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© 2015 The Authors.Clinical and population research on dementia and related neurologic conditions, including Alzheimer's disease, faces several unique methodological challenges. Progress to identify preventive and therapeutic strategies rests on valid and

Importance: Lack of a US dementia surveillance system hinders efforts to support and address disparities among persons living with Alzheimer disease and related dementias (ADRD)., Objective: To review diagnosis and prescription drug code ADRD identification algorithms to develop and implement case definitions for national surveillance., Design, Setting, and Participants: In this cross-sectional study, a systematic literature review was conducted to identify unique International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) and prescription drug codes used by researchers to identify ADRD in administrative records. Code frequency of use, characteristics of beneficiaries identified by codes, and expert and author consensus around code definitions informed code placement into categories indicating highly likely, likely, and possible ADRD. These definitions were applied cross-sectionally to 2017 to 2019 Medicare fee-for-service (FFS) claims and Medicare Advantage (MA) encounter data to classify January 2019 Medicare enrollees. Data analysis was conducted from September 2022 to March 2024., Exposures: ICD-10-CM and national drug codes in FFS claims or MA encounters., Main Outcomes and Measures: The primary outcome was counts and rates of beneficiaries meeting each case definition. Category-specific age, sex, race and ethnicity, MA enrollment, dual-eligibility, long-term care utilization, mortality, and rural residence distributions, as well as frailty scores and FFS monthly expenditures were also analyzed. Beneficiary characteristics were compared across categories, and age-standardized to minimize confounding by age., Results: Of the 60 000 869 beneficiaries included (50 853 806 aged 65 years or older [84.8%]; 32 567 891 female [54.3%]; 5 555 571 Hispanic [9.3%]; 6 318 194 non-Hispanic Black [10.5%]; 44 384 980 non-Hispanic White [74.0%]), there were 4 312 496 (7.2%) with highly likely ADRD, 1 124 080 (1.9%) with likely ADRD, and 2 572 176 (4.3%) with possible ADRD, totaling more than 8.0 million with diagnostic evidence of at least possible ADRD. These beneficiaries were older, more frail, more likely to be female, more likely to be dual-eligible, more likely to use long-term care, and more likely to die in 2019 compared with beneficiaries with no evidence of ADRD. These differences became larger when moving from the possible ADRD group to the highly likely ADRD group. Mean (SD) FFS monthly spending was $2966 ($4921) among beneficiaries with highly likely ADRD compared with $936 ($2952) for beneficiaries with no evidence of ADRD. Differences persisted after age standardization., Conclusions and Relevance: This cross-sectional study of 2019 Medicare beneficiaries identified more than 5.4 million Medicare beneficiaries with evidence of at least likely ADRD in 2019 using the diagnostic case definition. Pending validation against clinical and other methods of ascertainment, this approach can be adopted provisionally for national surveillance.

Background: Reported associations between particulate matter with aerodynamic diameter ≤2.5 μm (PM 2.5 ) and cognitive outcomes remain mixed. Differences in exposure estimation method may contribute to this heterogeneity., Objectives: To assess agreement between PM 2.5 exposure concentrations across 11 exposure estimation methods and to compare resulting associations between PM 2.5 and cognitive or MRI outcomes., Methods: We used Visit 5 (2011-2013) cognitive testing and brain MRI data from the Atherosclerosis Risk in Communities (ARIC) Study. We derived address-linked average 2000-2007 PM 2.5 exposure concentrations in areas immediately surrounding the four ARIC recruitment sites (Forsyth County, NC; Jackson, MS; suburbs of Minneapolis, MN; Washington County, MD) using 11 estimation methods. We assessed agreement between method-specific PM 2.5 concentrations using descriptive statistics and plots, overall and by site. We used adjusted linear regression to estimate associations of method-specific PM 2.5 exposure estimates with cognitive scores (n = 4678) and MRI outcomes (n = 1518) stratified by study site and combined site-specific estimates using meta-analyses to derive overall estimates. We explored the potential impact of unmeasured confounding by spatially patterned factors., Results: Exposure estimates from most methods had high agreement across sites, but low agreement within sites. Within-site exposure variation was limited for some methods. Consistently null findings for the PM 2.5 -cognitive outcome associations regardless of method precluded empirical conclusions about the potential impact of method on study findings in contexts where positive associations are observed. Not accounting for study site led to consistent, adverse associations, regardless of exposure estimation method, suggesting the potential for substantial bias due to residual confounding by spatially patterned factors., Discussion: PM 2.5 estimation methods agreed across sites but not within sites. Choice of estimation method may impact findings when participants are concentrated in small geographic areas. Understanding unmeasured confounding by factors that are spatially patterned may be particularly important in studies of air pollution and cognitive or brain health., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Melinda Power reports financial support was provided by National Institutes of Health.Melinda Power reports a relationship with National Institutes of Health that includes: funding grants. Melinda Power reports a relationship with U.S. Department of Defense that includes: funding grants. Melinda Power reports a relationship with DC DEPARTMENT OF HEALTH that includes: funding grants. Melinda Power reports a relationship with Biogen that includes: consulting or advisory. Erin Bennett reports a relationship with Massachusetts General Hospital that includes: consulting or advisory. Eun Sug Park reports a relationship with National Institutes of Health that includes: funding grants. Jeff D. Yanosky reports a relationship with National Institutes of Health that includes: funding grants. Duanping Liao reports a relationship with National Institutes of Health that includes: funding grants. Joel D. Kaufman reports a relationship with National Institutes of Health that includes: funding grants. Joel D. Kaufman reports a relationship with U.S. Environmental Protection Agency that includes: funding grants. Lianne Sheppard reports a relationship with National Institutes of Health that includes: funding grants. Lianne Sheppard reports a relationship with Health Effects Institute that includes: funding grants. Adam Szpiro reports a relationship with National Institutes of Health that includes: funding grants. Adam Szpiro reports a relationship with Health Effects Institute that includes: funding grants. Adam Szpiro reports a relationship with Health Effects Institute that includes: consulting or advisory. Eric Whitsel reports a relationship with National Institutes of Health that includes: funding grants. Eric Whitsel reports a relationship with USFederal Aviation Administration that includes: funding grants.If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: There is limited evidence about factors related to the timeliness of dementia diagnosis in healthcare settings., Methods: In five prospective cohorts at Rush Alzheimer's Disease Center, we identified participants with incident dementia based on annual assessments and examined the timing of healthcare diagnoses in Medicare claims. We assessed sociodemographic, health, and psychosocial correlates of timely diagnosis., Results: Of 710 participants, 385 (or 54%) received a timely claims diagnosis within 3 years prior to or 1 year following dementia onset. In logistic regressions accounting for demographics, we found Black participants (odds ratio [OR] = 2.15, 95% confidence interval [CI]: 1.21 to 3.82) and those with better cognition at dementia onset (OR = 1.48, 95% CI: 1.10 to 1.98) were at higher odds of experiencing a diagnostic delay, whereas participants with higher income (OR = 0.89, 95% CI: 0.81 to 0.97) and more comorbidities (OR = 0.94, 95% CI: 0.89 to 0.98) had lower odds., Discussion: We identified characteristics of individuals who may miss the optimal window for dementia treatment and support., Highlights: We compared the timing of healthcare diagnosis relative to the timing of incident dementia based on rigorous annual evaluation. Older Black adults with lower income, higher cognitive function, and fewer comorbidities were less likely to be diagnosed in a timely manner by the healthcare system., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: We evaluated whether participants in the landmark Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial represent US adults aged ≥40 with diabetes., Methods: Using the nationally representative 2017-2020 prepandemic National Health and Nutrition Examination Survey data, we made operational definitions of ACCORD eligibility criteria. We calculated the percentage of individuals aged ≥40 with diabetes and HbA1c ≥ 6.0% or ≥ 7.5% who met operational ACCORD eligibility criteria., Results: Applying survey sampling weights to 715 National Health and Nutrition Examination Survey participants aged ≥40 with diabetes and HbA1c ≥ 6.0% (representing 29,717,406 individuals), 12% (95% confidence interval [CI] = 8%, 18%) met the operational ACCORD eligibility criteria. Restricting to HbA1c ≥ 7.5%, 39% (95% CI = 28%, 51%) of respondents met the operational ACCORD eligibility criteria., Conclusions: ACCORD represented a minority of US middle-aged and older adults with diabetes. Given the differential risk profile between ACCORD participants and the general population with diabetes, extrapolating the trial findings may not be appropriate., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Increasing evidence links higher air pollution exposures to increased risk of cognitive impairment. While midlife risk factors are often most strongly linked to dementia risk, few studies have considered associations between midlife roadway proximity or ambient air pollution exposure and incident dementia decades later, in late life., Objectives: Our objective was to determine if midlife exposures to ambient air pollution or roadway proximity are associated with increased risk of dementia in the Atherosclerosis Risk in Communities (ARIC) study over up to 29 years of follow-up., Methods: Our eligible sample included Black and White ARIC participants without dementia at Visit 2 (1990-1992). Participants were followed through Visit 7 (2018-2019), with dementia status and onset date defined based on formal dementia ascertainment at study visits, informant interviews, and surveillance efforts. We used adjusted Weibull survival models to assess the associations of midlife ambient air pollution and road proximity with incident dementia., Results: The median age at baseline (1990-1992, Visit 2) of the 12,700 eligible ARIC participants was 57.0 years; 56.0% were female, 24.2% were Black, and 78.9% had at least a high school education. Over up to 29 years of follow-up, 2511 (19.8%) persons developed dementia. No associations were found between ambient air pollutants and proximity to major roadways with risk of incident dementia. In exploratory analyses, living closer to roadways in midlife increased dementia risk in individuals younger at baseline and those without midlife hypertension, and there was evidence of increased risk of dementia with increased midlife exposure to NO x , several PM 2.5 components, and trace metals among those with diabetes in midlife., Conclusions: Midlife exposure to ambient air pollution and midlife roadway proximity was not associated with dementia risk over decades of follow-up. Further investigation to explore potential for greater susceptibility among specific subgroups identified here is needed., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Melinda C. Power reports a relationship with Biogen Healthy Lives, Healthy Climate that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Evidence linking gaseous air pollution to late-life brain health is mixed., Objective: We explored associations between exposure to gaseous pollutants and brain magnetic resonance imaging (MRI) markers among Atherosclerosis Risk in Communities (ARIC) Study participants, with attention to the influence of exposure estimation method and confounding by site., Methods: We considered data from 1,665 eligible ARIC participants recruited from four US sites in the period 1987-1989 with valid brain MRI data from Visit 5 (2011-2013). We estimated 10-y (2001-2010) mean carbon monoxide (CO), nitrogen dioxide ( NO 2 ), nitrogen oxides ( NO x ), and 8- and 24-h ozone ( O 3 ) concentrations at participant addresses, using multiple exposure estimation methods. We estimated site-specific associations between pollutant exposures and brain MRI outcomes (total and regional volumes; presence of microhemorrhages, infarcts, lacunes, and severe white matter hyperintensities), using adjusted linear and logistic regression models. We compared meta-analytically combined site-specific associations to analyses that did not account for site., Results: Within-site exposure distributions varied across exposure estimation methods. Meta-analytic associations were generally not statistically significant regardless of exposure, outcome, or exposure estimation method; point estimates often suggested associations between higher NO 2   and   NO x and smaller temporal lobe, deep gray, hippocampal, frontal lobe, and Alzheimer disease signature region of interest volumes and between higher CO and smaller temporal and frontal lobe volumes. Analyses that did not account for study site more often yielded significant associations and sometimes different direction of associations., Discussion: Patterns of local variation in estimated air pollution concentrations differ by estimation method. Although we did not find strong evidence supporting impact of gaseous pollutants on brain changes detectable by MRI, point estimates suggested associations between higher exposure to CO, NO x , and NO 2 and smaller regional brain volumes. Analyses of air pollution and dementia-related outcomes that do not adjust for location likely underestimate uncertainty and may be susceptible to confounding bias. https://doi.org/10.1289/EHP13906.

Background: In stroke patients with insulin resistance (IR), post-stroke cognitive impairment (PSCI) is associated with higher risk of recurrent stroke, but the effect of pioglitazone on that risk has not been explored. The goal of this study was to compare the secondary stroke prevention effect of pioglitazone against placebo in patients with versus without PSCI., Methods: We studied patients enrolled in the Insulin Resistance Intervention after Stroke (IRIS) trial with a post-stroke modified Mini-Mental State Examination (3MS) cognitive assessment (mean time of assessment: 79 days post-stroke). We considered a baseline score of ⩽ 88 on the 3MS to indicate global PSCI, and domain-specific summary scores in the lowest quartile to indicate attention, language, memory, orientation, and visuospatial impairments., Results: In n = 3338 patients with IR, the effect of pioglitazone versus placebo on secondary stroke significantly differed by initial post-stroke global (interaction p = 0.0127) and memory impairment status (interaction p = 0.0003). Hazard ratios (HRs) were time-dependent such that, among those with either global or memory impairment, pioglitazone has an increasingly stronger protective effect at later timepoints. There was no statistically significant effect of pioglitazone among those without either global or memory impairment. The effect of pioglitazone versus placebo on myocardial infarction (MI) also significantly differed by global impairment status (interaction p = 0.030). Pioglitazone was protective among those with global impairment (HR = 0.23 [95% CI: 0.08, 0.71]) but not among those without (HR = 0.88 [95% CI: 0.59, 1.31])., Conclusion: These data indicate that pioglitazone treatment may be more effective at reducing risk of recurrent stroke and MI in stroke patients with PSCI. Simple cognitive testing 2-3 months post-stroke may identify patients for whom treatment would be most beneficial., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction: The results of the CLARITY-AD, GRADUATE I and II, and TRAILBLAZER-ALZ 2 trials have rekindled discussion on the impact of amyloid-targeting drugs. We use a Bayesian approach to quantify how rational observers would have updated their prior beliefs based on new trial results., Methods: We used publicly available data from the CLARITY-AD, GRADUATE I and II, and TRAILBLAZER-ALZ 2 trials to estimate the effect of reducing amyloid on the clinical dementia rating scale, sum of boxes (CDR-SB) score. A range of prior positions were then updated according to Bayes' theorem using these estimates., Results: After updating with new trial data, a wide range of starting positions resulted in credible intervals that did not include no effect of amyloid reduction on CDR-SB score., Discussion: For a range of starting beliefs and assuming the veracity of the underlying data, rational observers would conclude there is a small benefit of amyloid reductions on cognition. This benefit must be weighed against opportunity cost and side-effect risk., Highlights: The results of recent trials of amyloid-targeting drugs have rekindled discussion on the impact of amyloid reductions achieved with amyloid-targeting drugs on cognition. Prior to the announcement of trial results, beliefs about the effects of altering amyloid levels varied. For a range of starting beliefs, one would conclude there is a small benefit of amyloid reductions due to amyloid-targeting drugs on cognition. The perceived value of individual drugs must balance the magnitude of this benefit against opportunity cost and risk of side effects., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Many approaches to quantifying air pollution exposures have been developed. However, the impact of choice of approach on air pollution estimates and health-effects associations remains unclear., Objectives: Our objective is to compare particulate matter with aerodynamic diameter ≤ 2.5 μ m ( PM 2.5 ) concentrations and resulting health effects associations using multiple estimation approaches previously used in epidemiologic analyses., Methods: We assigned annual PM 2.5 exposure estimates from 1999 to 2004 derived from 11 different approaches to Women's Health Initiative Memory Study (WHIMS) participant addresses within the contiguous US. Approaches included geostatistical interpolation approaches, land-use regression or spatiotemporal models, satellite-derived approaches, air dispersion and chemical transport models, and hybrid models. We used descriptive statistics and plots to assess relative and absolute agreement among exposure estimates and examined the impact of approach on associations between PM 2.5 and death due to natural causes, cardiovascular disease (CVD) mortality, and incident CVD events, adjusting for individual-level covariates and climate-based region., Results: With a few exceptions, relative agreement of approach-specific PM 2.5 exposure estimates was high for PM 2.5 concentrations across the contiguous US. Agreement among approach-specific exposure estimates was stronger near PM 2.5 monitors, in certain regions of the country, and in 2004 vs. 1999. Collectively, our results suggest but do not quantify lower agreement at local spatial scales for PM 2.5 . There was no evidence of large differences in health effects associations with PM 2.5 among estimation approaches in analyses adjusted for climate region., Conclusions: Different estimation approaches produced similar spatial patterns of PM 2.5 concentrations across the contiguous US and in areas with dense monitoring data, and PM 2.5 -health effects associations were similar among estimation approaches. PM 2.5 estimates and PM 2.5 -health effects associations may differ more in samples drawn from smaller areas or areas without substantial monitoring data, or in analyses with finer adjustment for participant location. Our results can inform decisions about PM 2.5 estimation approach in epidemiologic studies, as investigators balance concerns about bias, efficiency, and resource allocation. Future work is needed to understand whether these conclusions also apply in the context of other air pollutants of interest. https://doi.org/10.1289/EHP12995.

Background: Evidence indicates the health care system disproportionately misses dementia in African American compared to White individuals. In preliminary data, we examined factors related to dementia identification by the health care system among African Americans., Methods: We leveraged linked Medicare fee-for-service claims and detailed annual cohort evaluations in African Americans from 4 cohorts at Rush Alzheimer's Disease Center., Results: Among 88 African Americans with cognitive impairment (mean = 10 years follow-up), Medicare claims identified dementia <2 years from cohort diagnosis in 55%; 27% were identified 2-9.9 years after cohort diagnosis, and in 18% there was either no claims diagnosis during the study period, or claims identified dementia 10+ years after cohort diagnosis. Claims identification of dementia was related to older age at cohort diagnosis (eg, <2 years between cohort and claims: mean = 82 years; 10+ years/no diagnosis: mean = 77 years, p = .04), lower Mini-Mental State Examination (MMSE) score (<2 years: mean = 24; 10+ years/no diagnosis: mean = 26, p = .04), more depressive symptoms (<2 years: mean = 2.1 symptoms; 10+ years/no diagnosis: mean = 1.2, p = .04), and more comorbidity (<2 years: mean = 5.6 comorbidities; 10+ years/no diagnosis, mean = 3.0, p = .02)., Conclusions: Among African Americans, preliminary data indicate the health care system most rapidly identifies dementia in older individuals, with worse cognitive and physical health. The health care system may miss opportunities for early support of African Americans with dementia, and caregivers., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Diagnostic delay in dementia is common in the U.S. Drivers of diagnostic delay are poorly understood, but appear related to misconceptions about dementia, stigma, concerns about autonomy, the nature of the diagnostic process, and provider-related factors. There is little quantitative evidence underlying cited risks and benefits of receiving a diagnosis around the time of dementia onset, including impacts on physical health, impacts on mental health, care partner interactions, costs of care, increased time for care planning, or earlier access to treatment. While various groups continue to push for reductions in diagnostic delay, realization of benefits and mitigation of harms will require new research on potential benefits and harms. Workforce and resource constraints, coupled with the expected growth in the number of persons living with dementia, may be a barrier to realization of potential benefits and mitigation of identified harms, which will require adequate access to providers, services, and supports., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Melinda C. Power reports grants from the United States (US) National Institutes of Health (NIH), U.S. Department of Defense (DOD), and District of Columbia Department of Health (DC Health) and prior service on the Biogen Healthy Lives, Healthy Climate Scientific Advisory Board. Victoria Willens and Dr. Yi Chen report no conflicts of interest. Dr. Christina Prather reports grants from the United States (U.S.) National Institutes of Health (NIH), Agency for Healthcare Research and Quality (AHRQ), and District of Columbia Department of Health (DC Health) and serves as a consultant to the Alzheimer’s Association Project Echo program. Dr. Ali Moghtaderi reports grants from the US National Institutes of Health. Dr. Kan Z. Gianattasio reports current funding support from grants and contracts from the United States (U.S.) National Institutes of Health (NIH), the Centers for Medicare and Medicaid Services (CMS), the Maryland Health Care Commission (MHCC), and the SCAN Foundation Dr. Francine Grodstein reports grants from the US National Institutes of Health. Dr. Raj C. Shah reports grants from the US National Institutes of Health and being the site principal investigator or sub-investigator for Alzheimer’s disease clinical trials for which his institution (Rush University Medical Center) is compensated [Amylyx Pharmaceuticals, Inc., Athira Pharma, Inc., Edgewater NEXT, Eli Lilly & Co., Inc., and Genentech, Inc.]. Dr. Bryan D. James reports grants from the United States (U.S.) National Institutes of Health (NIH), serves as a consultant to the Alzheimer’s Association, serves on the Vivid Genomics, Inc. Scientific Advisory Board, and has served on a drug advisory board for Eisai, Inc., (© The Author(s) 2023.)

Incomplete longitudinal data are common in life-course epidemiology and may induce bias leading to incorrect inference. Multiple imputation (MI) is increasingly preferred for handling missing data, but few studies explore MI-method performance and feasibility in real-data settings. We compared 3 MI methods using real data under 9 missing-data scenarios, representing combinations of 10%, 20%, and 30% missingness and missing completely at random, at random, and not at random. Using data from Health and Retirement Study (HRS) participants, we introduced record-level missingness to a sample of participants with complete data on depressive symptoms (1998-2008), mortality (2008-2018), and relevant covariates. We then imputed missing data using 3 MI methods (normal linear regression, predictive mean matching, variable-tailored specification), and fitted Cox proportional hazards models to estimate effects of 4 operationalizations of longitudinal depressive symptoms on mortality. We compared bias in hazard ratios, root mean square error, and computation time for each method. Bias was similar across MI methods, and results were consistent across operationalizations of the longitudinal exposure variable. However, our results suggest that predictive mean matching may be an appealing strategy for imputing life-course exposure data, given consistently low root mean square error, competitive computation times, and few implementation challenges., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: During the first year of the COVID-19 pandemic, more than one-third of US older adults (aged 65 years and older) reported delaying medical care. Delayed health care may exacerbate short- and long-term health changes in older adults. Older adults more likely to delay health care may benefit from targeted follow-up to return these individuals to the health care system., Objective: The aim of this study was to describe pre-pandemic sociodemographic, psychological, cognitive, and medical factors associated with delayed health care among US older adults during the COVID-19 pandemic., Design: We conducted a secondary analysis of 2905 participants from the National Health and Aging Trends Study (NHATS), a nationally representative, prospective cohort of US older adult Medicare beneficiaries., Methods: Pre-pandemic factors were reported at the Round 9 interview (2019). Delayed health care, including medical (e.g. usual doctor) and supplementary (e.g. dental) care, was reported on the COVID-19 questionnaire (2020). We calculated adjusted odds ratios using weighted logistic regression, accounting for the NHATS sampling design., Results: Overall, 40% of participants reported delayed care. After adjustment, female participants and those reporting fair (vs good) health were consistently more likely to delay health care while persons with lower income or excellent health were less likely to delay care. Other associations varied by care type., Conclusion: Women and those with higher income or fair health before the COVID-19 pandemic were more likely to delay care during the pandemic. Our results may inform targeted outreach to older adults who delayed care during the COVID-19 pandemic, or other disruptions to the health care system, to return these individuals to care and promote better management of their health needs., (© The Author(s) 2023.)

Importance: Prior studies suggested that metformin may be associated with reduced dementia incidence, but associations may be confounded by disease severity and prescribing trends. Cessation of metformin therapy in people with diabetes typically occurs due to signs of kidney dysfunction but sometimes is due to less serious adverse effects associated with metformin., Objective: To investigate the association of terminating metformin treatment for reasons unrelated to kidney dysfunction with dementia incidence., Design, Setting, and Participants: This cohort study was conducted at Kaiser Permanente Northern California, a large integrated health care delivery system, among a cohort of metformin users born prior to 1955 without history of diagnosed kidney disease at metformin initiation. Dementia follow-up began with the implementation of electronic health records in 1996 and continued to 2020. Data were analyzed from November 2021 through September 2023., Exposures: A total of 12 220 early terminators, individuals who stopped metformin with normal estimated glomerular filtration rate (eGFR), were compared with routine metformin users, who had not yet terminated metformin treatment or had terminated (with or without restarting) after their first abnormal eGFR measurement. Early terminators were matched with routine users of the same age and gender who had diabetes for the same duration., Main Outcomes and Measures: The outcome of interest was all-cause incident dementia. Follow-up for early terminators and their matched routine users was started at age of termination for the early terminator. Survival models adjusted for sociodemographic characteristics and comorbidities at the time of metformin termination (or matched age). Mediation models with HbA1c level and insulin usage 1 and 5 years after termination tested whether changes in blood glucose or insulin usage explained associations between early termination of metformin and dementia incidence., Results: The final analytic sample consisted of 12 220 early terminators (5640 women [46.2%]; mean [SD] age at start of first metformin prescription, 59.4 [9.0] years) and 29 126 routine users (13 582 women [46.6%]; mean [SD] age at start of first metformin prescription, 61.1 [8.9] years). Early terminators had 1.21 times the hazard of dementia diagnosis compared with routine users (hazard ratio, 1.21; 95% CI, 1.12 to 1.30). In mediation analysis, contributions to this association by changes in HbA1c level or insulin use ranged from no contribution (0.00 years; 95% CI, -0.02 to 0.02 years) for insulin use at 5 years after termination to 0.07 years (95% CI, 0.02 to 0.13 years) for HbA1c level at 1 year after termination, suggesting that the association was largely independent of changes in HbA1c level and insulin usage., Conclusions and Relevance: In this study, terminating metformin treatment was associated with increased dementia incidence. This finding may have important implications for clinical treatment of adults with diabetes and provides additional evidence that metformin is associated with reduced dementia risk.

Background: Studies suggest associations between long-term ambient air pollution exposure and outcomes related to Alzheimer's disease (AD). Whether a link exists between pollutants and brain amyloid accumulation, a biomarker of AD, is unclear. We assessed whether long-term air pollutant exposures are associated with late-life brain amyloid deposition in Atherosclerosis Risk in Communities (ARIC) study participants., Methods: We used a chemical transport model with data fusion to estimate ambient concentrations of PM 2.5 and its components, NO 2 , NO x , O 3 (24-hour and 8-hour), CO, and airborne trace metals. We linked concentrations to geocoded participant addresses and calculated 10-year mean exposures (2002 to 2011). Brain amyloid deposition was measured using florbetapir amyloid positron emission tomography (PET) scans in 346 participants without dementia in 2012-2014, and we defined amyloid positivity as a global cortical standardized uptake value ratio ≥ the sample median of 1.2. We used logistic regression models to quantify the association between amyloid positivity and each air pollutant, adjusting for putative confounders. In sensitivity analyses, we considered whether use of alternate air pollution estimation approaches impacted findings for PM 2.5 , NO 2 , NO x , and 24-hour O 3 ., Results: At PET imaging, eligible participants (N = 318) had a mean age of 78 years, 56% were female, 43% were Black, and 27% had mild cognitive impairment. We did not find evidence of associations between long-term exposure to any pollutant and brain amyloid positivity in adjusted models. Findings were materially unchanged in sensitivity analyses using alternate air pollution estimation approaches for PM 2.5 , NO 2 , NO x , and 24-hour O 3 ., Conclusions: Air pollution may impact cognition and dementia independent of amyloid accumulation, though whether air pollution influences AD pathogenesis later in the disease course or at higher exposure levels deserves further consideration., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2023 American Neurological Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Introduction: As the number of U.S. veterans over age 65 has increased, interest in whether military service affects late-life health outcomes has grown. Whether military employment is associated with increased risk of cognitive decline and dementia remains unclear., Materials and Methods: We used data from 4,370 participants of the longitudinal Adult Changes in Thought (ACT) cohort study, enrolled at age 65 or older, to examine whether military employment was associated with greater cognitive decline or higher risk of incident dementia in late life. We classified persons as having military employment if their first or second-longest occupation was with the military. Cognitive status was assessed at each biennial Adult Changes in Thought study visit using the Cognitive Abilities Screening Instrument, scored using item response theory (CASI-IRT). Participants meeting screening criteria were referred for dementia ascertainment involving clinical examination and additional cognitive testing. Primary analyses were adjusted for sociodemographic characteristics and APOE genotype. Secondary analyses additionally adjusted for indicators of early-life socioeconomic status and considered effect modification by age, gender, and prior traumatic brain injury with loss of consciousness TBI with LOC., Results: Overall, 6% of participants had military employment; of these, 76% were males. Military employment was not significantly associated with cognitive change (difference in modeled 10-year cognitive change in CASI-IRT scores in SD units (95% confidence interval [CI]): -0.042 (-0.19, 0.11), risk of dementia (hazard ratio [HR] [95% CI]: 0.92 [0.71, 1.18]), or risk of Alzheimer's disease dementia (HR [95% CI]: 0.93 [0.70, 1.23]). These results were robust to additional adjustment and sensitivity analyses. There was no evidence of effect modification by age, gender, or traumatic brain injury with loss of consciousness., Conclusions: Among members of the Adult Changes in Thought cohort, military employment was not associated with increased risk of cognitive decline or dementia. Nevertheless, military veterans face the same high risks for cognitive decline and dementia as other aging adults., (© The Association of Military Surgeons of the United States 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Persons with military involvement may be more likely to have Parkinson's disease (PD) risk factors. As PD is rare, case finding remains a challenge, contributing to our limited understanding of PD risk factors. Here, we explore the validity of case-finding strategies and whether military employment is associated with PD., Materials and Methods: We identified Adult Changes in Thought (ACT) study participants reporting military employment as their longest or second longest occupation. We used self-report and prescription fills to identify PD cases and validated this case-finding approach against medical record review., Results: At enrollment, 6% of 5,125 eligible participants had military employment and 1.8% had prevalent PD; an additional 3.5% developed PD over follow-up (mean: 8.3 years). Sensitivity of our case-finding approach was higher for incident (80%) than prevalent cases (54%). Specificity was high (>97%) for both. Military employment was not associated with prevalent PD. Among nonsmokers, point estimates suggested an increased risk of incident PD with military employment, but the result was non-significant and based on a small number of cases., Conclusions: Self-report and prescription medications can accurately identify incident PD cases relative to the reference method of medical record review. We found no association between military employment and PD.

Context: The 2014 Improving Medicare Post-Acute Care Transformation (IMPACT) Act systemized audits of long hospice stays, and the 2016 two-tier payment system decreased daily reimbursement rates after 60 days of enrollment. Both aimed to reduce long stays., Objectives: Examine how live discharge rates and length of stay changed in relation to the policies., Methods: We computed monthly hospice-level percent live discharges and length of stay using 2008-2019 Medicare hospice claims. We compared prepolicies trends and postpolicies trends overall, within Alzheimer's disease and related dementias (ADRD) patients, within lung cancer patients, and stratified by hospice ownership (for-profit vs. nonprofit/government-owned)., Results: We included 10,539,912 and 10,453,025 episodes of care in the analytical samples for live discharge and length of stay analyses, respectively. Overall percent live discharges declined during the prepolicies period (-0.13 percentage-points per month, 95% CI: -0.14, -0.12), but exhibited no significant change during the postpolicies period. Trends were driven primarily by for-profits, with similar patterns within ADRD and lung cancer patients. Overall, mean length of stay increased over time, with greater rate of increase during the postpolicies period (0.41 days per month, 95% CI: 0.39, 0.42) compared to the prepolicies period (0.12 days per month, 95% CI: 0.10, 0.14). Length-of-stay increased faster among ADRD patients, but changed minimally for lung cancer patients., Conclusion: Live discharge rates declined significantly during the prepolicies period, but plateaued after implementation of the policies, driven by changes in for-profits. However, the policies did not reduce length of stay, which increased at faster rates, suggesting that postpolicies excess live discharges were not restricted to long-stay patients., (Copyright © 2022 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Background: The long-term effects of traumatic brain injury (TBI) with loss of consciousness (LOC) on magnetic resonance imaging (MRI) markers of brain health and on dementia risk are still debated., Objective: To investigate the associations of history of TBI with LOC with incident dementia and neuroimaging markers of brain structure and small vessel disease lesions., Methods: The analytical sample consisted in 4,144 participants aged 65 and older who were dementia-free at baseline from the Three City -Dijon study. History of TBI with LOC was self-reported at baseline. Clinical Dementia was assessed every two to three years, up to 12 years of follow-up. A subsample of 1,675 participants <80 years old underwent a brain MRI at baseline. We investigated the associations between history of TBI with LOC and 1) incident all cause and Alzheimer's disease (AD) dementia using illness-death models, and 2) neuroimaging markers at baseline., Results: At baseline, 8.3% of the participants reported a history of TBI with LOC. In fully-adjusted models, participants with a history of TBI with LOC had no statistically significant differences in dementia risk (HR = 0.90, 95% CI = 0.60-1.36) or AD risk (HR = 1.03, 95% CI = 0.69-1.52), compared to participants without TBI history. History of TBI with LOC was associated with lower white matter volume (β= -4.58, p = 0.048), but not with other brain volumes, white matter hyperintensities volume, nor covert brain infarct., Conclusion: This study did not find evidence of an association between history of TBI with LOC and dementia or AD dementia risks over 12-year follow-up, brain atrophy, or markers of small vessel disease.

Background: Coronary atherosclerosis assessed in vivo was associated with cognitive impairment; however, conflicting findings have been reported in autopsy samples., Objective: Our aims were to assess the association between atherosclerotic stenosis in the coronary arteries and cognitive impairment and to investigate the possibility of selection bias in an autopsy study., Methods: Coronary arteries were collected, and the largest luminal stenosis was measured. Sociodemographic, clinical, and cognitive information were reported by a reliable next-of-kin. The association was tested using logistic and linear regressions adjusted for sociodemographic and clinical variables. We restricted the sample to individuals that were born in 1935 or earlier and stratified the analysis by cause of death to investigate the role of selection bias., Results: In 253 participants (mean age = 78.0±8.5 years old, 48% male), stenosis was not associated with cognitive impairment (OR = 0.85, 95% CI = 0.69; 1.06, p = 0.15). In individuals who were born before 1936 in the absence of cardiovascular disease as the cause of death, greater stenosis was associated with cognitive impairment (OR = 4.02, 95% CI = 1.39; 11.6, p = 0.01). On the other hand, this association was not present among those born in 1935 or earlier who died of cardiovascular diseases (OR = 0.83, 95% CI = 0.60; 1.16, p = 0.28)., Conclusion: We found that higher coronary stenosis was associated with cognitive impairment only in individuals born in 1935 or earlier and who had not died from cardiovascular diseases. Selection bias may be an important issue when investigating risk factors for chronic degenerative diseases in older individuals using autopsy samples.

Background: Prior studies into the association of head trauma with neuropathology have been limited by incomplete lifetime neurotrauma exposure characterization., Objective: To investigate the neuropathological sequelae of traumatic brain injury (TBI) in an autopsy sample using three sources of TBI ascertainment, weighting findings to reflect associations in the larger, community-based cohort., Methods: Self-reported head trauma with loss of consciousness (LOC) exposure was collected in biennial clinic visits from 780 older adults from the Adult Changes in Thought study who later died and donated their brain for research. Self-report data were supplemented with medical record abstraction, and, for 244 people, structured interviews on lifetime head trauma. Neuropathology outcomes included Braak stage, CERAD neuritic plaque density, Lewy body distribution, vascular pathology, hippocampal sclerosis, and cerebral/cortical atrophy. Exposures were TBI with or without LOC. Modified Poisson regressions adjusting for age, sex, education, and APOE ɛ4 genotype were weighted back to the full cohort of 5,546 participants., Results: TBI with LOC was associated with the presence of cerebral cortical atrophy (Relative Risk 1.22, 95% CI 1.02, 1.42). None of the other outcomes was associated with TBI with or without LOC., Conclusion: TBI with LOC was associated with increased risk of cerebral cortical atrophy. Despite our enhanced TBI ascertainment, we found no association with the Alzheimer's disease-related neuropathologic outcomes among people who survived to at least age 65 without dementia. This suggests the pathophysiological processes underlying post-traumatic neurodegeneration are distinct from the hallmark pathologies of Alzheimer's disease.

Although observational studies have identified modifiable risk factors for Alzheimer disease and related dementias (ADRD), randomized controlled trials (RCTs) of risk factor modification for ADRD prevention have been inconsistent or inconclusive. This finding suggests a need to improve translation between observational studies and RCTs. However, many common features of observational studies reduce their relevance to designing related RCTs. Observational studies routinely differ from RCTs with respect to eligibility criteria, study population, length of follow-up, treatment conditions, outcomes, and effect estimates. Using the motivating example of blood pressure reduction for ADRD prevention, we illustrate the need for a tighter connection between observational studies and RCTs, discuss barriers to using typically reported observational evidence in developing RCTs, and highlight methods that may be used to make observational research more relevant to clinical trial design. We conclude that the questions asked and answered by observational research can be made more relevant to clinical trial design and that better use of observational data may increase the likelihood of successful, or at least definitive, trials. Although we focus on improving translation of observational studies on risk factors for ADRD to RCTs in ADRD prevention, the overarching themes are broadly applicable to many areas of biomedical research., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Post-stroke cognitive impairment (PSCI) is associated with etiology, severity, and functional outcome of stroke. The risks of recurrent stroke and death in patients with PSCI and insulin resistance (IR) is unknown. The goal of this study was to determine whether global and domain-specific cognitive impairment after stroke in patients with IR was associated with recurrent stroke and death., Materials and Methods: We studied patients with recent stroke or transient ischemic attack (TIA) and IR with a baseline Modified Mini-Mental State Examination (3MS) cognitive exam at median of 79 days after stroke. We considered a baseline score of ≤ 88 on the 3MS to indicate global cognitive impairment, and domain-specific summary scores in the lowest quartile to indicate language, attention, orientation, memory and visuospatial impairments. The primary endpoint was fatal or non-fatal recurrent stroke, and the secondary endpoints were all-cause mortality, and fatal or non-fatal myocardial infarction (MI)., Results: Among studied n = 3,338 patients 13.6% had global cognitive impairment. During the median 4.96 years of follow-up, 7.4% patients experienced recurrent stroke, 3.5% MI, and 7.3% died. In the fully adjusted model, impairment in language (HR 1.35; 95% CI 1.01-1.81) and orientation (HR 1.41; 95% CI: 1.06-1.87) were associated with a higher risk of recurrent stroke, while attention impairment was associated with all-cause mortality (HR 1.34; 95% CI: 1.01-1.78)., Discussion/conclusion: In patients with recent stroke/TIA and IR, post-stroke language and orientation impairments independently predicted recurrent stroke, while attention deficit was associated with increased risk of all-cause mortality., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Dietary copper intake may be associated with cognitive decline and dementia. We used data from 10,269 participants of the Atherosclerosis Risks in Communities Study to study the associations of dietary copper intake with 20-year cognitive decline and incident dementia. Dietary copper intake from food and supplements was quantified using food frequency questionnaires. Cognition was assessed using 3 cognitive tests at study visits; dementia was ascertained at study visits and via surveillance. Multiple imputation by chained equations was applied to account for the missing information of cognitive function during follow-up. Survival analysis with parametric models and mixed-effect models were used to estimate the associations for incident dementia and cognitive decline, respectively. During 20 years of follow-up (1996-1998 to 2016-2017), 1,862 incident cases of dementia occurred. Higher intake of dietary copper from food was associated with higher risk of incident dementia among those with high intake of saturated fat (hazard ratio = 1.49, 95% confidence interval: 1.04, 1.95). Higher intake of dietary copper from food was associated with greater decline in language overall (beta = -0.12, 95% confidence interval: -0.23, -0.02). Therefore, a diet high in copper, particularly when combined with a diet high in saturated fat, may increase the risk of cognitive impairment., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Medicare fee-for-service (FFS) claims data are increasingly leveraged for dementia research. Few studies address the validity of recent claim data to identify dementia, or carefully evaluate characteristics of those assigned the wrong diagnosis in claims., Methods: We used claims data from 2014 to 2018, linked to participants administered rigorous, annual dementia evaluations in 5 cohorts at the Rush Alzheimer's Disease Center. We compared prevalent dementia diagnosed through the 2016 cohort evaluation versus claims identification of dementia, applying the Bynum-standard algorithm., Results: Of 1 054 participants with Medicare Parts A and B FFS in a 3-year window surrounding their 2016 index date, 136 had prevalent dementia diagnosed during cohort evaluations; the claims algorithm yielded 217. Sensitivity of claims diagnosis was 79%, specificity 88%, positive predictive value 50%, negative predictive value 97%, and overall accuracy 87%. White participants were disproportionately represented among detected dementia cases (true positive) versus cases missed (false negative) by claims (90% vs 75%, respectively, p = .04). Dementia appeared more severe in detected than missed cases in claims (mean Mini-Mental State Exam = 15.4 vs 22.0, respectively, p < .001; 28% with no limitations in activities of daily living versus 45%, p = .046). By contrast, those with "over-diagnosis" of dementia in claims (false positive) had several worse health indicators than true negatives (eg, self-reported memory concerns = 51% vs 29%, respectively, p < .001; mild cognitive impairment in cohort evaluation = 72% vs 44%, p < .001; mean comorbidities = 7 vs 4, p < .001)., Conclusions: Recent Medicare claims perform reasonably well in identifying dementia; however, there are consistent differences in cases of dementia identified through claims than in rigorous cohort evaluations., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Hospice is an important end-of-life service for patients with Alzheimer disease and related dementias (ADRD)., Objective: To determine whether hospice use among patients with ADRD changed in association with recent policies aimed at reducing hospice misuse and long hospice stays, an outcome that may have disproportionately affected patients with ADRD because of their lengthy end-of-life trajectories., Design Setting and Participants: This observational cross-sectional study used Medicare hospice claims data from Medicare hospice episodes of care beginning between July 2008 and December 2019 among Medicare hospice beneficiaries 65 years or older at time of enrollment. Data analysis was conducted between September 2019 and June 2021., Exposures: The 2014 Improving Medicare Post-Acute Care Transformation (IMPACT) Act, which systematized audits of hospices with a high proportion of long stays, and the 2016 2-tier payment system, which reduced daily reimbursement rates after 60 days., Main Outcomes and Measures: Monthly percentage of (1) new patient enrollees, (2) patient census, and (3) care days provided to patients with an ADRD code., Results: The sample included 11 124 992 unique hospice episodes between 2008 and 2019; mean (SD) patient enrollment age ranged from 82.0 (8.2) years to 82.8 (8.7) years; the percentage of male patients ranged from 40.5% to 42.7%, and the percentage of Black, Hispanic, and White patients ranged from 7.7% to 8.2%, 1.5% to 2.0%, and 86.2% to 88.8%, respectively, across years. The percentage of new enrollees with an ADRD code dropped significantly during the months of IMPACT passage (-1.42 percentage points; 95% CI, -2.13 to -0.71) and implementation (-1.98 percentage points; 95% CI, -2.70 to -1.26) but rose again during the following months. While no significant changes were observed at the time of 2-tier payment implementation (0.15 percentage points; 95% CI, -0.21 to 0.51), the average rate of increase during the subsequent period was slower (0.01 percentage points per month; 95% CI, 0-0.02) than in earlier periods (0.05; 95% CI, 0.04-0.06 during the baseline period). Similar patterns were observed for the percentage of patient census and care days provided to patients with an ADRD code., Conclusions and Relevance: The results of this cross-sectional study of Medicare hospice claims data suggested that recent Medicare policies were associated with immediate and lasting reductions in the share of patients receiving hospice care with an ADRD code compared with expectations from preimplementation trends. Future research should examine mechanisms through which hospices enacted change and consequences for quality of care., Competing Interests: Conflict of Interest Disclosures: Dr Gianattasio reported grants from National Institute of Aging (NIA; 5R03AG061499-02) during the conduct of the study. Dr Moghtaderi reported grants from the NIA during the conduct of the study. Dr Lupu reported grants from George Washington University during the conduct of the study and research support George Washington University outside the submitted work, as well as a patent for copyright with royalties from Oxford University Press. Dr Prather reported grants from the National Institutes of Health during the conduct of the study. Dr Power reported grants from NIA during the conduct of the study and personal fees from Biogen and grants from DC Health outside the submitted work., (Copyright 2022 Gianattasio KZ et al. JAMA Health Forum.)

Background: Diagnosis of pneumonia remains challenging. Digitally recorded and remote human classified lung sounds may offer benefits beyond conventional auscultation, but it is unclear whether classifications differ between the two approaches. We evaluated concordance between digital and conventional auscultation., Methods: We collected digitally recorded lung sounds, conventional auscultation classifications and clinical measures and samples from children with pneumonia (cases) in low-income and middle-income countries. Physicians remotely classified recordings as crackles, wheeze or uninterpretable. Conventional and digital auscultation concordance was evaluated among 383 pneumonia cases with concurrently (within 2 hours) collected conventional and digital auscultation classifications using prevalence-adjusted bias-adjusted kappa (PABAK). Using an expanded set of 737 cases that also incorporated the non-concurrently collected assessments, we evaluated whether associations between auscultation classifications and clinical or aetiological findings differed between conventional or digital auscultation using χ 2 tests and logistic regression adjusted for age, sex and site., Results: Conventional and digital auscultation concordance was moderate for classifying crackles and/or wheeze versus neither crackles nor wheeze (PABAK=0.50), and fair for crackles-only versus not crackles-only (PABAK=0.30) and any wheeze versus no wheeze (PABAK=0.27). Crackles were more common on conventional auscultation, whereas wheeze was more frequent on digital auscultation. Compared with neither crackles nor wheeze, crackles-only on both conventional and digital auscultation was associated with abnormal chest radiographs (adjusted OR (aOR)=1.53, 95% CI 0.99 to 2.36; aOR=2.09, 95% CI 1.19 to 3.68, respectively); any wheeze was inversely associated with C-reactive protein >40 mg/L using conventional auscultation (aOR=0.50, 95% CI 0.27 to 0.92) and with very severe pneumonia using digital auscultation (aOR=0.67, 95% CI 0.46 to 0.97). Crackles-only on digital auscultation was associated with mortality compared with any wheeze (aOR=2.70, 95% CI 1.12 to 6.25)., Conclusions: Conventional auscultation and remotely-classified digital auscultation displayed moderate concordance for presence/absence of wheeze and crackles among cases. Conventional and digital auscultation may provide different classification patterns, but wheeze was associated with decreased clinical severity on both., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Few dementia incidence studies have been performed in Latin America. We aimed to provide the incidence of dementia in a Brazilian community-dwelling elderly population., Methods: This study was conducted in urban and rural areas of Tremembé. The 520 participants without dementia at baseline were invited to participate in the follow-up., Results: After a median follow-up of 5 years, the incidence rate of dementia was 26.1 per 1000 person-years (PY) (95% confidence interval  = 18.7-36.6/1000PY). This rate increased exponentially with age (8.3/1000PY for 60- to 64-year-olds to 110.2/1000PY for ≥80-year-olds) and lower education (10.5/1000PY for > 8 years of education to 59.2/1000PY for illiterates). Higher dementia risk was found among individuals with cognitive impairment no dementia at baseline., Discussion: The dementia incidence rate found was higher than in other countries in people under 65 years. Higher incidence in younger individuals is expected in developing countries probably due to low education and a high burden of cardiovascular diseases., (© 2021 the Alzheimer's Association.)

Background: Hearing loss is prevalent and associated with adverse functional outcomes in older adults. Prevention thus has far-reaching implications, yet few modifiable risk factors have been identified. Hypertension may contribute to age-related hearing loss, but epidemiologic evidence is mixed. We studied a prospective cohort of 3343 individuals from the Atherosclerosis Risk in Communities study, aged 44-65 years at baseline with up to 30 years of follow-up., Methods: Hearing was assessed in late life (2016-2017) using a better-ear audiometric pure tone average (0.5, 1, 2, 4 kHz) and the Quick Speech-in-Noise (QuickSIN) test. Hypertension was defined as systolic blood pressure ≥140 mmHg, diastolic blood pressure ≥90 mmHg, or antihypertensive medication use. Midlife hypertension was defined by hypertension at 2 consecutive visits between 1987-1989 and 1996-1998. Late-life hypertension was defined in 2016-2017. Late-life low blood pressure was defined as a systolic blood pressure less than 90 mmHg or diastolic blood pressure less than 60 mmHg, irrespective of antihypertensive medication use. Associations between blood pressure patterns from mid- to late life and hearing outcomes were assessed using multivariable-adjusted linear regression., Results: Compared to persistent normotension, persistent hypertension from mid- to late life was associated with worse central auditory processing (difference in QuickSIN score = -0.66 points, 95% CI: -1.14, -0.17) but not with audiometric hearing., Conclusions: Participants with persistent hypertension had poorer late-life central auditory processing. These findings suggest that hypertension may be more strongly related to hearing-related changes in the brain than in the cochlea., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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.

Current efforts to characterize movers and identify predictors of moving have been limited. We used the ARIC cohort to characterize non-movers, short-distance movers, and long-distance movers, and employed best subset algorithms to identify important predictors of moving, including interactions between characteristics. Short- and long-distance movers were notably different from non-movers, and important predictors of moving differed based on the distance of the residential move. Importantly, systematic inclusion of interaction terms enhanced model fit and was substantively meaningful. This work has important implications for epidemiologic studies of contextual exposures and those treating residential mobility as an exposure., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Ensuring adequate and equitable distribution of resources to support persons living with dementia relies on understanding the burden and distribution of dementia in a population. Our goal was to develop an approach to estimate dementia prevalence at the local level in the United States using publicly available data., Methods: Our approach combines publicly available data on dementia prevalence and demographic data from the US Census to estimate dementia prevalence. We illustrate this approach by estimating dementia prevalence in persons aged 65 and older in Philadelphia, PA; Chicago, IL; and Atlanta, GA., Results: Overall, we estimate the prevalence of dementia among those 65 and older to be 11.9% in Philadelphia, 11.8% Chicago, and 12.3% in Atlanta. Estimates across Philadelphia localities vary from 9.3% to 15.9%., Discussion: Our approach provides a cost-effective method to generate estimates of dementia prevalence at the local level., Highlights: Brain health needs assessments require understanding of local dementia prevalence.Our approach can be used to estimate dementia prevalence in individual communities.This information can inform decisions about distribution of resources., Competing Interests: Melinda C. Power reports grants from the United States National Institutes of Health (NIH), Department of Defense (DOD), and DC Health. N Maritza Dowling reports grants from the United States National Institutes of Health (NIH). All authors were supported by a grant from DC Health., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Objective: To determine associations of traumatic brain injury (TBI) and military employment with activities of daily living (ADL) in late life., Design: Population-based prospective cohort study with biennial follow-up and censoring at the time of dementia diagnosis., Setting: Community-based integrated health care delivery system., Participants: Participants (N=4953) were men (n=2066) and women (n=2887) aged ≥65 years who were dementia free., Interventions: Not applicable., Main Outcome Measures: ADL difficulties at baseline and accumulation during follow-up., Results: TBI with loss of consciousness (LOC) before the age of 40 years was associated with slightly higher ADL difficulty at baseline for women (rate ratio [RR], 1.44; 95% confidence interval [CI], 1.08-1.93; P=.01). For men, TBI with LOC at any age was associated with greater ADL difficulty at baseline (age <40y: RR, 1.58; 95% CI, 1.20-2.08; P=.001; age ≥40y: RR, 2.14; 95% CI, 1.24-3.68; P=.006). TBI with LOC was not associated with the rate of accumulation of ADL difficulties over time in men or women. There was no evidence of an association between military employment and either outcome, nor of an interaction between military employment and TBI with LOC. Findings were consistent across a variety of sensitivity analyses., Conclusions: Further investigation into factors underlying greater late life functional impairment among survivors of TBI is warranted., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Hearing impairment is associated with poor cognitive test performance in older adults. However, hearing's impact on cognitive test completion is poorly described, and missing cognitive data due to hearing impairment could misestimate the association., Methods: We investigated if hearing impairment is associated with missing neurocognitive scores in 3678 adults (72-94 years). Hearing impairment was defined by the better-ear pure tone average of speech-frequency thresholds (0.5-4 kHz) >25 decibels., Results: Hearing impairment was associated with greater missingness on all auditory-only tests, including Logical Memory (prevalence ratio [PR] comparing ≥ moderate impairment vs normal hearing:1.68, 95% confidence interval [CI] 1.26, 2.25) and Digits Backwards (PR 1.62; 95% CI 1.21, 2.17); and two non-auditory tests, Boston Naming (PR 1.61; 95% CI 1.21, 2.17) and Trail Making B (PR 1.55; 95% CI 1.29, 1.86). Models that imputed missing cognitive scores showed the strongest hearing-cognition associations., Discussion: Older adults with hearing impairment are less likely to complete cognitive testing, thereby underestimating the hearing impairment-cognition relationship., (© 2021 the Alzheimer's Association.)

Background: Dementia is a devastating neurologic condition that is common in older adults. We previously reviewed the epidemiological evidence examining the hypothesis that long-term exposure to air pollution affects dementia risk. Since then, the evidence base has expanded rapidly., Objectives: With this update, we collectively review new and previously identified epidemiological studies on air pollution and late-life cognitive health, highlighting new developments and critically discussing the merits of the evidence., Methods: Using a registered protocol (PROSPERO 2020 CRD42020152943), we updated our literature review to capture studies published through 31 December 2020, extracted data, and conducted a bias assessment., Results: We identified 66 papers (49 new) for inclusion in this review. Cognitive level remained the most commonly considered outcome, and particulate matter (PM) remained the most commonly considered air pollutant. Since our prior review, exposure estimation methods in this research have improved, and more papers have looked at cognitive change, neuroimaging, and incident cognitive impairment/dementia, though methodological concerns remain common. Many studies continue to rely on administrative records to ascertain dementia, have high potential for selection bias, and adjust for putative mediating factors in primary models. A subset of 35 studies met strict quality criteria. Although high-quality studies of fine particulate matter with aerodynamic diameter ≤ 2.5 μ m ( PM 2.5 ) and cognitive decline generally supported an adverse association, other findings related to PM 2.5 and findings related to particulate matter with aerodynamic diameter ≤ 10 μ m ( PM 10 , NO 2 , and NO x ) were inconclusive, and too few papers reported findings with ozone to comment on the likely direction of association. Notably, only a few findings on dementia were included for consideration on the basis of quality criteria., Discussion: Strong conclusions remain elusive, although the weight of the evidence suggests an adverse association between PM 2.5 and cognitive decline. However, we note a continued need to confront methodological challenges in this line of research. https://doi.org/10.1289/EHP8716.

Background: Integrating results from multiple samples is often desirable, but privacy restrictions may preclude full data pooling, and most datasets do not include fully harmonized variable sets. We propose a simulation-based method leveraging partial information across datasets to guide creation of synthetic data based on explicit assumptions about the underlying causal structure that permits pooled analyses that adjust for all desired confounders in the context of privacy restrictions., Methods: This proof-of-concept project uses data from the Health and Retirement Study (HRS) and Atherosclerosis Risk in Communities (ARIC) study. We specified an estimand of interest and a directed acyclic graph (DAG) summarizing the presumed causal structure for the effect of glycated hemoglobin (HbA1c) on cognitive change. We derived publicly reportable statistics to describe the joint distribution of each variable in our DAG. These summary estimates were used as data-generating rules to create synthetic datasets. After pooling, we imputed missing covariates in the synthetic datasets and used the synthetic data to estimate the pooled effect of HbA1c on cognitive change, adjusting for all desired covariates., Results: Distributions of covariates and model coefficients and associated standard errors for our model estimating the effect of HbA1c on cognitive change were similar across cohort-specific original and preimputation synthetic data. The estimate from the pooled synthetic incorporates control for confounders measured in either original dataset., Discussion: Our approach has advantages over meta-analysis or individual-level pooling/data harmonization when privacy concerns preclude data sharing and key confounders are not uniformly measured across datasets., Competing Interests: The authors report no conflicts of interest. None of the funders had any role in design and conduct of the study; management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Clinic-based study samples, including the Alzheimer's Disease Neuroimaging Initiative (ADNI), offer rich data, but findings may not generalize to community-based settings. We compared associations in ADNI to those in the Atherosclerosis Risk in Communities (ARIC) study to assess generalizability across the two settings., Methods: We estimated cohort-specific associations among risk factors, cognitive test scores, and neuroimaging outcomes to identify and quantify the extent of significant and substantively meaningful differences in associations between cohorts. We explored whether using more homogenous samples improved comparability in effect estimates., Results: The proportion of associations that differed significantly between cohorts ranged from 27% to 34% across sample subsets. Many differences were substantively meaningful (e.g., odds ratios [OR] for apolipoprotein E ε4 on amyloid positivity in ARIC: OR = 2.8, in ADNI: OR = 8.6)., Discussion: A higher proportion of associations differed significantly and substantively than would be expected by chance. Findings in clinical samples should be confirmed in more representative samples., (© 2021 the Alzheimer's Association.)

Importance: In the US, dementia risk is higher in non-Hispanic Black individuals than in non-Hispanic White individuals. To evaluate progress toward reducing such disparities, tracking secular trends in racial disparities in dementia prevalence is essential., Objective: To examine whether relative racial disparities in dementia prevalence or incidence have changed in the US from 2000 to 2016., Design, Settings, and Participants: The Health and Retirement Study (HRS) is a nationally representative study of adults 50 years or older. New participants are recruited every 6 years, and study visits occur biennially. Approximately 17 000 to 22 000 respondents have been surveyed at each wave since 2000, achieving response rates of 81% to 89%. Data for this cohort study were obtained from non-Hispanic White and non-Hispanic Black participants aged 70 years and older from the 2000 to 2016 waves. For analyses of secular trends in racial disparities in dementia prevalence, each HRS wave was considered separately (range of participants meeting eligibility criteria in each wave, 6322-7579). For analyses of secular trends in racial disparities in dementia incidence, 7 subcohorts were created (range of participants meeting eligibility criteria in each subcohort, 5322-5961) following up people without dementia for 4 years from subcohort baseline visits in 2000, 2002, 2004, 2006, 2008, 2010, and 2012. Data were analyzed from October 2019 to August 2020., Exposures: Race based on self-response to closed-ended survey questions., Main Outcomes and Measures: Dementia status was determined using 3 algorithms with similar sensitivity and specificity across non-Hispanic White and Black participants. Disparities were characterized using ratio measures., Results: In this study, the mean age and percentage of male participants eligible for inclusion in analyses of racial disparities in dementia prevalence increased over time among non-Hispanic White participants (from 78.2 years and 40% in 2000 to 78.7 years and 44% in 2016) but remained steady in non-Hispanic Black participants during the same period (from 78.0 years and 37% in 2000 to 77.9 years and 38% in 2016). Prevalence ratios comparing Black and White participants ranged from approximately 1.5 to 1.9 across algorithms and years, whereas hazard ratios ranged from approximately 1.4 to 1.8. Although results suggest stable or declining dementia risk overall, there was no evidence suggesting change in relative racial disparities in dementia prevalence or incidence during follow-up., Conclusions and Relevance: This study did not find evidence to suggest that the ratio of dementia risk across Black and White individuals changed in the US between 2000 and 2016. Additional efforts to identify and mitigate the source of these disparities is warranted.

Objective: To test the hypothesis that greater levels of leisure-time moderate to vigorous intensity physical activity (MVPA) in midlife or late life are associated with larger gray matter volumes, less white matter disease, and fewer cerebrovascular lesions measured in late life, we utilized data from 1,604 participants enrolled in the Atherosclerosis Risk in Communities study., Methods: Leisure-time MVPA was quantified using a past-year recall, interviewer-administered questionnaire at baseline and 25 years later and classified as none, low, middle, and high at each time point. The presence of cerebrovascular lesions, white matter hyperintensities (WMH), white matter integrity (mean fractional anisotropy [FA] and mean diffusivity [MD]), and gray matter volumes were quantified with 3T MRI in late life. The odds of cerebrovascular lesions were estimated with logistic regression. Linear regression estimated the mean differences in WMH, mean FA and MD, and gray matter volumes., Results: Among 1,604 participants (mean age 53 years, 61% female, 27% Black), 550 (34%), 176 (11%), 250 (16%), and 628 (39%) reported no, low, middle, and high MVPA in midlife, respectively. Compared to no MVPA in midlife, high MVPA was associated with more intact white matter integrity in late life (mean FA difference 0.13 per SD [95% confidence interval (CI) 0.004, 0.26]; mean MD difference -0.11 per SD [95% CI -0.21, -0.004]). High MVPA in midlife was also associated with a lower odds of lacunar infarcts (odds ratio 0.68, 95% CI 0.46, 0.99). High MVPA was not associated with gray matter volumes. High MVPA compared to no MVPA in late life was associated with most brain measures., Conclusion: Greater levels of physical activity in midlife may protect against cerebrovascular sequelae in late life., (© 2021 American Academy of Neurology.)

Background: Traumatic brain injury (TBI) and military service are common lifetime exposures among current older adults that may affect late-life mental health. The objective of the present study was to evaluate the association between TBI with loss of consciousness (LOC) and military employment and late-life depressive symptom severity trajectory., Methods: 1445 males and 2096 females adults at least 65 years old without dementia or recent TBI were enrolled and followed biennially for up to 10 years in the Adult Changes in Thought study from Kaiser Permanente Washington in Seattle, Washington., Results: Using group-based trajectory modeling, we documented four distinct depressive symptom severity trajectories that followed a similar course in males and females (Minimal, Decreasing, Increasing, and Persistent). In multinomial regression analyses, TBI with LOC in males was associated with greater likelihood of Persistent versus Minimal depressive symptom severity compared to individuals without TBI (OR = 1.51, 95% CI: 1.01, 2.27; p=0.046). Males reporting past military employment had greater likelihood of Decreasing versus Minimal depressive symptom severity compared to individuals without past military employment (OR = 1.54, 95% CI: 1.03, 2.31; p=0.035). There was no association between TBI or military employment and depression trajectories in females, and no evidence of effect modification by age or between exposures., Limitations: Lifetime history of TBI was ascertained retrospectively and may be subject to recall bias. Also, past military employment does not presuppose combat exposure., Conclusions: Remote TBI and past military employment are relevant to late-life trajectories of depressive symptom severity in dementia-free older males., (Copyright © 2020. Published by Elsevier B.V.)

Introduction: Patients with poststroke cognitive impairment appear to be at higher risk of recurrent stroke and death. However, whether cognitive impairment after lacunar stroke is associated with recurrent stroke and death remains unclear. We assessed whether global or domain-specific cognitive impairment after lacunar stroke is associated with recurrent stroke and death., Methods: We considered patients from the Secondary Prevention of Small Subcortical Strokes (SPS3) trial with a baseline cognitive exam administered in English by certified SPS3 personnel, 14-180 days after qualifying lacunar stroke. We considered a baseline score of ≤86 on the Cognitive Assessment Screening Instrument to indicate global cognitive impairment, <10 on the Clock Drawing on Command test to indicate executive function impairment, and domain-specific summary scores in the lowest quartile to indicate memory and nonmemory impairment. We used Cox proportional hazards models to estimate the association between poststroke cognitive impairment and subsequent risk of recurrent stroke and death., Results: The study included 1,528 participants with a median enrollment time of 62 days after qualifying stroke. During a mean follow-up of 3.9 years, 11.4% of participants had recurrent stroke and 8.2% died. In the fully adjusted models, memory impairment was independently associated with an increased risk of recurrent stroke (hazard ratio, 1.48; 95% confidence interval [95% CI]: 1.04-2.09) and death (hazard ratio, 1.87; 95% CI: 1.25-2.79). Global impairment (hazard ratio, 1.66; 95% CI: 1.06-2.59) and nonmemory impairment (hazard ratio, 1.74; 95% CI: 1.14-2.67) were associated with an increased risk of death., Discussion/conclusion: After lacunar stroke, memory impairment was an independent predictor of recurrent stroke and death, while global and nonmemory impairment were associated with death. Cognitive screening in lacunar stroke may help identify populations at higher risk of recurrent stroke and death., (© 2021 S. Karger AG, Basel.)

Background: Limited information exists regarding the association between midlife lipid levels and late-life total and regional brain volumes., Methods: We studied 1872 participants in the longitudinal community-based Atherosclerosis Risk in Communities Neurocognitive Study. Serum lipid levels were measured in 1987-1989 (mean age, 53 ± 5 years). Participants underwent 3T brain MRI scans in 2011-2013. Brain volumes were measured using FreeSurfer image analysis software. Linear regression models were used to assess the associations between serum lipids and brain volumes modeled in standard deviation (SD) units, adjusting for potential confounders., Results: In adjusted analyses, one SD higher low-density lipoprotein cholesterol (LDL) levels were associated with larger total brain volumes (β 0.033, 95% CI 0.006-0.060) as well as larger volumes of the temporal (β 0.038, 95% CI 0.003-0.074) and parietal lobes (β 0.044, 95% CI 0.009-0.07) and Alzheimer disease-related region (β 0.048, 95% CI 0.048-0.085). Higher triglyceride levels were associated with smaller total brain volumes (β -0.033, 95% CI -0.060, -0.007). The associations between LDL levels and brain volumes were modified by age (P for interaction <0.001), with higher LDL levels associated with larger total and regional brain volumes only among adults >53 years at baseline, and were attenuated after application of weights to account for informative attrition, although associations with the parietal and Alzheimer's disease-related region remained significant. High-density lipoprotein cholesterol was not associated with brain volumes., Conclusion: Higher LDL levels in late midlife were associated with larger brain volumes later in life, while higher triglyceride levels were associated with smaller brain volumes. These associations were driven by adults >53 years at baseline., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: As hearing loss has been identified as an important risk factor for dementia, we aimed to assess the association between hearing loss and microstructural integrity of the brain., Methods: A total of 1086 dementia-free participants (mean age = 75.2 [standard deviation: 4.9], 61.4% female) of the population-based Atherosclerosis Risk in Communities (ARIC) study underwent hearing assessment (2016-2017) and magnetic resonance imaging of the brain (2011-2013). Microstructural integrity was determined with diffusion tensor imaging. Multivariable linear regression was used to investigate associations between hearing loss and microstructural integrity of different brain regions and white matter (WM) tracts., Results: Hearing loss was associated with lower WM microstructural integrity in the temporal lobe, lower gray matter integrity of the hippocampus, and with lower WM microstructural integrity of the limbic tracts and the uncinate fasciculus., Conclusion: Our results demonstrate that hearing loss is indepedently associated with lower microstructural integrity in brain regions that are important for different cognitive processes., (© 2020 the Alzheimer's Association.)

Elevated low-density lipoprotein cholesterol and total cholesterol in midlife and decline in total cholesterol from mid- to late-life are associated with incident dementia. Whether brain amyloid deposition mediates this relationship is unclear. We explored the association between midlife blood lipid levels and mid- to late-life change in lipid levels with brain amyloid deposition assessed using florbetapir PET scans in a biracial sample of 325 nondemented participants of the Atherosclerosis Risk in Communities-PET Amyloid Imaging study. Midlife total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides were not significantly associated with late-life amyloid burden after adjusting for covariates. Associations between changes in lipids and late-life amyloid deposition were similarly null. Lipids may contribute to dementia risk through alternate mechanisms., (Copyright © 2020 Elsevier Inc. All rights reserved.)