assessed whether the association between eGFR and dementia is altered when cystatin C and ß2-microglobulin (B2M) levels are used for GFR estimation. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: Two baselines from the Atherosclerosis Risk in Communities (ARIC) Study were used: visit 4 (1996-1998), including 9,967 participants 54 to 74 years old, and visit 5 (2011-2013), including 4,626 participants 70 to 90 years old. Participants were followed up until 2017. PREDICTORS: Log(UACR); eGFR based on creatinine, cystatin C, creatinine and cystatin C, or B2M levels (denoted as eGFRcr, eGFRcys, eGFRcr-cys, and eGFRB2M). OUTCOME: Incident dementia. ANALYTICAL APPROACH: Multivariable Cox proportional hazards regression models fit separately for each of the 5 predictors and based on a change in the predictor equivalent to the interquartile range for that predictor at visit 4 (IQRV4). eGFR models were adjusted for log(UACR) and log(UACR) models were adjusted for eGFRcys. RESULTS: We observed 1,821 dementia cases after visit 4 and 438 cases after visit 5. Dementia risk increased with higher albuminuria levels (HRs per IQRV4 [equivalent to 4.2-fold greater log albuminuria] of 1.15 [95% CI, 1.09-1.21] after visit 4 and 1.27 [95% CI, 1.13-1.42] after visit 5). An association with lower eGFR was seen for only eGFRcys (HRs per IQRV4 [equivalent to 24.3mL/min/1.73m2 lesser eGFRcys] of 1.12 [95% CI, 1.04-1.21] after visit 4 and 1.30 [95% CI, 1.12-1.52] after visit 5) and eGFRB2M (HRs per IQRV4 [equivalent to 18.3mL/min/1.73m2 lesser eGFRB2M] of 1.15 [95% CI, 1.07-1.23] after visit 4 and 1.34 [95% CI, 1.17-1.55] after visit 5). Differences between these associations in midlife and older age were not statistically significant. LIMITATIONS: Changes in potentially time-varying covariates were not measured. Dementia was not subclassified by cause. CONCLUSIONS: Albuminuria was consistently associated with dementia incidence. Lower eGFR based on cystatin C or B2M, but not creatinine, levels was also associated with dementia. Risk associations were similar when kidney measures were assessed at midlife and older age.

Association Between Microvascular Retinal Signs and Age-Related Hearing Loss in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS).

Importance: Given that age-related hearing loss is highly prevalent and treatable, understanding its causes may have implications for disease prevention. Objective: To investigate whether microvascular retinal signs are associated with age-related hearing loss attributable to a hypothesized underlying shared pathologic entity involving microvascular disease. Design, Setting, and Participants: The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) is a community-based prospective cohort study of 15 792 men and women aged 45 to 64 years at baseline. The ARIC-NCS participants returned for a fifth clinic visit in 2011-2013 and a sixth clinic visit in 2016-2017. Participants were recruited from 4 US communities (Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and Minneapolis suburbs, Minnesota). Participants included a subset of the ARIC-NCS cohort with complete covariate data who underwent retinal fundus photography at visit 5 (2011-2013) and completed hearing assessment at visit 6 (2016-2017) (N = 1458). Overall, 453 participants had diabetes; of those, 68 had retinopathy. Of 1005 participants without diabetes, 42 had retinopathy. Exposures: Microvascular retinal signs included retinopathy, arteriovenous (AV) nicking, and generalized arteriolar narrowing measured using the central retinal arteriolar equivalent (CRAE). Main Outcomes and Measures: Hearing was measured using the better-hearing ear pure-tone average (PTA) of air conduction speech thresholds (0.5, 1, 2, and 4 kHz). Multivariable-adjusted linear and ordered logistic regression was used to estimate the association between microvascular retinal signs and age-related hearing loss to describe the precision of the estimates and provide a plausible range for the true association. Results: After full adjustment among 1458 individuals in the analytic cohort (mean [SD] age, 76.1 [5.0] years [age range, 67-90 years]; 825 women [56.6%]; 285 black [19.5%]), the difference in PTA per dB hearing level in persons with and without retinopathy was 2.21 (95% CI, -0.22 to 4.63), suggesting that retinopathy is associated with poorer hearing, although the width of the 95% CI prevents definitive conclusions about the strength of the observed association. Restricting the analysis to participants without diabetes, the difference in PTA associated with retinopathy was even greater (4.14; 95% CI, 0.10-8.17 dB hearing level), but the large width of the 95% CI prevents definitive conclusions about the association. In analyses quantifying the mean differences in hearing thresholds at individual frequencies by retinopathy status, the estimates trended toward retinopathy being associated, contrary to expectation, with better high-frequency hearing. At 8 kHz, the estimated difference in hearing thresholds in persons with retinopathy vs those without was -4.24 (95% CI, -7.39 to -1.09). Conclusions and Relevance: In this population-based study, an association between the presence of microvascular retinal signs and hearing loss was observed, suggesting that retinopathy may have the potential to identify risk for hearing loss in persons without diabetes. The precision of these estimates is low; therefore, additional epidemiologic studies are needed to better define the degree of microvascular contributions to age-related hearing loss.

Central arterial stiffness and retinal vessel calibers: the Atherosclerosis Risk in Communities Study-Neurocognitive Study.

BACKGROUND: The retinal microvasculature provides a window to the cerebral vasculature and enables examination of changes in retinal caliber that may mimic those occurring in cerebrovascular disease. The association of central arterial stiffness and retinal vessel caliber in a population sample is not fully understood. METHODS: In 1706 older adults (mean age 76.3, 58.1% women) from the population-based Atherosclerosis Risk in Communities Study, we examined the cross-sectional association of central arterial stiffness [carotid-femoral pulse wave velocity (cfPWV)] with retinal vessel calibers [central retinal arteriolar equivalent (CRAE) and central retinal vein equivalent (CRVE)]. We estimated the association of cfPWV with CRAE narrowing (<25th percentile) and CRVE widening (>75th percentile) after adjustment for age, sex, race-field center, BMI, smoking, and type 2 diabetes. We tested for effect modification by sex, hypertension, and type 2 diabetes. RESULTS: Carotid-femoral PWV (m/s) was not associated with the odds of CRAE narrowing [odds ratio (OR): 0.99; 95% CI: 0.95-1.03]. The association of cfPWV with CRVE widening was stronger in those without hypertension (OR: 1.10; 95% CI: 1.01-1.20) versus those with hypertension (OR: 1.01 95% CI: 0.96-1.05) and slightly stronger in those with type 2 diabetes (OR: 1.07; 95% CI: 1.00-1.14) versus without type 2 diabetes (OR: 1.01; 95% CI: 0.96-1.06). CONCLUSIONS: In older adults, cfPWV was associated with wider retinal venular caliber, particularly in individuals without hypertension. Central arterial stiffening may be associated with cerebral microvascular changes, as exhibited in its retinal vasculature component.

Relationship of Cigarette Smoking and Time of Quitting with Incident Dementia and Cognitive Decline.

OBJECTIVES: Understanding how dementia risk is impacted by timing of smoking cessation has public health implications for prevention efforts. We investigated the relationship of cigarette smoking and cessation with dementia risk and cognitive decline in the Atherosclerosis Risk in Communities (ARIC) study. DESIGN: Ongoing prospective cohort study. SETTING: Begun in 1987-1989, ARIC was conducted in four US communities. PARTICIPANTS: A total of 13 002 men and women (25% African American) aged 52 to 75 years. MEASUREMENTS: All-cause dementia was defined using standardized algorithms incorporating longitudinal cognitive data, proxy report, and hospital and death certificate dementia codes. Cognitive decline was measured using a composite cognitive score created from three tests measured at two time points (1996-1998 and 2011-2013). Smoking and cessation status were defined by self-report using data from 1987-1989 (visit 1) and 1996-1998 (visit 4). Incident dementia risk and differences in cognitive change by smoking status were estimated with Cox proportional hazards and linear regression models, respectively. To address smoking-related attrition, cognitive scores were imputed for living participants with incomplete cognitive testing. RESULTS: The proportion of never, former, and current smokers was 44%, 41%, and 14%; 79% of former smokers quit 9 years or more before baseline. A total of 1347 participants developed dementia. After adjustment, compared with never smoking, the hazard ratio for all-cause dementia for current smoking was 1.33 (95% confidence interval [CI] = 1.12-1.59) and for recent quitting (<9 y before baseline) was 1.24 (95% CI = 1.01-1.52). Quitting 9 years or more before baseline was not associated with dementia. We found no differences in rates of cognitive decline by smoking status. CONCLUSION: Although quitting at any time suggested benefit, dementia risk depended on time since smoking cessation. Our study highlights the importance of early midlife cessation to decrease dementia risk. J Am Geriatr Soc 68:337-345, 2020.

The Association of Severe Hypoglycemia With Incident Cardiovascular Events and Mortality in Adults With Type 2 Diabetes.

OBJECTIVE: There is suggestive evidence linking hypoglycemia with cardiovascular disease, but few data have been collected in a community-based setting. Information is lacking on individual cardiovascular outcomes and cause-specific mortality. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort analysis of 1,209 participants with diagnosed diabetes from the Atherosclerosis Risk in Communities (ARIC) study (analytic baseline, 1996-1998). Severe hypoglycemic episodes were identified using first position ICD-9 codes from hospitalizations, emergency department visits, and ambulance calls through 2013. Cardiovascular events and deaths were captured through 2013. We used adjusted Cox regression models with hypoglycemia as a time-varying exposure. RESULTS: There were 195 participants with at least one severe hypoglycemic episode during a median fellow-up of 15.3 years. After severe hypoglycemia, the 3-year cumulative incidence of coronary heart disease was 10.8% and of mortality was 28.3%. After adjustment, severe hypoglycemia was associated with coronary heart disease (hazard ratio [HR] 2.02, 95% CI 1.27-3.20), all-cause mortality (HR 1.73, 95% CI 1.38-2.17), cardiovascular mortality (HR 1.64, 95% CI 1.15-2.34), and cancer mortality (HR 2.49, 95% CI 1.46-4.24). Hypoglycemia was not associated with stroke, heart failure, atrial fibrillation, or noncardiovascular and noncancer death. Results were robust within subgroups defined by age, sex, race, diabetes duration, and baseline cardiovascular risk. CONCLUSIONS: Severe hypoglycemia is clearly indicative of declining health and is a potent marker of high absolute risk of cardiovascular events and mortality.

Neuroimaging Correlates of Cerebral Microbleeds: The ARIC Study (Atherosclerosis Risk in Communities).

BACKGROUND AND PURPOSE: Cerebral microbleed (CMB) location (deep versus strictly lobar) may elucidate underlying pathology with deep CMBs being more associated with hypertensive vascular disease and lobar CMBs being more associated with cerebral amyloid angiopathy. The objective of this study was to determine whether neuroimaging signs of vascular disease and Alzheimer pathology are associated with different types of CMBs. METHODS: Among 1677 nondemented ARIC (Atherosclerosis Risk in Communities) participants (mean age=76±5 years; 40% men; 26% black) with 3-Tesla MRI scans at the fifth examination (2011-2013), we fit multinomial logistic regression models to quantify relationships of brain volumes (Alzheimer disease signature regions, total gray matter, frontal gray matter, and white matter hyperintensity volumes), infarct frequencies (lacunar, nonlacunar, and total), and apolipoprotein E (number of ε4 alleles) with CMB location (none, deep/mixed, or strictly lobar CMBs). Models were weighted for the sample selection scheme and adjusted for age, sex, education, hypertension, ever smoking status, diabetes mellitus, race site membership, and estimated intracranial volume (brain volume models only). RESULTS: Deep/mixed and strictly lobar CMBs had prevalences of 8% and 16%, respectively. Larger white matter hyperintensity burden, greater total infarct frequency, smaller frontal volumes (in women only), and smaller total gray matter volume were associated with greater risk of both deep and lobar CMBs relative to no CMBs. Greater white matter hyperintensity volume was also associated with greater risk of deep relative to lobar CMBs. Higher lacunar and nonlacunar infarct frequencies were associated with higher risk of deep CMBs, whereas smaller Alzheimer disease signature region volume and apolipoprotein E ε4 homozygosity were associated with greater risk of lobar CMBs. CONCLUSIONS: CMBs are a common vascular pathology in the elderly. Markers of hypertensive small-vessel disease may contribute to deep CMBs while cerebral amyloid angiopathy may drive development of lobar CMBs.

Physical Activity in Midlife is not Associated with Cognitive Health in Later Life Among Cognitively Normal Older Adults.

BACKGROUND: Links between physical activity and dementia are based primarily on cross-sectional data or studies with unsatisfactory follow-up. OBJECTIVE: We leveraged three decades of follow-up from an established cohort to determine whether physical activity in midlife is associated with late-life cognition and dementia. METHODS: The Johns Hopkins Precursors study (n = 646) enrolled participants from 1948-1964 and administered questions about physical activity, from which we calculated metabolic equivalents (MET h/day), and exercise from 1978-present. Cognitive tests were administered in 2008. Dementia was adjudicated through 2011. To characterize associations with midlife physical activity, we used linear regression for cognitive tests and Cox proportional hazards models for dementia onset. Models adjusted for age, sex, smoking, diabetes, and hypertension. RESULTS: No physical activity measure from 1978 was associated with late-life cognition or onset of dementia. Both MET h/day (ß= 0.007, 95% CI: 0.002, 0.013) and regular exercise (ß= 0.357, 95% CI: 0.202, 0.513) in 2006, however, were associated with better cognition in 2008. CONCLUSION: Findings from this 30-year cohort study that physical activity measured recently, but not in mid-life, is associated with late-life cognition fits with null findings from randomized trials and other observational studies with extensive follow-up. Cross-sectional findings may be misleading due to reverse causation.

Associations Between Midlife Vascular Risk Factors and 25-Year Incident Dementia in the Atherosclerosis Risk in Communities (ARIC) Cohort.

Importance: Vascular risk factors have been associated with cognitive decline. Midlife exposure to these factors may be most important in conferring late-life risk of cognitive impairment. Objectives: To examine Atherosclerosis Risk in Communities (ARIC) participants in midlife and to explore associations between midlife vascular risk factors and 25-year dementia incidence. Design, Setting, and Participants: This prospective cohort investigation of the Atherosclerosis Risk in Communities (ARIC) Study was conducted from 1987-1989 through 2011-2013. The dates of this analysis were April 2015 through August 2016. The setting was ARIC field centers (Washington County, Maryland; Forsyth County, North Carolina; Jackson, Mississippi; and Minneapolis suburbs, Minnesota). The study comprised 15 744 participants (of whom 27.1% were black and 72.9% white) who were aged 44 to 66 years at baseline. Main Outcomes and Measures: Demographic and vascular risk factors were measured at baseline (obesity, smoking, diabetes, prehypertension, hypertension, and hypercholesterolemia) as well as presence of the APOE ε4 genotype. After the baseline visit, participants had 4 additional in-person visits, for a total of 5 in-person visits, hospitalization surveillance, telephone calls, and repeated cognitive evaluations. Most recently, in 2011-2013, through the ARIC Neurocognitive Study (ARIC-NCS), participants underwent a detailed neurocognitive battery, informant interviews, and adjudicated review to define dementia cases. Additional cases were identified through the Telephone Interview for Cognitive Status-Modified or informant interview, for participants not attending the ARIC-NCS visit, or by an International Classification of Diseases, Ninth Revision dementia code during a hospitalization. Fully adjusted Cox proportional hazards regression was used to evaluate associations of baseline vascular and demographic risk factors with dementia. Results: In total, 1516 cases of dementia (57.0% female and 34.9% black, with a mean [SD] age at visit 1 of 57.4 [5.2] years) were identified among 15 744 participants. Black race (hazard ratio [HR], 1.36; 95% CI, 1.21-1.54), older age (HR, 8.06; 95% CI, 6.69-9.72 for participants aged 60-66 years), lower educational attainment (HR, 1.61; 95% CI, 1.28-2.03 for less than a high school education), and APOE ε4 genotype (HR, 1.98; 95% CI, 1.78-2.21) were associated with increased risk of dementia, as were midlife smoking (HR, 1.41; 95% CI, 1.23-1.61), diabetes (HR, 1.77; 95% CI, 1.53-2.04), prehypertension (HR, 1.31; 95% CI, 1.14-1.51), and hypertension (HR, 1.39; 95% CI, 1.22-1.59). The HR for dementia for diabetes was almost as high as that for APOE ε4 genotype. Conclusions and Relevance: Midlife vascular risk factors are associated with increased risk of dementia in black and white ARIC Study participants. Further studies are needed to evaluate the mechanism of and opportunities for prevention of the cognitive sequelae of these risk factors in midlife.

Association Between Midlife Vascular Risk Factors and Estimated Brain Amyloid Deposition.

IMPORTANCE: Midlife vascular risk factors have been associated with late-life dementia. Whether these risk factors directly contribute to brain amyloid deposition is less well understood. OBJECTIVE: To determine if midlife vascular risk factors are associated with late-life brain amyloid deposition, measured using florbetapir positron emission tomography (PET). DESIGN, SETTING, AND PARTICIPANTS: The Atherosclerosis Risk in Communities (ARIC)-PET Amyloid Imaging Study, a prospective cohort study among 346 participants without dementia in 3 US communities (Washington County, Maryland; Forsyth County, North Carolina; and Jackson, Mississippi) who have been evaluated for vascular risk factors and markers since 1987-1989 with florbetapir PET scans in 2011-2013. Positron emission tomography image analysis was completed in 2015. EXPOSURES: Vascular risk factors at ARIC baseline (age 45-64 years; risk factors included body mass index ≥30, current smoking, hypertension, diabetes, and total cholesterol ≥200 mg/dL) were evaluated in multivariable models including age, sex, race, APOE genotype, and educational level. MAIN OUTCOMES AND MEASURES: Standardized uptake value ratios (SUVRs) were calculated from PET scans and a mean global cortical SUVR was calculated. Elevated florbetapir (defined as a SUVR >1.2) was the dependent variable. RESULTS: Among 322 participants without dementia and with nonmissing midlife vascular risk factors at baseline (mean age, 52 years; 58% female; 43% black), the SUVR (elevated in 164 [50.9%] participants) was measured more than 20 years later (median follow-up, 23.5 years; interquartile range, 23.0-24.3 years) when participants were between 67 and 88 (mean, 76) years old. Elevated body mass index in midlife was associated with elevated SUVR (odds ratio [OR], 2.06; 95% CI, 1.16-3.65). At baseline, 65 participants had no vascular risk factors, 123 had 1, and 134 had 2 or more; a higher number of midlife risk factors was associated with elevated amyloid SUVR at follow-up (30.8% [n = 20], 50.4% [n = 62], and 61.2% [n = 82], respectively). In adjusted models, compared with 0 midlife vascular risk factors, the OR for elevated SUVR associated with 1 vascular risk factor was 1.88 (95% CI, 0.95-3.72) and for 2 or more vascular risk factors was 2.88 (95% CI, 1.46-5.69). No significant race × risk factor interactions were found. Late-life vascular risk factors were not associated with late-life brain amyloid deposition (for ≥2 late-life vascular risk factors vs 0: OR, 1.66; 95% CI, 0.75-3.69). CONCLUSIONS AND RELEVANCE: An increasing number of midlife vascular risk factors was significantly associated with elevated amyloid SUVR; this association was not significant for late-life risk factors. These findings are consistent with a role of vascular disease in the development of Alzheimer disease.