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No known studies have examined the relationships between urban heat islands, historic redlining, and neighborhood walking in older adults. We assessed whether (1) individual and neighborhood characteristics (including redlining score) differ by neighborhood summer land surface temperature (LST); (2) higher LST is associated with less neighborhood walking, and whether associations differ by historic redlining score; and (3) neighborhoods with discriminatory redlining scores have greater LSTs. We used data on 3982 ≥ 65 years old from the 2017 National Household Travel Survey. Multivariable negative binomial and linear regressions tested associations between LST z-score (comparing participant's neighborhood LST to surrounding region's LST) and self-reported neighborhood walking and the association between living in neighborhoods redlined as "definitely declining" or "hazardous" (versus "still desirable"/"best") and LST z-score. LSTs were higher for those in neighborhoods with higher area deprivation scores and more African American/Black residents. Older adults living in neighborhoods with higher summer LST z-scores had fewer minutes of neighborhood walking/day. This association seemed limited to individuals with neighborhood redlining scores of "still desirable"/"best." Neighborhood redlining scores of "definitely declining" or "hazardous" (versus "still desirable" and "best") were associated with greater neighborhood summer LSTs. Overall, these findings suggest that historically redlined neighborhoods may experience urban heat island effects more often. While older adults living in hotter neighborhoods with "still desirable" or "best" redlining scores may less often engage in neighborhood walking, those in neighborhoods with redlining scores of "definitely declining" and "hazardous" do not seem to decrease neighborhood walking with higher LSTs. Future work is needed to elucidate the impact of extreme heat on health-promoting behaviors such as walking and the types of interventions that can successfully counteract negative impacts on historically disadvantaged communities., (© 2024. The New York Academy of Medicine.)

Background: Few studies have investigated associations between perceived social determinants of health (SDOH) and Alzheimer's disease and related dementia (ADRD) biomarkers or between SDOH and resilience against ADRD., Objective: To examine associations between perceived and objective SDOH and ADRD-related outcomes., Methods: We used cross-sectional data on≥50-year-olds without dementia in the Healthy Brain Initiative (n = 162). Questionnaires captured trust in neighbors and indices of perceived neighborhood greenspace access, time spent in neighborhood greenspaces, and interpersonal discrimination. Residential addresses were linked to 2021 Area Deprivation Index scores. The Vulnerability Index (VI) is based on 12 dementia risk factors (e.g., age, race/ethnicity, diabetes) and Resilience Index (RI) is based on 6 protective factors (e.g., diet, mindfulness, physical activity). Cognitive measured included number symbol coding task and Montreal Cognitive Assessment. Biomarkers included Aβ 42/40 and pTau-217/npTau-217, hippocampal and white matter hyperintensity volume, lipoprotein A, and high-sensitivity c-reactive protein., Results: Perceived greater access to greenspaces (estimate = 2.83, 95% CI = 1.40-4.26) and greater time in neighborhood greenspaces were associated with greater RI scores (estimate = 2.30, 95% CI = 1.24-3.35). Reporting greater discrimination (estimate = 0.10, 95% CI = 0.04-0.16) and living in higher deprivation neighborhoods were associated with greater VI scores (estimate = 0.017, 95% CI = 0.003-0.032). Greater discrimination was associated with greater white matter hyperintensity volume (estimate = 0.27, 95% CI = 0.04-0.51)., Conclusions: Perceived greenspace access and time spent in greenspaces were associated with resilience against ADRD, and interpersonal discrimination was associated with vulnerability to ADRD. Future work needs to validate perceived SDOH measures, examine associations in racially/ethnic diverse populations, and investigate longitudinal associations between SDOH and ADRD-related biomarkers., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 – The authors. Published by IOS Press.)

Objective: Synthesize longitudinal research evaluating neighborhood environments and cognition to identify methodological approaches, findings, and gaps. Methods: Included studies evaluated associations between neighborhood and cognition longitudinally among adults >45 years (or mean age of 65 years) living in developed nations. We extracted data on sample characteristics, exposures, outcomes, methods, overall findings, and assessment of disparities. Results: Forty studies met our inclusion criteria. Most (65%) measured exposure only once and a majority focused on green space and/or blue space (water), neighborhood socioeconomic status, and recreation/physical activity facilities. Similarly, over half studied incident impairment, cognitive function or decline (70%), with one examining MRI (2.5%) or Alzheimer's disease (7.5%). While most studies used repeated measures analysis to evaluate changes in the brain health outcome (51%), many studies did not account for any type of correlation within neighborhoods (35%). Less than half evaluated effect modification by race/ethnicity, socioeconomic status, and/or sex/gender. Evidence was mixed and dependent on exposure or outcome assessed. Conclusion: Although longitudinal research evaluating neighborhood and cognitive decline has expanded, gaps remain in types of exposures, outcomes, analytic approaches, and sample diversity., Competing Interests: The authors declare that they do not have any conflicts of interest., (Copyright © 2024 Michael, Senerat, Buxbaum, Ezeanyagu, Hughes, Hayden, Langmuir, Besser, Sánchez and Hirsch.)

Built environments have the potential to favorably support cognitive function. Despite growing work on this topic, most of the work has ignored variation in the spatial scale of the effect. The issue with spatial scale effects is that the size and shape of the areal unit within which built environment characteristics are measured naturally influence the built environment exposure metric and thus the estimated associations with health. We used spatial distributed lag modeling (DLM) to estimate how associations between built environment exposures (walkable destinations [WD], social destinations [SD]) and change in cognition varied across distance of these destinations from participants' residences. Cognition was assessed as maintained/improved processing speed (PS) and global cognition (GC). Person-level data from Exam 5 (2010-2012) and Exam 6 (2016-2018) of the Multi-Ethnic Study of Atherosclerosis was used (N = 1380, mean age 67). Built environment data were derived from the National Establishment Time Series. Higher availability of walkable and social destinations at closer distance from participants' residence was associated with maintained/improved PS. The adjusted associations between maintained/improved PS and destinations waned with increasing distance from the residence; associations were evident until approximately 1.9-km for WD and 1.5-km for SD. Associations were most apparent for participants living in areas with high population density. We found little evidence for associations between change in GC and built environment at any distance. These results highlight the importance of identifying appropriate spatial scale to understand the mechanisms for built environment-cognition associations., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The Health Brain Initiative (HBI), established by University of Miami's Comprehensive Center for Brain Health (CCBH), follows racially/ethnically diverse older adults without dementia living in South Florida. With dementia prevention and brain health promotion as an overarching goal, HBI will advance scientific knowledge by developing novel assessments and non-invasive biomarkers of Alzheimer's disease and related dementias (ADRD), examining additive effects of sociodemographic, lifestyle, neurological and biobehavioral measures, and employing innovative, methodologically advanced modeling methods to characterize ADRD risk and resilience factors and transition of brain aging., Methods: HBI is a longitudinal, observational cohort study that will follow 500 deeply-phenotyped participants annually to collect, analyze, and store clinical, cognitive, behavioral, functional, genetic, and neuroimaging data and biospecimens. Participants are ≥50 years old; have no, subjective, or mild cognitive impairment; have a study partner; and are eligible to undergo magnetic resonance imaging (MRI). Recruitment is community-based including advertisements, word-of-mouth, community events, and physician referrals. At baseline, following informed consent, participants complete detailed web-based surveys (e.g., demographics, health history, risk and resilience factors), followed by two half-day visits which include neurological exams, cognitive and functional assessments, an overnight sleep study, and biospecimen collection. Structural and functional MRI is completed by all participants and a subset also consent to amyloid PET imaging. Annual follow-up visits repeat the same data and biospecimen collection as baseline, except that MRIs are conducted every other year after baseline., Ethics and Expected Impact: HBI has been approved by the University of Miami Miller School of Medicine Institutional Review Board. Participants provide informed consent at baseline and are re-consented as needed with protocol changes. Data collected by HBI will lead to breakthroughs in developing new diagnostics and therapeutics, creating comprehensive diagnostic evaluations, and providing the evidence base for precision medicine approaches to dementia prevention with individualized treatment plans., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Besser et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: We examined whether a combined measure of neighborhood greenspace and neighborhood median income was associated with white matter hyperintensity (WMH) and ventricle size changes., Methods: The sample included 1260 cognitively normal ≥ 65-year-olds with two magnetic resonance images (MRI; ≈ 5 years apart). WMH and ventricular size were graded from 0 (least) to 9 (most) abnormal (worsening = increase of ≥1 grade from initial to follow-up MRI scans). The four-category neighborhood greenspace-income measure was based on median neighborhood greenspace and income values at initial MRI. Multivariable logistic regression tested associations between neighborhood greenspace-income and MRI measures (worsening vs. not)., Results: White matter grade worsening was more likely for those in lower greenspace-lower income neighborhoods than higher greenspace-higher income neighborhoods (odds ratio = 1.73; 95% confidence interval = 1.19-2.51)., Discussion: The combination of lower neighborhood income and lower greenspace may be a risk factor for worsening white matter grade on MRI. However, findings need to be replicated in more diverse cohorts., Highlights: Population-based cohort of older adults (≥ 65 years) with greenspace and MRI dataCombined measure of neighborhood greenspace and neighborhood income at initial MRIMRI outcomes included white matter hyperintensities (WMH) and ventricular sizeLongitudinal change in MRI outcomes measured approximately 5 years apartWorsening WMH over time more likely for lower greenspace-lower income neighborhoods., Competing Interests: Lilah Besser, Gina Lovasi, Joyce Jimenez Zambrano, Simone Camacho, Devi Dhanekula, Yvonne L. Michael, Parveen Garg, Jana Hirsch, David Siscovick, Philip M. Hurvitz, Mary Lou Biggs, James Galvin, and Traci Bartz have no conflicts of interest. Will Longstreth serves as a co‐PI for the NIH‐funded ARCADIA trial, which receives in‐kind study drug from the BMS‐Pfizer Alliance and ancillary funding from Roche Diagnostics. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: With the rapid expansion of the aging population, the burden of Alzheimer's disease related dementias (ADRD) is anticipated to increase in racialized and minoritized groups who are at disproportionately higher risk. To date, research emphasis has been on further characterizing the existence of racial disparities in ADRD through comparisons to groups racialized as White that are assumed to be normative. Much of the literature on this comparison insinuates that racialized and minoritized groups experience poorer outcomes due to genetics, culture, and/or health behaviors., Methods: This perspective shines a light on a category of ADRD research that employs ahistorical methodological approaches to describe racial disparities in ADRD that puts us on a merry-go-round of research with no benefits to society., Methods: This commentary provides historical context for the use of race in ADRD research and justification for the study of structural racism. The commentary concludes with recommendations to guide future research., (© 2023 the Alzheimer's Association.)

Introduction: The projected growth of Alzheimer's disease (AD) and AD-related dementia (ADRD) cases by midcentury has expanded the research field and impelled new lines of inquiry into structural and social determinants of health (S/SDOH) as fundamental drivers of disparities in AD/ADRD., Methods: In this review, we employ Bronfenbrenner's ecological systems theory as a framework to posit how S/SDOH impact AD/ADRD risk and outcomes., Results: Bronfenbrenner defined the "macrosystem" as the realm of power (structural) systems that drive S/SDOH and that are the root cause of health disparities. These root causes have been discussed little to date in relation to AD/ADRD, and thus, macrosystem influences, such as racism, classism, sexism, and homophobia, are the emphasis in this paper., Discussion: Under Bronfenbrenner's macrosystem framework, we highlight key quantitative and qualitative studies linking S/SDOH with AD/ADRD, identify scientific gaps in the literature, and propose guidance for future research., Highlights: Ecological systems theory links structural/social determinants to AD/ADRD. Structural/social determinants accrue and interact over the life course to impact AD/ADRD. Macrosystem is made up of societal norms, beliefs, values, and practices (e.g., laws). Most macro-level determinants have been understudied in the AD/ADRD literature., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

We developed the Life Course Sociodemographics and Neighborhood Questionnaire (LSNEQ) to query older adults about perceived neighborhood greenspaces across the life course (i.e., distance to park, number of neighborhood parks/playgrounds, and neighborhood greenness) and about characteristics hypothesized to confound or moderate/mediate greenspace-health associations. Six perceived life course indices are derived from the LSNEQ: neighborhood socioeconomic status, neighborhood walking/biking, urbanicity, neighborhood amenities, neighborhood park access, and neighborhood greenness. Older adults from St. Louis, Missouri, and Sacramento, California, completed the LSNEQ in 2020-2021. The indices demonstrated borderline acceptable to good internal consistency (alpha = 0.60-0.79) and good to excellent test-retest reliability (ICC = 0.71-0.96) and detected different patterns of park access and neighborhood greenness by racialized group and location. Individuals with index scores indicating more neighborhood walking/biking and greater presence of neighborhood amenities over their life course were more likely to report neighborhood-based walking in older age. Overall, the LSNEQ is a reliable instrument to assess perceptions of life course social determinants of health including neighborhood greenspaces., Competing Interests: Declaration of competing interest Dr. Besser, Dr. Meyer, Ms. Streitz, Dr. Farias, Dr. Olichney, Dr. Mitsova, and Dr. Galvin have no conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Studies examining associations between greenspace and Alzheimer's disease and related dementia (ADRD) outcomes are rapidly on the rise, yet no known literature reviews have summarized the racialized/ethnic group and geographic variation of those published studies. This is a significant gap given the known disparities in both greenspace access and ADRD risk between racialized/ethnic groups and between developed versus developing countries. In this rapid literature review, we (1) describe the diversity of published greenspace-brain health studies with respect to racialized/ethnic groups and geographic regions; (2) determine the extent to which published studies have investigated racialized/ethnic group differences in associations; and (3) review methodological issues surrounding studies of racialized/ethnic group disparities in greenspace and brain health associations. Of the 57 papers meeting our inclusion criteria as of 4 March 2022, 21% ( n = 12) explicitly identified and included individuals who were Black, Hispanic/Latinx, and/or Asian. Twenty-one percent of studies ( n = 12) were conducted in developing countries (e.g., China, Dominican Republic, Mexico), and 7% ( n = 4) examined racialized/ethnic group differences in greenspace-brain health associations. None of the studies were framed by health disparities, social/structural determinants of health, or related frameworks, despite the known differences in both greenspace availability/quality and dementia risk by racialized/ethnic group and geography. Studies are needed in developing countries and that directly investigate racialized/ethnic group disparities in greenspace-brain health associations to target and promote health equity.

Introduction: We investigated associations between neighborhood racial/ethnic segregation and cognitive change., Methods: We used data (n = 1712) from the Multi-Ethnic Study of Atherosclerosis. Racial/ethnic segregation was assessed using Getis-Ord (Gi*) z-scores based on American Community Survey Census tract data (higher Gi* = greater spatial clustering of participant's race/ethnicity). Global cognition and processing speed were assessed twice, 6 years apart. Adjusted multilevel linear regression tested associations between Gi* z-scores and cognition. Effect modification by race/ethnicity, income, education, neighborhood socioeconomic status, and neighborhood social support was tested., Results: Participants were on average 67 years old; 43% were White, 11% Chinese, 29% African American/Black, 17% Hispanic; 40% had high neighborhood segregation (Gi* > 1.96). African American/Black participants with greater neighborhood segregation had greater processing speed decline in stratified analyses, but no interactions were significant., Discussion: Segregation was associated with greater processing speed declines among African American/Black participants. Additional follow-ups and comprehensive cognitive batteries may further elucidate these findings., Highlights: A study of neighborhood racial/ethnic segregation and change in cognition. Study was based on a racially and geographically diverse, population-based cohort of older adults. Racial/ethnic segregation (clustering) was measured by the Getis-ord (Gi*) statistic. We saw faster processing speed decline among Black individuals in segregated neighborhoods., (© 2022 the Alzheimer's Association.)

Problem Research Strategy and Findings: Health impact assessment (HIA) reports are used by government agencies, other organizations, and stakeholders to evaluate potential health effects of plans/policies/projects. HIAs have the potential to promote anti-racist practices. We developed and used the Tool for the Racial/Ethnic Equity Evaluation of Health Impact Assessments (TREE-HIA) to score 50 U.S. HIA reports on planning-related projects/plans involving parks and greenspaces (2005-2020). More recent and more comprehensive HIA reports addressed racial/ethnic equity to a greater degree (e.g., median TREE-HIA scores: -1.3 in 2009-2012, 4.0 in 2017-2020, where higher scores indicate greater racial/equity considerations). Overall, HIA reports addressed racial/ethnic equity to a lesser degree than expected given the principal tenet of equity guiding HIAs and urban planning alike (42% had negative TREE-HIA scores indicating inadequate racial/ethnic equity consideration). However, the limited number and types of HIAs included in this study may affect generalization to all HIAs., Takeaway for Practice: HIAs incorporating racial/ethnic equity comprehensively throughout the HIA process will better enable urban planners, HIA practitioners, decision makers, and communities of color to work together to combat racist planning practices through the shared goals of addressing health disparities and equity. TREE-HIA provides professionals and researchers with a brief tool that can be used/adapted to guide and evaluate future HIAs for racial/ethnic equity considerations., Competing Interests: Declaration of Interest The authors have no conflicts of interest to declare.

Objectives: We examined whether greenspace measures (overall percent greenspace and forest, and number of greenspace types) were associated with clinically adjudicated dementia status., Methods: In a sample of non-demented older adults (n = 2141, average age = 75.3 years) from the Cardiovascular Health and Cognition Study, Cox proportional hazard and logistic regression analyses were used to estimate associations of baseline greenspace with risks of incident dementia and MCI, respectively, while adjusting for demographics, co-morbidities, and other neighborhood factors. We derived quartiles of percent greenness (greenspace), forest (percent tree canopy cover), and tertiles of greenspace diversity (number of greenspace types) for 5-km radial buffers around participant's residences at study entry (1989-1990) from the 1992 National Land Cover Dataset. Dementia status and mild cognitive impairment (MCI) over 10 years was clinically adjudicated., Results: We observed no significant association between overall percent greenspace and risk of mild cognitive impairment or dementia and mostly null results for forest and greenspace diversity. Forest greenspace was associated with lower odds of MCI (OR quartile 4 versus 1: 0.54, 95% CI: 0.29-0.98) and greenspace diversity was associated with lower hazard of incident dementia (HR tertile 2 versus 1: 0.70, 95% CI = 0.50-0.99)., Discussion: We found divergent results for different types of greenspace and mild cognitive impairment or dementia. Improved greenspace type and diversity measurement could better characterize the association between greenspace and cognition., Competing Interests: Declaration of competing interest No conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: In the 1930s, Black, working-class, and immigrant neighborhoods were color coded on maps (i.e., redlining) indicating investment risk, which negatively impacted mortgage attainment/homeownership for these groups and led to long-standing segregation by race/ethnicity and socioeconomic status. Limited studies have investigated the health impacts of redlining, particularly among older adults who tend to stay closer to their residences. This study examines whether older adults in historically redlined neighborhoods report less neighborhood walking and whether associations vary by race/ethnicity and income., Methods: The sample included 4,651 individuals aged ≥65 years from the 2017 U.S. National Household Travel Survey. U.S. Census tract‒based redlining scores were 1=best, 2=still desirable, 3=definitely declining, and 4=hazardous. Multivariable negative binomial regression tested the associations between redlining and neighborhood walking/day in the overall sample and with stratification by poverty status (analyzed in 2022)., Results: Participants were on average aged 73 years, and 11% were African/American Black, 75% were White, 8% were Hispanic/Latinx, and 6% were of other race/ethnicity. Participants reported a mean of 7.1 neighborhood walking minutes/day (SD=20.6), and 60% lived in definitely declining or hazardous neighborhoods. Individuals in hazardous neighborhoods (versus those in best neighborhoods) reported less neighborhood walking (prevalence ratio=0.64; 95% CI=0.43, 0.97). Among those living in poverty, living in definitely declining and hazardous neighborhoods was associated with less neighborhood walking (prevalence ratio=0.39 [95% CI=0.20, 0.79] and 0.39 [95% CI=0.18, 0.82], respectively)., Conclusions: Less neighborhood walking was reported among individuals living in neighborhoods with a historic redlining score of definitely declining or hazardous. Future studies using larger, more diverse cohorts may elucidate whether associations differ by race/ethnicity and geographic location/city., (Copyright © 2022 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: The burden of Alzheimer's disease (AD) and AD-related dementias (ADRD) is increasing nationally and globally, with disproportionate impacts on lower-income, lower education and systematically marginalised older adults. Presence of inequalities in neighbourhood factors (eg, social context, physical and built environments) may affect risk of cognitive decline and be key for intervening on AD/ADRD disparities at the population level. However, existing studies are limited by a dearth of longitudinal, detailed neighbourhood measures linked to rich, prospective cohort data. Our main objective is to identify patterns of neighbourhood change related to prevalence of-and disparities in-cognitive decline and dementia., Methods and Analyses: We describe the process of collecting, processing and linking extensive neighbourhood data to the Multi-Ethnic Study of Atherosclerosis (MESA), creating a 25+ years dataset. Within the MESA parent study, the MESA Neighborhoods and Aging cohort study will characterise dynamic, longitudinal neighbourhood social and built environment variables relevant to cognition for residential addresses of MESA participants. This includes administering new surveys, expanding residential address histories, calculating new measures derived from spatial data and implementing novel deep learning algorithms on street-level imagery. Applying novel statistical techniques, we will examine associations of neighbourhood environmental characteristics with cognition and clinically relevant AD/ADRD outcomes. We will investigate determinants of disparities in outcomes by socioeconomic position and race/ethnicity and assess the contribution of neighbourhood environments to these disparities. This project will provide new evidence about pathways between neighbourhood environments and cognitive outcomes, with implications for policies to support healthy ageing., Ethics and Dissemination: This project was approved by the University of Washington and Drexel University Institutional Review Boards (protocols #00009029 and #00014523, and #180900605). Data will be distributed through the MESA Coordinating Center. Findings will be disseminated in peer-reviewed scientific journals, briefs, presentations and on the participant website., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Greater neighborhood greenspace has been associated with brain health, including better cognition and lower odds of Alzheimer's disease in older adults. We investigated associations between neighborhood greenspace and brain-based magnetic resonance imaging (MRI) measures and potential effect modification by sex or apolipoprotein E genotype (APOE), a risk factor for Alzheimer's disease., Methods: We obtained a sample of non-demented participants 65 years or older (n = 1125) from the longitudinal, population-based Cardiovascular Health Study (CHS). Greenspace data were derived from the National Land Cover Dataset. Adjusted multivariable linear regression estimated associations between neighborhood greenspace five years prior to the MRI and left and right hippocampal volume and 10-point grades of ventricular size and burden of white matter hyperintensity. Interaction terms tested effect modification by APOE genotype and sex. CHS data (1989-1999) were obtained/analyzed in 2020., Results: Participants were on average 79 years old [standard deviation (SD) = 4], 58% were female, and 11% were non-white race. Mean neighborhood greenspace was 38% (SD = 28%). Greater proportion of greenspace in the neighborhood five years before MRI was borderline associated with lower ventricle grade (estimate: - 0.30; 95% confidence interval: - 0.61, 0.00). We observed no associations between greenspace and the other MRI outcome measures and no evidence of effect modification by APOE genotype and sex., Conclusion: This study suggests a possible association between greater greenspace and less ventricular enlargement, a measure reflecting global brain atrophy. If confirmed in other longitudinal cohort studies, interventions and policies to improve community greenspaces may help to maintain brain health in older age., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Few studies have examined associations between neighborhood built environments (BE) and longitudinally measured cognition. We examined whether four BE characteristics were associated with six-year change in global cognition and processing speed. We obtained data on 1816 participants without dementia from the Multi-Ethnic Study of Atherosclerosis. BE measures included social destination density, walking destination density, proportion of land dedicated to retail, and network ratio (street connectivity). Global cognition was measured with the Cognitive Abilities Screening Instrument (CASI) and processing speed with the Digit Symbol Coding test (DSC). Multivariable random intercept logistic models tested associations between neighborhood BE at 2010-2012 and maintained/improved cognition (versus decline) from 2010-2018, and mediation by minutes of physical activity (PA)/week. The sample was an average of 67 years old (standard deviation = 8.2) (first cognitive measurement) and racially/ethnically diverse (29% African American, 11% Chinese, 17% Hispanic, 44% White). Compared to individuals with no walking destinations in the 1-mile surrounding their residence, those with 716 walking destinations (maximum observed) were 1.24 times more likely to have maintain/improved DSC score (Odds ratio: 1.24; 95% confidence interval: 1.03-1.45). No other associations were observed between BE and cognition, and PA minutes/week did not mediate the association between walking destination density and DSC change. This study provides limited evidence for an association between greater neighborhood walking destinations and maintained/improved processing speed in older age and no evidence for associations between the other BE characteristics and cognition. Future studies with finer grained BE and cognitive measures and longer-term follow up may be required.

Background: Social environments are a contributing determinant of health and disparities. This scoping review details how social environments have been operationalized in observational studies of cognitive aging and dementia., Methods: A systematic search in PubMed and Web of Science identified studies of social environment exposures and late-life cognition/dementia outcomes. Data were extracted on (1) study design; (2) population; (3) social environment(s); (4) cognitive outcome(s); (5) analytic approach; and (6) theorized causal pathways. Studies were organized using a 3-tiered social ecological model at interpersonal, community, or policy levels., Results: Of 7802 non-duplicated articles, 123 studies met inclusion criteria. Eighty-four studies were longitudinal (range 1-28 years) and 16 examined time-varying social environments. When sorted into social ecological levels, 91 studies examined the interpersonal level; 37 examined the community/neighborhood level; 3 examined policy level social environments; and 7 studies examined more than one level., Conclusions: Most studies of social environments and cognitive aging and dementia examined interpersonal factors measured at a single point in time. Few assessed time-varying social environmental factors or considered multiple social ecological levels. Future studies can help clarify opportunities for intervention by delineating if, when, and how social environments shape late-life cognitive aging and dementia outcomes.

Introduction: Greenspace exposure has been associated with physical activity, but few studies have investigated its association with physical activity in the residential neighborhood. This study investigates whether greater amounts of neighborhood open space and forest are associated with neighborhood-based walking in older adults., Methods: In 2020, cross-sectional analyses were conducted on those aged ≥65 years from the 2017 National Household Travel Survey. Minutes of neighborhood walking per day were derived from travel diaries. Green land cover measures from the 2011 National Land Cover Dataset were linked to respondent data by the U.S. census tract. Adjusted linear regression models, using weights accounting for survey sampling, tested the associations between the percentage of green land cover in the neighborhood (open space, forest) and minutes of neighborhood walking per day. Adjusted models were stratified to examine whether the associations varied by an individual- and neighborhood-level SES, sex, and race/ethnicity., Results: Respondents (N=72,753) were aged 74 (SD=7) years on average. Greater percentage of open space was associated with more neighborhood walking in African Americans (estimate=0.069, 95% CI=0.005, 0.133). Greater percentage of forest was associated with more neighborhood walking in the overall sample (estimate=0.028, 95% CI=0.006, 0.050), women (estimate=0.025, 95% CI=0.005, 0.045), and Whites (estimate=0.034, 95% CI=0.004, 0.064)., Conclusions: Type of neighborhood green land cover (open space versus forest) may be differentially associated with neighborhood walking depending on race/ethnicity. This study suggests a possible association between greater neighborhood open space and greater walking among African Americans that must be confirmed in future studies., (Copyright © 2021 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Preliminary evidence suggests that neighborhood environments, such as socioeconomic disadvantage, pedestrian and physical activity infrastructure, and availability of neighborhood destinations (e.g., parks), may be associated with late-life cognitive functioning and risk of Alzheimer's disease and related disorders (ADRD). The supposition is that these neighborhood characteristics are associated with factors such as mental health, environmental exposures, health behaviors, and social determinants of health that in turn promote or diminish cognitive reserve and resilience in later life. However, observed associations may be biased by self-selection or reverse causation, such as when individuals with better cognition move to denser neighborhoods because they prefer many destinations within walking distance of home, or when individuals with deteriorating health choose residences offering health services in neighborhoods in rural or suburban areas (e.g., assisted living). Research on neighborhood environments and ADRD has typically focused on late-life brain health outcomes, which makes it difficult to disentangle true associations from associations that result from reverse causality. In this paper, we review study designs and methods to help reduce bias due to reverse causality and self-selection, while drawing attention to the unique aspects of these approaches when conducting research on neighborhoods and brain aging.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.

Background: Preliminary evidence suggests associations between neighborhood park access and better late-life cognition and reduced Alzheimer's disease (AD) risk., Objective: Examine associations between neighborhood park access and longitudinal change in cognition among U.S. older adults without dementia., Methods: We used 2000-2018 observational data from the population-based, multi-site Multi-Ethnic Study of Atherosclerosis (n = 1,733). Measures included proportion of neighborhood park space (park access), distance to nearest park, and 6-year dichotomous and continuous change in scores on the Cognitive Abilities Screening Instrument (CASI; global cognition) and Digit Symbol Coding task (processing speed). Multivariable random intercept models tested main associations and mediation by depressive symptoms, physical activity, and PM2.5 exposure. Effect modification by race (African Americans/Blacks versus Whites) was tested using interaction terms., Results: Greater park access (equivalent to 10%more in 1/2-mile around home) was associated with maintained/improved CASI score over six years independent of several covariates including individual- and neighborhood-level socioeconomic status (Odds ratio: 1.04; 95%confidence interval: 1.00-1.08). No other associations were observed with the dichotomous or continuous measures of cognitive change and no mediators were found. While a borderline association was seen between greater park access and maintained/improved CASI for African Americans/Blacks but not for Whites, effect modification was not confirmed by testing interaction terms., Conclusion: Neighborhood park access may help maintain/improve late-life global cognition. However, our findings need replication in other population-based studies and regions. Additionally, studies are needed to determine if associations between park access and change in cognition vary by race/ethnicity to inform intervention efforts.

Background: Neighborhood walking connotes physical activity and opportunities for social and cognitive engagement and improved mental health, factors previously associated with outcomes including mortality, cardiovascular disease, and dementia. Few studies have examined correlates of neighborhood-specific walking in older adults., Purpose: We investigated the individual and neighborhood/regional correlates of neighborhood-based walking among US older adults., Methods: We obtained cross-sectional data on ≥ 65 year olds from the population-based 2017 National Household Travel Survey (n = 73,523). Respondents completed diaries detailing trips during an assigned travel day. Adjusted logistic regression (using survey weights) tested associations between individual, neighborhood, and regional characteristics and ≥ 1 versus no neighborhood walk trips/day (from travel diary)., Results: Twelve percent had ≥ 1 neighborhood walk trip/day and 54% of the neighborhood walkers achieved ≥ 30 min of walking/day. African Americans/Blacks (versus non-Hispanic Whites) and working individuals (versus retired) had lower odds of neighborhood walking. Individuals without cars, bus/train users, and those with higher neighborhood housing density had greater odds of neighborhood walking. Utilitarian walking was less likely among African Americans/Blacks and Hispanics but more likely among Asians (versus non-Hispanic Whites). Social/recreational neighborhood walking was more likely for those without cars, bus/train users, and those with greater neighborhood housing density., Conclusion: Few US older adults walked in their neighborhoods, suggesting a potentially fruitful target for health promotion efforts and community interventions to improve health and quality of life in older adults. Future work is needed to determine other neighborhood factors associated with greater neighborhood walking., Competing Interests: 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., (© 2020 The Author(s).)

We used cross-sectional Multi-Ethnic Study of Atherosclerosis data from six US cities/counties and adjusted multilevel linear regression to examine park space-cognition associations among non-demented older adults (n = 4084). We found that greater neighborhood park space 1-mile around the residence (measured continuously) was associated with better processing speed in the overall sample (estimate: 0.48; 95% CI: 0.03, 0.92). However, greater neighborhood park space (½-mile around residence) was associated with worse global cognition in Los Angeles, California (estimate: -2.66; 95% CI: -4.70, -0.62) and worse processing speed in Forsyth County, North Carolina (estimate: -0.72; 95% CI: -1.37, -0.08). Dichotomizing at the mean, having ≥6% park space (½-mile around residence) was associated with better global cognition in Saint Paul, Minnesota (estimate: 0.21; 95% CI: 0.05, 0.38), and better processing speed in New York City (estimate: 0.19; 95% CI: 0.04, 0.35). Park space-cognition associations varied by city/county, suggesting problems with pooling multiple sites without accounting for geographic context or regionally-varying park characteristics (e.g., quality)., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To examine whether neuropathologic burden is associated with hearing impairment., Methods: We studied 2,755 autopsied participants ≥55 years of age from the National Alzheimer's Coordinating Center database. Participants had at least 1 clinical evaluation at US National Institute on Aging-funded Alzheimer's Disease Center no more than 2 years before death. Patients were classified as hearing impaired by clinician report at baseline. Common dementia neuropathologies included Alzheimer disease pathologic change (Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque density, neurofibrillary degeneration Braak stage), Lewy body disease, gross infarcts, and microinfarcts. Logistic regression models predicted impaired hearing with adjustment for age at death, sex, race, education, center, and follow-up time. Relative risks were calculated with the use of marginal standardization., Results: Impaired hearing was common (32%). In participants who were cognitively normal at baseline (n = 580), impaired hearing was associated with higher Braak stage (relative risk [RR] 1.33 per 2-stage increase, 95% confidence interval [CI] 1.06-1.66) but not other pathologies. In participants with dementia (n = 2,175), impaired hearing was positively associated with microinfarcts (RR 1.18, 95% CI 1.00-1.39) and inversely associated with neuritic plaque density (RR 0.91 per score increase, 95% CI 0.85-0.99). Development of impaired hearing in those with cognitive impairment was associated with neocortical Lewy bodies (1.26, 95% CI 1.02-1.55)., Conclusions: Impaired hearing, reported before the onset of cognitive impairment, was associated with increased neurofibrillary tangle burden. Impaired hearing in those with cognitive impairment was associated with microinfarcts and neocortical Lewy bodies but not typical Alzheimer disease pathologic change. Functional hearing problems may be a preclinical marker of neurofibrillary neurodegeneration, although replication is needed., (© 2020 American Academy of Neurology.)

Objective: To describe the experience of obtaining a diagnosis of frontotemporal degeneration (FTD) for patients and caregivers., Methods: Data came from a 2017 web-based survey of 698 FTD caregivers. Clinical characteristics and diagnostic experiences were described according to the phenotype of the patient with FTD (behavioral variant FTD, primary progressive aphasia, FTD with motor neuron disease, or progressive supranuclear palsy/corticobasal syndrome). Unadjusted and adjusted logistic regression analyses determined associations between patient with FTD and caregiver characteristics and (1) receiving a diagnosis >1 year after initial symptoms and (2) first receiving a non-FTD diagnosis., Results: Mean age was 66 ± 9 years for patients with FTD and 61 ± 10 years for FTD caregivers. Forty-four percent of patients took more than 1 year; 65% saw 3 or more doctors; and 84% required 3 or more visits to establish an FTD diagnosis. Initial diagnosis was depression or other psychiatric condition in 21% of patients. Twenty-eight percent of caregivers and 26% of patients lost ≥11 work days seeking diagnosis. The majority of diagnoses (66%) were made by neurologists. Patient and caregiver age, having a spouse caregiver, rural residency, and mood changes as first symptom were associated with a longer time to receive FTD diagnosis. Caregivers frequently rated diagnosing doctors as good/excellent in knowledge of FTD but as inadequate/poor on knowledge of available community resources., Conclusions: This study, which quantifies the patient with FTD and caregiver burden before receiving the FTD diagnosis, can inform clinical practice, interventions to address diagnostic delays, and programs and services to support patients/caregivers during and following the diagnosis., (© 2019 American Academy of Neurology.)

It remains unclear what clinical features inform the accuracy of a clinical diagnosis of Alzheimer disease (AD). Data were obtained from the National Alzheimer's Coordinating Center to compare clinical and neuropathologic features among participants who did or did not have Alzheimer disease neuropathologic changes (ADNC) at autopsy. Participants (1854) had a clinical Alzheimer dementia diagnosis and ADNC at autopsy (Confirmed-AD), 204 participants had an AD diagnosis and no ADNC (AD-Mimics), and 253 participants had no AD diagnosis and ADNC (Unidentified-AD). Compared to Confirmed-AD participants, AD-Mimics had less severe cognitive impairment, while Unidentified-AD participants displayed more parkinsonian signs, depression, and behavioral problems. This study highlights the importance of developing a complete panel of biomarkers as a tool to inform clinical diagnoses, as clinical phenotypes that are typically associated with diseases other than AD may result in inaccurate diagnoses., (© 2020 American Association of Neuropathologists, Inc. All rights reserved.)

A random digit dialing sample from Missouri (USA) was used to compare associations between psychosocial factors and Alzheimer's disease (AD) screening intention based on residential locale. Linear regression associations between demographics and five psychosocial constructs (dementia knowledge, perceived screening benefits, preventive health behaviors, perceived susceptibility, and self-efficacy) and screening intention were compared by residential locale. Participants ( n = 932) had a mean age of 62 years (urban: n = 375; suburban: n = 319, rural: n = 238). African Americans more often lived in urban than suburban/rural neighborhoods, and more urban than suburban/rural residents reported insufficient income. Preventative health behaviors (e.g., dentist visits) were higher in urban and suburban versus rural participants. AD screening intention did not differ by residential locale. Among urban participants, self-efficacy to get screened was associated with screening intention. Among rural participants, dementia knowledge was associated with screening intention. Perceived screening benefits and perceived susceptibility to AD were associated with screening intention regardless of locale. Unlike urban participants, rural participants demonstrated greater screening intention with greater dementia knowledge. Our findings suggest that psychosocial factors associated with AD screening intention differ depending on residential locale. Strategies to increase dementia screening may need to account for regional variations to be maximally effective.

Recently, a consensus working group provided new terminology for a common disease entity, limbic predominant age-related TDP-43 encephalopathy (LATE), and its neuropathological substrate (LATE-NC). LATE-NC not only often co-occurs with Alzheimer disease neuropathological change (ADNC), but also may present in isolation. The present study aimed to investigate potential risk factors and neuropathological characteristics associated with LATE-NC. A sample of 616 autopsied participants (>75 years at death), with TDP-43 immunohistochemical studies performed, was obtained from the National Alzheimer's Coordinating Center. Logistic regression analyses examined associations between demographic, clinical and neuropathological characteristics and LATE-NC (TDP-43 in amygdala, hippocampus, or entorhinal/inferior temporal cortex) (alpha = 0.05). Adjusted models indicated that ADNC, hippocampal sclerosis (HS), arteriolosclerosis, and limbic or amygdala-predominant Lewy body disease (LBD), but not other LBD subtypes, were associated with higher odds of LATE-NC, whereas congestive heart failure (CHF) and motor problems as first predominant symptom were associated with lower odds of LATE-NC. Our findings corroborate previous studies indicating associations between LATE-NC and ADNC, HS, and arteriolosclerosis. Novel findings suggest the association with LATE-NC is restricted to amygdala/limbic-predominant subtype of LBD, and a possible protective (or competing risk) association with CHF. This study may inform future hypothesis-driven research on LATE-NC, a common brain disease of aging., (© 2019 American Association of Neuropathologists, Inc. All rights reserved.)

Primary age-related tauopathy is increasingly recognized as a separate neuropathological entity different from Alzheimer's disease. Both share the neuropathological features of tau aggregates and neuronal loss in the temporal lobe, but primary age-related tauopathy lacks the requisite amyloid plaques central to Alzheimer's disease. While both have similar clinical presentations, individuals with symptomatic primary age-related tauopathy are commonly of more advanced ages with milder cognitive dysfunction. Direct comparison of the neuropsychological trajectories of primary age-related tauopathy and Alzheimer's disease has not been thoroughly evaluated and thus, our objective was to determine how cognitive decline differs longitudinally between these two conditions after the onset of clinical symptoms. Data were obtained from the National Alzheimer's Coordinating Center on participants with mild cognitive impairment at baseline and either no neuritic plaques (i.e. primary age-related tauopathy) or moderate to frequent neuritic plaques (i.e. Alzheimer neuropathological change) at subsequent autopsy. For patients with Alzheimer's disease and primary age-related tauopathy, we compared rates of decline in the sum of boxes score from the CDR® Dementia Staging Instrument and in five cognitive domains (episodic memory, attention/working memory, executive function, language/semantic memory, and global composite) using z-scores for neuropsychological tests that were calculated based on scores for participants with normal cognition. The differences in rates of change were tested using linear mixed-effects models accounting for clinical centre clustering and repeated measures by individual. Models were adjusted for sex, age, education, baseline test score, Braak stage, apolipoprotein ε4 (APOE ε4) carrier status, family history of cognitive impairment, and history of stroke, hypertension, or diabetes. We identified 578 participants with a global CDR of 0.5 (i.e. mild cognitive impairment) at baseline, 126 with primary age-related tauopathy and 452 with Alzheimer's disease. Examining the difference in rates of change in CDR sum of boxes and in all domain scores, participants with Alzheimer's disease had a significantly steeper decline after becoming clinically symptomatic than those with primary age-related tauopathy. This remained true after adjusting for covariates. The results of this analysis corroborate previous studies showing that primary age-related tauopathy has slower cognitive decline than Alzheimer's disease across multiple neuropsychological domains, thus adding to the understanding of the neuropsychological burden in primary age-related tauopathy. The study provides further evidence to support the hypothesis that primary age-related tauopathy has distinct neuropathological and clinical features compared to Alzheimer's disease., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Previous studies have provided equivocal evidence of antidepressant use on subsequent cognitive impairment; this could be due to inconsistent modeling approaches. Our goals are methodological and clinical. We evaluate the impact of statistical modeling approaches on the associations between antidepressant use and risk of Mild Cognitive Impairment (MCI) in older adults with depression., Methods: 716 participants were enrolled. Our primary analysis employed a time-dependent Cox proportional hazards model. We also implemented two fixed-covariate proportional hazards models-one based on having ever used antidepressants during follow-up, and the other restricted to baseline use only., Results: Treating antidepressant use as a time-varying covariate, we found no significant association with incident MCI (HR = 0.92, 95% CI: 0.70, 1.20). In contrast, when antidepressant use was treated as a fixed covariate, we observed a significant association between having ever used antidepressants and lower risk of MCI (HR = 0.40, 95% CI: 0.28, 0.56). However, in the baseline-use only model, the association was non-significant (HR = 0.84, 95% CI: 0.60, 1.17)., Discussion: Our results were dependent upon statistical models and suggest that antidepressant use should be modeled as a time-varying covariate. Using a robust time-dependent analysis, antidepressant use was not significantly associated with incident MCI among cognitively normal persons with depression., Competing Interests: The authors have declared that no competing interests exist.

Background: Frontotemporal degeneration (FTD) dementia often begins before age 60 and predominantly presents as four subtypes with prominent features of language, behavior, cognition, and motor symptoms. The early onset and unique symptoms place a distinct burden on caregivers of individuals with FTD versus other dementia types, such as Alzheimer's disease. This is the first known study to examine the domains of the FTD caregiver burden and the caregiver and patient characteristics associated with these domains., Methods: In 2017, 674 FTD caregivers in the United States (US) completed a web-based survey of caregiver and patient demographics, disease severity/symptoms, caregiver burden, and financial costs of caregiving. The major factors of caregiver burden (Zarit Burden Inventory) were determined using a principal axis factor analysis with varimax rotation. Multiple linear regression analyses examined caregiver and patient characteristics associated with overall burden and three major factors of burden: role strain, personal strain, and performance strain., Results: Increased neuropsychiatric symptoms was associated with overall caregiver burden and greater role, personal, and performance strain. Younger caregivers experienced greater overall burden and performance strain, female caregivers experienced increased role strain, and male caregivers experienced greater performance strain. Financial costs of caregiving and experiencing a caregiving crisis in the past year were associated with higher overall burden and role strain., Conclusions: This study suggests that the severity and sources of burden differ for caregivers of FTD patients versus patients with other dementia types. Differing predictors for each burden domain suggest targeted interventions to address the unique FTD caregiving challenges.

Primary age-related tauopathy (PART) is increasingly recognized as a pathologic entity distinct from Alzheimer's disease (AD). Given that the diagnosis of PART is an autopsy diagnosis, it is unclear how PART is perceived in clinical practice. Thus, we investigated the presumptive primary and contributing diagnoses in individuals who had cognitive impairment while alive and who met neuropathologic criteria for PART at autopsy. We also compared these clinical diagnoses for people with PART to those with AD neuropathology (ADNP). We used data on 1354 participants from the National Alzheimer's Coordinating Center, restricting to those with no neuritic plaques (PART) or moderate/frequent neuritic plaques (ADNP); clinical visit within two years of autopsy; and mild cognitive impairment (MCI) or dementia at last visit. To assess if PART participants were less likely to receive a clinical diagnosis of AD at their last visit prior to autopsy, we used logistic regression, controlling for age, sex, education, and APOE ε4 status. There were 161 PART individuals (n = 49 MCI; n = 112 dementia) and 1193 individuals with ADNP (n = 75 MCI; n = 1118 dementia). Primary clinical diagnosis of AD was more common in those with ADNP (MCI: 69%; demented: 86%) than PART (MCI: 57%; demented: 52%). In the adjusted analysis, primary and contributing clinical diagnoses of AD remained less likely in PART vs. ADNP participants with dementia (OR: 0.22, 95% CI: 0.13-0.38). This study suggests that clinicians recognize a distinction in the clinical presentation between PART and ADNP, diagnosing AD less frequently in those with PART. Nonetheless, clinical AD was diagnosed greater than 50% of the time in PART participants with MCI or dementia. Ante-mortem criteria for diagnosis of PART need to be established, as PART is a neuropathological entity that is distinct from AD and has its own clinical and cognitive outcomes.

Introduction: Recent research with neuropathologic or biomarker evidence of Alzheimer's disease (AD) casts doubt on traumatic brain injury (TBI) as a risk factor for AD. We leveraged the National Alzheimer's Coordinating Center to examine the association between self-reported TBI with loss of consciousness and AD neuropathologic changes, and with baseline and longitudinal clinical status., Methods: The sample included 4761 autopsy participants (453 with remote TBI with loss of consciousness; 2822 with AD neuropathologic changes) from National Alzheimer's Coordinating Center., Results: Self-reported TBI did not predict AD neuropathologic changes (P > .10). Reported TBI was not associated with baseline or change in dementia severity or cognitive function in participants with or without autopsy-confirmed AD., Discussion: Self-reported TBI with loss of consciousness may not be an independent risk factor for clinical or pathological AD. Research that evaluates number and severity of TBIs is needed to clarify the neuropathological links between TBI and dementia documented in other large clinical databases., (Copyright © 2019 the Alzheimer's Association. All rights reserved.)

Introduction: We investigated whether cholinesterase inhibitors (ChEIs) benefit cognitive outcomes in mild cognitive impairment due to Alzheimer disease (MCI-AD) and in mild AD dementia (ADdem)., Methods: Data from 2242 individuals, clinically diagnosed with MCI-AD [Clinical Dementia Rating (CDR), 0 or 0.5] or with mild ADdem (CDR, 0.5 or 1), were available from the National Alzheimer's Coordinating Center's (NACC) Uniform Data Set (UDS). General linear mixed models were used to examine the annual change in the CDR Sum of Boxes (CDR-SB) and in neuropsychological performance. We compared slopes before and after ChEI initiation among ChEI users, and also compared the change in scores of ChEI users versus nonusers., Results: Thirty-four percent of 944 MCI-AD and 72% of 1298 ADdem participants were ChEI users. Cognitive decline was greater after ChEI initiation in MCI-AD and ADdem groups (eg, MCI-AD, CDR-SB: 0.03 points/y before initiation; 0.61 points/y after initiation, P<0.0001). Both MCI-AD and ADdem groups had faster decline after ChEI initiation than nonusers (eg, MCI-AD, CDR-SB: 0.61 points/y, ChEI users; 0.24 points/y, nonusers, P<0.0001)., Discussion: This study suggests that ChEI use may not improve the cognitive course in MCI-AD and mild ADdem.

This study examined differences in neuropsychological test scores between individuals with primary age-related tauopathy (PART) and Alzheimer disease (AD) using cross-sectional data from the National Alzheimer's Coordinating Center. Linear regression tested for differences in 4 cognitive domains stratified by cognitive status (global Clinical Dementia Rating [CDR]). The sample included 240 participants with no neuritic plaques (NP) (definite PART), 186 with sparse NP (possible PART), and 510 with moderate/frequent NP (AD). Four cognitive domain z-score outcome variables (memory, attention, executive function, and semantic memory/language) were calculated using 12 neuropsychological tests. Definite PART participants had a sparing of semantic memory/language compared to those with AD, with a mean adjusted z-score difference of 0.37 (95% confidence interval [CI]: 0.16-0.58) for those with CDR = 0.5 or 1 and of 0.92 (CI: 0.22-1.63) for those with CDR = 2 or 3. Compared to participants with AD, definite PART participants with CDR = 0.5 or 1 had sparing of memory (adjusted z-score difference: 0.61; CI: 0.39-0.84) and definite PART participants with CDR = 2 or 3 had sparing of attention (adjusted z-score difference: 0.76: CI: 0.09-1.43). Patterns of cognitive impairment differed between definite PART and AD, suggesting significant differences in clinical presentation between individuals from these 2 groups., (© 2019 American Association of Neuropathologists, Inc. All rights reserved.)

Age-related changes in memory are not uniform, even in the absence of dementia. Characterization of non-disease associated cognitive changes is crucial to gain a more complete understanding of brain aging. Episodic memory was investigated in 13,037 ethnically diverse elderly (ages 72 to 85 years) with two to 15 years of follow-up, and with known dementia status, age, sex, education, and APOE genotypes. Adjusted trajectories of episodic memory performance over time were estimated using Latent Class Mixed Models. Analysis was conducted using two samples at baseline evaluation: i) non-cognitively impaired individuals, and ii) all individuals regardless of dementia status. We calculated the age-specific annual incidence rates of dementia in the non-demented elderly (n = 10,220). Two major episodic memory trajectories were estimated: 1) Stable-consisting of individuals exhibiting a constant or improved memory function, and 2) Decliner-consisting of individuals whose memory function declined. The majority of the study participants maintain their memory performance over time. Compared to those with Stable trajectory, individuals characterized as Decliners were more likely to have non-white ethnic background, fewer years of education, a higher frequency of ε4 allele at APOE gene and five times more likely to develop dementia. The steepest decline in episodic memory was observed in Caribbean-Hispanics compared to non-Hispanic whites (p = 4.3 x 10(-15)). The highest incident rates of dementia were observed in the oldest age group, among those of Caribbean-Hispanics ancestry and among Decliners who exhibited rates five times higher than those with Stable trajectories (11 per 100 person-years versus 3 per 100 person-years. Age, education, ethnic background and APOE genotype influence the maintenance of episodic memory. Declining memory is one of the strongest predictors of incident dementia., Competing Interests: The authors have declared that no competing interests exist.

Neuropathologic evaluation remains the gold standard for determining the presence and severity of aging-related neurodegenerative diseases. Researchers at U.S. Alzheimer's Disease Centers (ADCs) have worked for >30 years studying human brains, with the goals of achieving new research breakthroughs. Harmonization and sharing among the 39 current and past ADCs is promoted by the National Alzheimer's Coordinating Center (NACC), which collects, audits, and disburses ADC-derived data to investigators on request. The past decades have witnessed revised disease definitions paired with dramatic expansion in the granularity and multimodality of the collected data. The NACC database now includes cognitive test scores, comorbidities, drug history, neuroimaging, and links to genomics. Relatively, recent advances in the neuropathologic diagnoses of Alzheimer's disease, frontotemporal lobar degeneration (FTLD), and vascular contributions to cognitive impairment and dementia catalyzed a 2014 update to the NACC Neuropathology Form completed by all ADCs. New focal points include cerebrovascular disease (including arteriolosclerosis, microbleeds, and microinfarcts), hippocampal sclerosis, TDP-43, and FTLD. Here, we provide summary data and analyses to illustrate the potential for both hypothesis-testing and also generating new hypotheses using the NACC Neuropathology data set, which represents one of the largest multi-center databases of carefully curated neuropathologic information that is freely available to researchers worldwide.

Preliminary studies suggest that neighborhood social and built environment (BE) characteristics may affect cognition in older adults. Older adults are particularly vulnerable to the neighborhood environment due to a decreasing range of routine travel with increasing age. We examined if multiple neighborhood BE characteristics are cross-sectionally associated with cognition in a diverse sample of older adults, and if the BE-cognition associations vary by individual-level demographics. The sample included 4539 participants from the Multi-Ethnic Study of Atherosclerosis. Multivariable linear regression was used to examine the associations between five BE measures and four cognitive measures, and effect modification by individual-level education and race/ethnicity. In the overall sample, increasing social destination density, walking destination density, and intersection density were associated with worse overall cognition, whereas increasing proportion of land dedicated to retail was associated with better processing speed. Effect modification results suggest that the association between urban density and worse cognition may be limited to or strongest in those of non-white race/ethnicity. Although an increase in neighborhood retail destinations was associated with better cognition in the overall sample, these results suggest that certain BE characteristics in dense urban environments may have a disproportionately negative association with cognition in vulnerable populations. However, our findings must be replicated in longitudinal studies and other regional samples., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: White matter hyperintensities (WMH) on magnetic resonance imaging (MRI) have been postulated to be a core feature of Alzheimer's disease. Clinicopathological studies are needed to elucidate and confirm this possibility., Objective: This study examined: 1) the association between antemortem WMH and autopsy-confirmed Alzheimer's disease neuropathology (ADNP), 2) the relationship between WMH and dementia in participants with ADNP, and 3) the relationships among cerebrovascular disease, WMH, and ADNP., Methods: The sample included 82 participants from the National Alzheimer's Coordinating Center's Data Sets who had quantitated volume of WMH from antemortem FLAIR MRI and available neuropathological data. The Clinical Dementia Rating (CDR) scale (from MRI visit) operationalized dementia status. ADNP+ was defined by moderate to frequent neuritic plaques and Braak stage III-VI at autopsy. Cerebrovascular disease neuropathology included infarcts or lacunes, microinfarcts, arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy., Results: 60/82 participants were ADNP+. Greater volume of WMH predicted increased odds for ADNP (p = 0.037). In ADNP+ participants, greater WMH corresponded with increased odds for dementia (CDR≥1; p = 0.038). WMH predicted cerebral amyloid angiopathy, microinfarcts, infarcts, and lacunes (ps < 0.04). ADNP+ participants were more likely to have moderate-severe arteriolosclerosis and cerebral amyloid angiopathy compared to ADNP-participants (ps < 0.04)., Conclusions: This study found a direct association between total volume of WMH and increased odds for having ADNP. In patients with Alzheimer's disease, FLAIR MRI WMH may be able to provide key insight into disease severity and progression. The association between WMH and ADNP may be explained by underlying cerebrovascular disease.

Objective: To conduct a clinicopathologic study to characterize clinical and neuropathologic features associated with cognitive impairment in participants with no neuritic amyloid plaques (primary age-related tauopathy [PART] definite) and sparse neuritic plaques (amyloid sparse)., Methods: Using the National Alzheimer's Coordinating Center database, we identified 377 individuals who were PART definite (n = 170) or amyloid sparse (n = 207), clinically examined within 1 year of death, and autopsied at 1 of 26 National Institute on Aging-funded Alzheimer's Disease Centers. Factors associated with the odds of being symptomatic (global Clinical Dementia Rating [CDR] score >0) were identified with multivariable logistic regression., Results: PART-definite participants less often had a high Braak neurofibrillary tangle stage V or VI (4%) compared to amyloid sparse participants (28%, p < 0.001). Of the PART-definite participants, 98 were symptomatic and 72 asymptomatic according to their global CDR scores. PART-definite participants were less often symptomatic (58%) compared with amyloid sparse participants (80%, p < 0.001). Within the PART-definite group, independent predictors of symptomatic status included depression (adjusted odds ratio [aOR] 4.20, 95% confidence interval [CI] 2.15-8.19), Braak stage (aOR 1.42, 95% CI 1.04-1.95), and history of stroke (aOR 8.09, 95% CI 2.63-24.82). Within the amyloid sparse group, independent predictors of symptomatic status included education (aOR 0.80, 95% CI 0.65-0.99), Braak stage (aOR 1.91, 95% CI 1.07-3.43), and amyloid angiopathy (aOR 2.75, 95% CI 1.14-6.64)., Conclusions: These findings support the hypothesis that participants with PART have an amyloid-independent dementing Alzheimer disease-like temporal lobe tauopathy., (© 2017 American Academy of Neurology.)

Objective: Lumbar puncture (LP) is increasingly common in Alzheimer disease research; however, agreement to undergo LP varies. We sought to determine factors influencing LP consent at Alzheimer's Disease Centers (ADCs) in the United States., Methods: A 3-part survey was distributed to each ADC: (1) ADC LP Experience; (2) LP Requestor Experience; and (3) Patient LP Experience (both Initial and Follow-up). In all, 64 LP Requestor, 579 Patient/Initial, and 404 Patient/Follow-up surveys were collected. Logistic regression analyses with generalized estimating equations were used to assess factors associated with LP agreement and post-LP complications., Results: Asians and those viewing LP negatively were less likely to agree to LP. Three hundred fifty-two participants had an LP; LP headache occurred in 11.9% (blood patch required in 1.4%) and 9.9% reported other complications. Younger individuals, women, those diagnosed with mild cognitive impairment, use of a Quincke needle, ≤20 mL cerebrospinal fluid drawn, and hemorrhage during LP were associated with LP headache. Use of gravity flow during LP was associated with fewer other complications (nausea, dizziness, vasovagal response, back pain, neck stiffness, and/or nerve root pain)., Conclusions: LP in Alzheimer disease research is generally safe and well tolerated. Factors influencing LP agreement potentially could be studied to advance participant acceptance of the procedure.

Identifying asymptomatic older individuals at elevated risk for developing Alzheimer disease (AD) is of clinical importance. Among 1,081 asymptomatic older adults, a recently validated polygenic hazard score (PHS) significantly predicted time to AD dementia and steeper longitudinal cognitive decline, even after controlling for APOE ɛ4 carrier status. Older individuals in the highest PHS percentiles showed the highest AD incidence rates. PHS predicted longitudinal clinical decline among older individuals with moderate to high Consortium to Establish a Registry for Alzheimer's Disease (amyloid) and Braak (tau) scores at autopsy, even among APOE ɛ4 noncarriers. Beyond APOE, PHS may help identify asymptomatic individuals at highest risk for developing Alzheimer neurodegeneration. Ann Neurol 2017;82:484-488., (© 2017 American Neurological Association.)

Context: Some evidence suggests that treating vascular risk factors and performing mentally stimulating activities may delay cognitive impairment onset in older adults. Exposure to a complex neighborhood environment may be one mechanism to help delay cognitive decline., Evidence Acquisition: PubMed, Web of Science, and ProQuest Dissertation and Theses Global database were systematically reviewed, identifying 25 studies published from February 1, 1989 to March 5, 2016 (data synthesized, May 3, 2015 to October 7, 2016). The review was restricted to quantitative studies focused on: (1) neighborhood social and built environment and cognition; and (2) community-dwelling adults aged ≥45 years., Evidence Synthesis: The majority of studies were cross-sectional, U.S.-based, and found at least one significant association. The diversity of measures and neighborhood definitions limited the synthesis of findings in many instances. Evidence was moderately strong for an association between neighborhood SES and cognition, and modest for associations between neighborhood demographics, design, and destination accessibility and cognition. Most studies examining effect modification found significant associations, with some evidence for effect modification of the neighborhood SES-cognition association by individual-level SES. No studies had low risk of bias and many tested multiple associations that increased the chance of a statistically significant finding. Considering the studies to date, the evidence for an association between neighborhood characteristics and cognition is modest., Conclusions: Future studies should include longitudinal measures of neighborhood characteristics and cognition; examine potential effect modifiers, such as sex and disability; and study mediators that may help elucidate the biological mechanisms linking neighborhood environment and cognition., (Copyright © 2017 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

The relationship between late-life body mass index (BMI) and Alzheimer's disease (AD) is poorly understood due to the lack of research in samples with autopsy-confirmed AD neuropathology (ADNP). The role of cerebrovascular disease (CVD) in the interplay between late-life BMI and ADNP is unclear. We conducted a retrospective longitudinal investigation and used joint modeling of linear mixed effects to investigate causal relationships among repeated antemortem BMI measurements, CVD (quantified neuropathologically), and ADNP in an autopsy sample of subjects across the AD clinical continuum. The sample included 1,421 subjects from the National Alzheimer's Coordinating Center's Uniform Data Set and Neuropathology Data Set with diagnoses of normal cognition (NC; n = 234), mild cognitive impairment (MCI; n = 201), or AD dementia (n = 986). ADNP was defined as moderate to frequent neuritic plaques and Braak stageIII-VI. Ischemic Injury Scale (IIS) operationalized CVD. Joint modeling examined relationships among BMI, IIS, and ADNP in the overall sample and stratified by initial visit Clinical Dementia Rating score. Subject-specific random intercept for BMI was the predictor for ADNP due to minimal BMI change (p = 0.3028). Analyses controlling for demographic variables and APOE ɛ4 showed lower late-life BMI predicted increased odds of ADNP in the overall sample (p < 0.001), and in subjects with CDR of 0 (p = 0.0021) and 0.5 (p = 0.0012), but not ≥1.0 (p = 0.2012). Although higher IIS predicted greater odds of ADNP (p < 0.0001), BMI did not predict IIS (p = 0.2814). The current findings confirm lower late-life BMI confers increased odds for ADNP. Lower late-life BMI may be a preclinical indicator of underlying ADNP.

Vascular risk factors (VRFs) have been associated with clinically diagnosed Alzheimer disease (AD), but few studies have examined the association between VRF and AD neuropathology (ADNP) in cognitively normal individuals. We used longitudinal data from the National Alzheimer's Disease Center's Uniform Data Set and Neuropathology Data Set to examine the association between VRF and ADNP (moderate to frequent neuritic plaques; Braak stage III-VI) in those with normal cognition. Our sample included 53 participants with ADNP and 140 without ADNP. Body mass index (BMI), resting heart rate (HR), and pulse pressure (PP) were measured at each visit; values were averaged across participant visits and examined annual change in BMI, PP, and HR. Hypertension, diabetes, and hypercholesterolemia were self-reported. In the multivariable logistic regression analyses, average BMI and HR were associated with lower odds of ADNP, and annual increases in HR and BMI were associated with higher odds of ADNP. A previously experienced decline in BMI or HR in late-life (therefore, currently low BMI and low HR) as well as a late-life increase in BMI and HR may indicate underlying AD pathology. Additional clinicopathological research is needed to elucidate the role of changes in late-life VRF and AD pathogenesis., (© 2016 American Association of Neuropathologists, Inc. All rights reserved.)

Introduction: No known studies have compared longitudinal characteristics between individuals with incident mild cognitive impairment due to Parkinson's disease (PD-MCI) versus Alzheimer's Disease (AD-MCI)., Methods: We used longitudinal data from the National Alzheimer's Coordinating Center's Uniform Data Set to compare 41 PD-MCI and 191 AD-MCI participants according to their demographics, presence of ≥1 APOE e4 allele, and baseline and change over time in clinical characteristics, neuropsychological test scores, and Clinical Dementia Rating sum of boxes (CDR-SB). Multivariable linear regression models with generalized estimating equations were used to account for clustered data and to test for baseline and longitudinal differences in neuropsychological test scores., Results: PD-MCI and AD-MCI participants differed by many demographic and clinical characteristics. Significantly fewer PD-MCI participants developed dementia over one year. Compared to AD-MCI participants, PD-MCI participants performed better at baseline and over time on a global measure of cognition (Mini Mental State Exam), memory measures (immediate and delayed Logical Memory), and a language measure (Boston Naming Test), and additionally performed better over time on an attention measure (Digit Span Forward), a language measure (Vegetable List), a processing speed measure (Digit Symbol), and an overall measure of memory and functional impairment (CDR-SB)., Conclusion: Our study provides further evidence that PD-MCI is clinically distinct from AD-MCI and requires different tools for diagnosis and monitoring clinical progression. More importantly, this study suggests that PD-MCI takes longer to convert into dementia than AD-MCI, findings that require replication by other studies., (Copyright © 2016 Elsevier Ltd. All rights reserved.)