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Introduction: Associations of nonalcoholic fatty liver disease (NAFLD) with dementia are controversial. The full spectrum of NAFLD from simple steatosis to fibrosis has been less investigated. Hypothesis: The severity of NAFLD, especially with the stage of liver fibrosis, is associated with dementia. Methods: The associations between midlife (1990-92, N=9283, mean age 57, female 55%) and late-life (2011-13, N=5138, mean age 75, female 58%) NAFLD and all cause dementia were quantified by Cox regression. NAFLD was characterized using the fatty liver index and liver fibrosis assessment model (FIB-4). Dementia was adjudicated and ascertained through Dec. 31, 2019 from neuropsychological assessments, annual participant or informant contact, and medical record surveillance. We used Cox models with adjustment for demographics, APOE ε4, alcohol, and kidney function. Additional adjustments were made for metabolic factors to explore the independent contribution of NAFLD to dementia. Results: During a median follow-up of 24.5 years after midlife NAFLD assessment, 1854 participants developed dementia. During a median of 6.3 years in late-life, there were 893 dementia cases. A graded increase in dementia risk across the spectrum of NAFLD was observed at midlife (p-trend Figure ). In fact, NAFLD in late-life tended to be protective against dementia. After adjusting for the metabolic factors, the associations remained statistically significant in some categories. Conclusions: Remodeling of hepatic architecture and dysregulation in hepatocellular function in NAFLD at midlife plausibly induce peripheral promoters of neurodegeneration and may expose a large segment of the population to increased risk of dementia. The inverse association of NAFLD with dementia at late-life requires further investigation, possibly reflecting the depletion of susceptibles, the reversibility of NAFLD due to weight loss, and the lack of accuracy in identifying NAFLD using clinical prediction models at older age.

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.

Background: Stroke is associated with increased risk of mortality. However, studies on the association between stroke severity and mortality using prospective cohort data with details on cardiovascular risk factors at midlife have not been published in recent years in the US. We studied the association between stroke severity and subsequent all-cause mortality in the Atherosclerosis Risk in Communities Study (ARIC) study. Hypothesis: Risk of all-cause mortality increases after incident ischemic strokes with greater risk at higher stroke severity. Methods: Severity of incident ischemic strokes in ARIC from 1987 to 2018 was assessed through review of hospital records using the National Institutes of Health Stroke Scale (NIHSS) and categorized as minor, (NIHSS ≤5), mild (6-10), moderate (11-15), and severe (≥16). Deaths were ascertained through linkage with the National Death Index. We used Cox proportional hazard models adjusted for demographic variables and baseline risk factors to determine the hazard ratios (HRs) for all-cause mortality associated with each category of stroke severity, in participants after incident ischemic stroke compared to those who remained stroke-free throughout the study period. Results: Among 15661 participants free of stroke at baseline (1987-1989), 1036 developed incident ischemic stroke. There were 757 deaths among participants with incident ischemic stroke during the follow-up after stroke (median=16.1 years). Mean baseline age was 54.16 years, 55.2% women and 26.8% black participants. Cox proportional HRs of mortality after incident ischemic stroke controlling for demographics (Model 1) and further adjusted for risk factors at midlife (age 45-64) are displayed in Table 1. Conclusion: Compared to participants free from ischemic stroke, after adjustment for cardiovascular risk factors at midlife, risk of all-cause mortality was 2 to 12-folds higher in ARIC participants after incident ischemic stroke, with a greater risk of mortality observed in those with higher stroke severity.

Background: Stroke severity at hospital admission is the most important clinical predictor of short- and long-term functional outcome and mortality after stroke. Decreases in stroke severity over the last two decades have been reported in some countries; however, data on stroke severity from large prospective cohort studies in the US are not available for recent years. We studied trends in stroke severity of incident ischemic stroke from 1987 to 2018 in the prospective Atherosclerosis Risk in Communities (ARIC) study. Methods: Severity of stroke on admission was determined through review of ARIC hospital charts for incident ischemic strokes using the National Institutes of Health Stroke Scale (NIHSS). Events with inadequate information for NIHSS score determination were excluded (n=209). Severity was categorized as minor, NIHSS≤5; mild, 6-10; moderate, 11-15; and severe, ≥16. Mean NIHSS scores by year were presented by age group (Figure) and trends in NIHSS score from 1987 to 2018 were studied with linear regression model. Changes in the proportion of minor stroke compared to more severe stroke (NIHSS>5) were assessed using logistic regression. Multivariable models included age at stroke, sex, race-center, and baseline education level, hypertension, BMI, diabetes and smoking status as covariates. Results: Among 15,661 participants (age 45-64) free of stroke at baseline (1987-89), 1,036 incident stroke cases with severity scores (NIHSS: 638 [61.6%] minor, 222 [21.4%] mild, 88 [8.5%] moderate and 88 [8.5%] severe) were included. Mean age (SD) at incident stroke was 69.5 (9.9) years, 55.2% women and 26.8% Black. For each 1-year calendar time, the adjusted estimate for the continuous NIHSS score was -0.026 (SE=0.040), p=0.5109, and the adjusted OR (95% CI) for NIHSS≤5 compared to NIHSS>5 was 0.99 (0.97, 1.01). Conclusion: Among participants with incident ischemic stroke in the prospective ARIC study, no clear decrease in severity of stroke was observed from 1987 to 2018.

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

Background Multisystem dysregulation (Dm) shows promise as a metric of aging and predicts mortality. However, Dm needs to be studied with less severe endpoints indicating modifiable aging stages. Physical function, reflecting healthy longevity rather than just longevity, is more relevant to the goals of geroscience but has not been well investigated. Methods We tested the association of midlife Dm and its change over ~20 years with physical function in later life in 5 583 the Atherosclerosis Risk in Communities Study cohort participants (baseline mean age 54.7). Dm quantifies the multivariate statistical deviation of 17 physiologically motivated biomarkers relative to their distribution in a young healthy sample at baseline. Physical function was assessed from grip strength and the Short Physical Performance Battery (SPPB). Associations were quantified using linear regression and ordinal logistic regression adjusting for age, sex, race, and education. Results Each unit increment in midlife Dm was associated with 1.71 times the odds of having a lower SPPB score. Compared to the first quartile of midlife Dm, the odds ratios of having a lower SPPB score were 1.25, 1.56, and 2.45, respectively, for the second–fourth quartiles. Similar graded association patterns were observed for each SPPB component test and grip strength. An inverse monotonic relationship also was observed between the annual growth rate of Dm and physical function. Conclusion Greater Dm and progression in midlife were associated with lower physical function in later life. Future studies on the factors that lead to the progression of Dm may highlight opportunities to preserve physical function.

Background: Low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the low physiologic range, surrogate markers for reduced liver metabolic function, are associated with cerebral hypometabolism, impairment in neurotransmitter production and synaptic maintenance, and a higher prevalence of dementia. It is unknown whether a prospective association exists between low liver enzyme levels and incident dementia. Objective: To determine whether low levels of ALT and AST are associated with higher risk of incident dementia. Methods: Plasma ALT and AST were measured on 10,100 study participants (mean age 63.2 years, 55% female, 22% black) in 1996–1998. Dementia was ascertained from comprehensive neuropsychological assessments, annual contact, and medical record surveillance. Cox proportional hazards regression was used to estimate the association. Results: During a median follow-up of 18.3 years (maximum 21.9 years), 1,857 individuals developed dementia. Adjusted for demographic factors, incidence rates of dementia were higher at the lower levels of ALT and AST. Compared to the second quintile, ALT values

Nondaily smoking is increasing in the United States and common among Hispanic/Latino smokers. We characterized factors related to longitudinal smoking transitions in Hispanic/Latino nondaily smokers.The Hispanic Community Health Study/Study of Latinos is a population-based cohort study of Hispanics/Latinos aged 18-74 years. Multinomial logistic regression assessed the baseline factors (2008-2011) associated with follow-up smoking status (2014-2017) in nondaily smokers (n = 573), accounting for complex survey design.After ∼6 years, 41% of nondaily smokers became former smokers, 22% became daily smokers, and 37% remained nondaily smokers. Factors related to follow-up smoking status were number of days smoked in the previous month, household smokers, education, income, and insurance. Those smoking 16 or more of the last 30 days had increased risk of becoming a daily smoker [vs. 4 days; relative risk ratio (RRR) = 5.65, 95% confidence interval (95% CI) = 1.96-16.33]. Greater education was inversely associated with transitioning to daily smoking [high school vs.ninth grade: RRR (95% CI) = 0.30 (0.09-0.95)]. Living with smokers was associated with decreased likelihood of quitting [RRR (95% CI) = 0.45 (0.24-0.86)]. Having insurance was associated with quitting [RRR (95% CI) = 2.11 (1.18-3.76)] and becoming a daily smoker [RRR (95% CI) = 3.00 (1.39-6.48)].Many Hispanic/Latino nondaily smokers became daily smokers, which may increase their risk of adverse health outcomes. Addressing different smoking patterns in primary care may be useful to prevent smoking-related diseases.

Background: African-Americans experience a disproportionate burden of heart failure. Although previous research has identified neighborhoods as an important contributor to these disparities, less is understood about how psychosocial resilience factors, such as optimism, may provide protection from the effects of neighborhood disadvantage on heart failure risk. We tested the hypothesis that higher levels of optimism will attenuate the associations between greater neighborhood disadvantage and higher incidence of heart failure. Methods: Among 1,448 African-Americans dually enrolled in two community-based cohorts in Jackson, Mississippi—JHS and the ARIC study—who were free of heart failure as of January 1, 2000, 459 failure events classified by reviewer panel accrued through December 31, 2019. Multi-level age- and sex-adjusted Cox regression models with interaction terms were used to examine whether individual-level optimism moderated the associations of four measures of census tract-level neighborhood socioeconomic and social environment characteristics (the national Area Deprivation Index (ADI), a JHS neighborhood disadvantage score, racial residential segregation, and perceived physical disorder) on individual-level incident hospitalized heart failure. Results: Optimism moderated the associations of some neighborhood disadvantage measures (ADI and JHS neighborhood disadvantage score) on hospitalized heart failure risk (Table). Compared to participants reporting the lowest level of optimism, those in the highest tertile had 12%, 6%, 16%, and 9% lower rates of heart failure associated with increasing neighborhood disadvantage, respectively for each exposure. Interaction estimates for racial residential segregation and perceived physical disorder did not reach statistical significance. Conclusions: Optimism may provide resilience to the detrimental effects of neighborhood disadvantage on risk for heart failure.

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

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

Background: Dementia prevention largely focuses on the modification of vascular risk factors and is particularly important among stroke survivors, who have the highest burden of vascular risk factors and are at elevated risk of dementia. Low educational attainment is a risk factor not only for worse vascular profiles at midlife but also for incident dementia. It is unclear to what extent the relationship between education and dementia is mediated through these vascular risk factors. Methods: In a cohort of 14,059 Black and White older adults in four U.S. communities, we assessed the relationship between education and dementia among all participants and, separately, among those with incident stroke. We used causal mediation analysis to assess multiple mediation by midlife hypertension, diabetes, BMI and smoking of the relationship between educational attainment and dementia. Results: Participants with less education had higher prevalence of mid-life risk factors. Lower education was associated with 60% higher risk of dementia and 40% higher risk of post-stroke dementia. About half of the association between education and dementia was mediated through vascular risk factors (Table 1). Conclusion: A substantial proportion of the relationship between education and dementia risk is indeed not mediated through mid-life vascular risk factors. The association between education and dementia was weaker in the high-risk participants who have had an incident stroke, indicating that more proximal causes such as vascular disease prior to the stroke superseded the distal cause of differences in educational attainment. As such, any mediated effect of education on dementia is likely through vascular risk factors earlier on in the life-course. Our findings suggest that dementia prevention efforts must also address disparities in socioeconomic resources as well as other mediating pathways.

Introduction: Excessive ventricular ectopy (VE) is a risk factor for stroke. It is unclear whether higher frequency of VE is associated with the risk of dementia. Hypothesis: Higher frequency of VE, including ventricular tachycardias (VT) and premature ventricular contractions (PVC), are associated with a higher risk of dementia. Methods: We included 2167 participants without adjudicated dementia, stroke or atrial fibrillation (mean age, 79 years, 60% female, 26% Black). We measured burden of VT and PVC over 2 weeks at baseline (2016-17) with Zio XT patch: an ambulatory ECG recorder (iRhythm Technologies, Inc.). We quantified PVC burden as: 1) natural log of frequency in episodes/day (due to skewed distribution) and 2) dichotomously, split at the median level of frequency. We quantified VT burden as: 1) presence of any VT, 2) frequency of VT (episodes/day) split at the median, and 3) duration of the longest VT episode split at the median, using ‘no VT’ group as the referent in each case. We adjudicated dementia events through 2019 using cognitive testing at study visits, telephone cognitive interviews, and medical records. We calculated relative risk of incident dementia by Poisson regression with robust error variance. Results: At baseline, PVC and VT were present in 99% and 27% of participants, respectively. Over 2 years of follow-up, 66 (3.0%) participants developed dementia. Higher frequency of PVCs and VTs (≥ median vs none), and longer duration of the longest VT episode (≥ median vs none) were associated with a higher risk of dementia independent of cardiovascular (CV) disease and risk factors (Table). These associations were attenuated after adjusting for incident stroke. Conclusions: In older adults, higher VE frequency is associated with a higher dementia risk independent of CV risk factors. Our novel findings broaden the scope of “vascular contribution to cognitive impairment and dementia” to include ventricular arrhythmias as novel risk factors for dementia.

Introduction: In older adults without atrial fibrillation (AF), it is unclear if higher burden of supraventricular ectopy (SVE) is associated with dementia risk independent of cardiovascular risk factors and clinically documented stroke. Hypothesis: In older adults without AF, higher burden of SVE including premature atrial contractions (PAC) and atrial tachycardias (AT) are associated with a higher risk of dementia. Methods: Among 2167 participants (mean age, 79 years, 60% female, 26% Black) without adjudicated dementia, stroke or AF, at baseline (2016-17), AT and PAC were measured over 2 weeks by an ambulatory, continuous electrocardiogram recorder (Zio XT patch, iRhythm Technologies, Inc.). We quantified burden of PACs and ATs as: 1) natural log of frequency (episodes/day) due to skewed distributions, and 2) a dichotomous frequency measure, split at the median. Additionally, we dichotomized duration of the longest AT episode at the median. Dementia was adjudicated based on cognitive assessments through 2019 using the Clinical Dementia Rating scale at study visits or by telephone cognitive interviews, informant interviews, and ongoing linkage to medical records. We calculated relative risk of incident dementia using Poisson regression with robust error variance. Results: At baseline, median Zio XT patch wear time was 13.8 days (interquartile interval 13-14 days). Over 2 years of follow-up, 66 (3.0%) participants developed dementia. Higher frequency of AT and PAC (continuous or dichotomous) were associated with a higher risk of dementia independent of incident AF, stroke, and cardiovascular risk factors (Table). Conclusions: In older adults without AF, higher burden of SVE is associated with a greater risk of dementia independent of incident AF, stroke, and cardiovascular risk factors. Future research should define underlying mechanisms and evaluate the effect of lowering SVE burden on the risk of dementia in older adults with a higher SVE burden.

Introduction: Age-related homeostatic dysregulation (Dm), characterized by multi-biomarker composite measures, has shown promise as a rate-of-aging metric. We tested the association of midlife Dm and its change over ~20 years of follow-up with later life physical function. Methods: We studied 4617 ARIC cohort participants (mean age 54.8 years, 58% female, 20% Black) who completed in-person examinations from 1990-92 (baseline) through 2011-13. Dm quantifies the multivariate statistical deviation of 15 physiology-motivated biomarkers from the distribution in a healthy sample at baseline. Midlife Dm was grouped by quartiles (higher quartiles indicating greater homeostatic dysregulation) and temporal change in Dm was quantified continuously. Physical function was assessed in 2011-13 and included measures from the Short Physical Performance Battery (SPPB) including repeated chair stands, balance, 4-meter walk and grip strength. Associations were quantified using linear regression and ordinal logistic regression as applicable, adjusting for age, sex, race, and education. Results: A graded association was observed between midlife Dm and physical functional performance in late life (Table). Compared to the 1 st quartile of midlife Dm, the odds ratio of a lower SPPB score in late life was 1.19 (95%CI 1.04, 1.35) for the 2 nd quartile, 1.63 (1.41, 1.90) for the 3 rd quartile, and 3.14 (2.60, 3.79) for the 4 th quartile. Similar associations were observed for each of SPPB components and grip strength, either modeled ordinally or continuously. Each standard deviation increase in 10-year Dm change was associated with ~2-3 times the odds of having a poorer physical functional performance. Conclusions: Greater homeostatic dysregulation at midlife and increases in dysregulation during follow-up were associated with poorer physical function in late life. Insights into the factors that lead to progression of multisystem deterioration during midlife may highlight opportunities to preserve functional abilities in late life.

Introduction: Studies have found that smaller brain volumes, cerebral infarcts, and white matter abnormalities are associated with dementia and mild cognitive impairment. However, these studies have been limited by short follow-up precluding a strong establishment of temporality. Therefore, it is unknown whether brain imaging findings are preceded by long-term changes in cognition. We sought to address this gap by examining brain imaging and two decades of cognitive changes in and a large, representative population-based cohort of older adults of black and white race. Hypothesis: We hypothesized that 22-year declines in global cognitive factor scores (GCFS) would be associated with a pattern of smaller total brain and temporal lobe meta region of interest (likely to be affected by Alzheimer’s disease) volumes, larger white matter hyperintensity volumes, and greater odds of ≥1 lacunar infarct and elevated brain β-amyloid deposition. Methods: ARIC participants with brain imaging data, complete cognitive factor score, and not missing key covariates were included. GCFS were collected at three visits across 22 years (1990-2013), and brain MRI and florbetapir PET imaging were collected in 2011-13; PET in subset of n=327. Mixed effects models with random intercepts and slopes predicted individual change in GCFS. Outcomes of interest were total brain volume (cc), temporal lobe meta region volume, log 2 (white matter hyperintensity volume), ≥1 lacunar infarct, and elevated brain β-amyloid deposition (SUVR >1.2). Multivariable linear and logistic regression was used to relate outcomes to GCFS slopes after adjusting for confounders, including vascular risk factors. As appropriate, models were also adjusted for total intracranial volume. Results: Among 1957 with complete brain MRI imaging, 1830 were included in the study, 60% (n=1096) women and 26% (n=480) black. At the first visit, the mean (SD) baseline age was 55 (5.2) yrs. The mean (SD) observed GCFS at the three visits were 0.16 (0.79), 0.05 (0.75), and -0.78 (0.86). After adjustment, a 1-SD larger decline in GCFS was significantly associated with a smaller brain volume by 1.6% [95%CI: 1.3, 1.8] relative to mean brain volume, a smaller temporal lobe meta region volume by 2.4% [2.1, 2.8] relative to the mean volume, a 15% [11, 19] larger volume of white matter hyperintensities, 1.3-fold [1.2, 1.4] higher odds of having ≥1 lacune, and 1.8-fold [1.4, 2.4] higher odds of elevated brain β-amyloid deposition. Associations remained significant after further adjustment for first or last GCFS. Conclusions: Greater declines in long-term cognitive functioning were significantly associated with smaller brain volumes and dementia-related brain characteristics and were independent of last visit GCFS. This suggests long-term changes in cognition may precede late-life brain morphology and outperform cross-sectional cognitive measures.

Background: Central artery stiffness is a predictor of cardiovascular risk and mortality among individuals with diabetes. Few studies examined whether the duration of diabetes relates to arterial stiffening and its rate of progression. Objective: To examine the association of diabetes duration from midlife to older adulthood with arterial stiffness and its 5-year change. Methods: Diabetes (defined by fasting glycemia level >126 mg/dl or use of glucose lowering agents or self-reported) was ascertained at visit 1 (1988-1990), on repeated examinations and on telephone follow-up calls of 2,155 ARIC cohort members (58% women, 20% black, mean age 74 years), as well as time since ascertainment of diabetes. Carotid femoral pulse wave velocity (cfPWV), a measure of central artery stiffness, was obtained at cohort visits 5 (2011-13) and 6 or 7 (2016-19). Associations of duration of diabetes with visit 5 cfPWV and the 5-year cfPWV change from visit 5 to visit 6 or 7 were evaluated by multivariable linear regression adjusted for demographic factors. Results: Among study participants with diabetes ascertained from midlife to older adulthood (n=639 (29%)), the mean cfPWV at visit 5 was 78.6, 95%CI (52.9, 104.4) cm/s greater than those without diabetes. Over a mean of 4.9 (SD 3) years of follow-up, cfPWV increased by a median 137 cm/s. The 5-year change in cfPWV was 40.5, 95%CI (12.3, 68.8) cm/s greater among those with diabetes, as compared to those without diabetes. The mean diabetes duration was 8.1(SD 6.8) years for participants with diabetes. After adjusting for demographic factors, we observed a positive association of diabetes duration with the 5-year change in cfPWV in older adulthood (Figure). Conclusion: Duration of diabetes was associated with a greater rate of progression of central arterial stiffness in older adults.

Background: Cerebral microbleeds (CMBs) are associated with cognitive decline, but their importance outside of clinical cerebral amyloid angiopathy is less well understood, as are the mechanisms of their impact on cognition. In a community-based dementia-free cohort, we evaluate cross-sectional associations between CMB patterns and cerebral amyloid β (Aβ) deposition, measured by florbetapir PET. Methods: ARIC-PET recruited nondemented individuals from 3 US sites. Participants completed 3T brain MRI with T2*GRE (with CMBs read for presence, frequency, location (lobar vs subcortical), and pattern, as well as florbetapir (Aβ) PET (global cortical standardized uptake value ratio >1.2 as a positive scan). Multivariable (see Table) logistic regression models of Aβ+ scans evaluated CMB presence, frequency, location, and pattern, in separate models. Effect modification by sex, race, APOE status, and cognition (normal vs mild cognitive impairment) was evaluated. Results: Nearly 25% of the 322 individuals included had CMBs. No significant associations were found between CMBs (presence or number) and Aβ positivity, but a pattern of isolated lobar CMBs or superficial siderosis was associated with over a 4-fold higher odds of elevated Aβ vs having no CMBs, without a similar elevated risk in those with isolated subcortical CMBs or mixed subcortical + either lobar CMBs or superficial siderosis. Although no significant interactions were found, a mixed pattern was nonsignificantly protective (OR estimates 0.4-0.6) and lobar only CMBs had a (nonsignificantly) higher risk (OR up to 6.4) of Aβ for three subgroups: women (vs men); Blacks (vs whites), APOE ε4 noncarriers (vs carriers), and cognitively normal (vs MCI). Conclusions: A lobar-only pattern of CMBs is most strongly associated with brain Aβ, with no elevated risk for a mixed CMB pattern. Further study is needed to understand differences in these CMB patterns and their meaning across distinct demographic subgroups.

Background: Ischemic Stroke (IS) is associated with an increased risk of dementia, but the relative contribution of IS severity or recurrence to cognition is not known. We aimed to determine the risk of dementia after incident IS and how it varies by stroke severity and recurrence in the Atherosclerosis Risk in Communities (ARIC) study. Methods: 15,405 ARIC participants free of stroke and dementia at baseline (1987-9) were followed for IS and dementia through 2019. Incident and recurrent IS were classified by expert review of hospital records, with stroke severity by the National Institutes of Health Stroke Scale (NIHSS) classified as NIHSS≤5, 6-10, 11-15, ≥16. Dementia cases were adjudicated through expert review of in-person evaluations, informant interviews, phone assessments, hospitalization code or death certificates. Poisson regression models with robust error variance were used to estimate dementia incidence in participants with and without IS, and associations between time-dependent IS incidence (excluding dementia in the first year after stroke), frequency and severity, and dementia were studied with Cox proportional hazards models, adjusting for demographics, APOE ε4 and vascular risk factors . Results: 1151 IS (970 incident) and 2807 dementia cases were identified. NIHSS was available for 877 IS (76%). Adjusted incidence rates (95% CI) of dementia per 100 person-years were 0.45 (0.42-0.49) in participants without IS vs. 1.33 (1.15-1.55) in those with IS. Compared to no IS, risk of dementia (adjusted HR, 95% CI) increased with IS number and severity from 1.71 (1.47-1.99) for participants with one IS to 6.68 (3.58-12.46) for those with ≥3 events, and from 1.64 (1.36-1.98) for NIHSS≤5 to 4.43 (1.84-10.68) for NIHSS≥16 ( Table ). Conclusion: Risk of dementia is significantly increased after stroke, independent of vascular risk factors. These data suggest a dose-response relationship between number of stroke events and stroke severity, and risk of dementia.

Introduction Research indicates a link between adolescent e-cigarette use and combustible tobacco cigarette (CTC) initiation, and recent studies suggest their connection with marijuana uptake. Our 3-year longitudinal cohort study investigated the implications of adolescent, peer, and family e-cigarette use with adolescents’ expectations and willingness to initiate CTC use, and subsequent CTC and marijuana use. Aims and Methods Relationships were examined in a secondary analysis of a 3-year longitudinal cohort subsample involving adolescents enrolled in alternative California high schools (N = 1025). Analyses examined responses over three yearly observations. Family, peer, and respondents’ e-cigarette use, respondents’ positive cigarette expectancies and willingness to use CTCs were assessed in the study’s first year (T1). CTC use in the survey’s second year (T2) and marijuana use in the third year (T3) were assessed via path analysis. Results Respondents reporting at least one family member or peer using e-cigarettes were more likely to use e-cigarettes at T1 than those whose peers/family members did not. They reported more positive expectancies about CTCs and greater willingness to initiate use. These variables predicted CTC use at T2, which directly anticipated marijuana use in the survey’s third year (T3), as did adolescents’ use of e-cigarettes at T1. All model relations were statistically significant. Conclusions Analysis demonstrated the strong association of family members’ and peers’ behaviors with adolescent e-cigarette use, and the temporal precedence of e-cigarette use with subsequent CTC and marijuana uptake. The predictive implications of e-cigarettes for other dangerous substance use should be examined in future prevention campaigns. Implications The presented study expands upon existing literature connecting adolescent e-cigarette use and later CTC and marijuana use. The findings indicate the significant implications of exposure to e-cigarette use by parents and peers and demonstrate in a longitudinal 4-year panel survey the direct and indirect predictive implications of e-cigarette use for CTC and marijuana uptake. The research illustrates the utility of programs and campaigns that target peer and family groups to maximize impacts on adolescent willingness to try CTCs, positive expectancies, and possible onset of CTC and marijuana use.

In recent years, more than half of all drug overdose deaths in United States involved an opioid. To address this epidemic, antecedents to opioid misuse must be identified and empirically validated. The objective of the current investigation was to examine whether illicit drug use was prospectively associated with nonprescription opioid use among adolescents from a vulnerable population with a greater prevalence of substance abuse. A population-based cohort study of 1060 adolescents from 29 alternative high schools in southern California was conducted over a two-year period. A total of 929 adolescents (mean age 17.5 years, 49.9% female, 76.4% Hispanic) who had not experimented with nonprescription opioids at the baseline assessment were included in the analytic sample. The outcome was self-reported use of nonprescription opioids within two years. The predictors tested were illicit drug use, illicit drug use excluding marijuana, and the use of nonmedical marijuana. Covariates included age, sex, ethnicity, socioeconomic status, parental education, weekly income, sensation seeking, stress, anxiety, depression, and the use of alcohol and nicotine products. Multilevel, covariate-adjusted logistic regression models indicated that the odds of experimentation with nonprescription opioids was greater among adolescents who had used illicit drugs or illicit drugs excluding marijuana. Nonmedical marijuana use alone was a statistically significant predictor in unadjusted but not covariate-adjusted models. While prior studies have examined the progression from nicotine, alcohol, and marijuana use to nonprescription opioid use, the present findings emphasize the importance of illicit drug use as a detectable and empirically supported risk factor for future opioid misuse.

Introduction: Low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) among older adults are associated with mortality, and reportedly with lower cognitive performance, biomarkers of neurodegeneration, and dementia. We tested the associations of liver enzymes with cognition in ARIC-NCS. Methods: We studied 3191 participants (mean age 79 years, 59% female, 23% black) free of chronic liver disease and cirrhosis, and with AST:ALT ratio ≤2 at visit in 2016-2017. Serum ALT and AST were examined continuously and by quintiles, with the 3 rd quintile as the distribution-based modal reference range. Cognitive status (normal, mild cognitive impairment [MCI], dementia) was ascertained by an expert adjudication panel. A composite global cognition score was estimated from memory, executive function, and language tests. We used demographic and ApoE4 adjusted multinomial logistic and linear regressions. Results: Participants were classified as cognitively unimpaired (2375), MCI (602) or dementia (214). Lower levels of ALT and AST, and a higher AST:ALT ratio were associated with higher prevalence of dementia and lower global cognition scores ( Figure ). The prevalence odds ratio of dementia and MCI for the 1 st quintile, vs 3 rd quintile of ALT, were 1.73 (95% CI:1.06-2.81) and 1.27 (0.92-1.76), respectively. The corresponding estimates for AST were 1.71 (1.03-2.84) and 1.17 (0.87-1.59). Global cognition scores were lower in the 1 st vs 3 rd quintiles of ALT and AST by 0.13 (0.06-0.21) and 0.08 (0-0.15) standard deviation units, respectively. Additional adjustment for alcohol intake did not change the results. Conclusions: Liver hypometabolism is linked to reduced brain glucose metabolism, impaired production of neurotransmitters and synaptic maintenance, systemic insulin resistance and inflammation, while hepatic metabolite profiles are altered in dementia. Prospective assessments are warranted to characterize the role of hepatic metabolic dysfunction in cognitive impairment among older adults.

Background There is an unmet need for a tool that helps to evaluate patients who are at risk of progressing from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis (SPMS). A new tool supporting the evaluation of early signs suggestive of progression in multiple sclerosis (MS) has been developed. In the initial stage, concepts relevant to progression were identified using a mixed method approach involving regression on data from a real-world observational study and qualitative research with patients and physicians. The tool was drafted in a questionnaire format to assess these variables. Objective This study aimed to develop the scoring algorithm for the tool, using both quantitative and qualitative research methods. Methods The draft scoring algorithm was developed using two approaches: quantitative analysis of real-world data and qualitative analysis based on physician interviews and ranking and weighting exercises. Variables that were included in the draft tool and regarded as most clinically relevant were selected for inclusion in a multiple logistic regression. The analyses were run using physician-reported data and patient-reported data. Subsequently, a ranking and weighting exercise was conducted with 8 experienced neurologists as part of semistructured interviews. Physicians were presented with the variables included in the draft tool and were asked to rank them in order of strength of contribution to progression and assign a weight by providing a percentage of the overall contribution. Physicians were also asked to explain their ranking and weighting choices. Concordance between physicians was explored. Results Multiple logistic regression identified age, MS disease activity, and Expanded Disability Status Scale score as the most significant physician-reported predictors of progression to SPMS. Patient age, mobility, and self-care were identified as the strongest patient-reported predictors of progression to SPMS. In physician interviews, the variables ranked and weighted as most important were stability or worsening of symptoms, intermittent or persistent symptoms, and presence of ambulatory and cognitive symptoms. Across all physicians, the level of concordance was 0.278 (P Conclusions This study further confirms the need for a tool to provide a consistent, comprehensive approach across physicians to support the early evaluation of signs indicative of progression to SPMS. The novel and comprehensive approach to develop the draft scoring algorithm triangulates data obtained from ranking and weighting exercises, qualitative interviews, and a real-world observational study. Variables that go beyond the clinically most obvious impairment in lower limbs have been identified as relevant subtle/sensitive signs suggestive of progressive disease.

BACKGROUND Alzheimer's disease (AD) is one of the most costly conditions, both economically and regarding patient disability and dependency. The huge costs coupled with the predicted increase in prevalence worldwide are likely to challenge healthcare systems in the future. The classic version of the Alzheimer's Disease Assessment Scale-Cognition subscale (ADAS-Cog) is generally seen as the current gold standard primary outcome measure of cognitive symptom progression in dementia clinical trials. OBJECTIVE This study evaluated the relationship between ADAS-Cog scores as a measure of clinical progression and the healthcare resource utilization (HCRU)-measured burden of cognitive impairment in patients with mild cognitive impairment, AD, or suspected AD in the real world. METHODS A retrospective observational survey of physicians and their consulting patients with multiple ADAS-Cog scores. Regression models were constructed for HCRU variables (e.g., consultations, hospitalizations, caregiving requirements) with ADAS-Cog rate of change, baseline ADAS-Cog, and their interaction included as exposure variables. RESULTS 651 patient records were completed by 154 physicians. Approximately 70% of patients had mild to moderate dementia. In 56.7% of patients, clinical progression was maintained/stable from baseline. Mean change in ADAS-Cog (adjusted to 12 months) was 2.8 points and change scores increased with increasing dementia severity. Most HCRU variables increased significantly (p