Arenaza‐Urquijo, Eider M.

Abstract Background Neighborhood socio‐economic conditions may increase Alzheimer's disease (AD) risk through amyloid, tau, atrophy or vascular pathways, potentially varying by genetic risk, race or ethnicity and sex. We examined associations between Area Deprivation Index (ADI) and cognition, AD pathology, gray matter (GM) and white matter hyperintensities (WMH) volume in cognitively unimpaired older adults by race or ethnicity, sex and APOE4 status. Method We included 1896 non‐demented older adults from US POINTER study with available cognitive evaluations, ADI level – a census–based neighborhood disadvantage metric (categorized as low, moderate and high) and a subsample with neuroimaging data ( N = 806). Linear/logistic regressions were used to assess interactions of ADI with sex, race or ethnicity, and APOE4 on (1) the Preclinical Alzheimer's Cognitive Composite, (PACC‐5), (2) MRI‐derived GM volume meta‐ROI (entorhinal, fusiform, parahippocampal, mid‐temporal, inferior temporal), (3) WMH and (4) AD pathology (amyloid and tau PET), adjusted by age, sex and intracranial volume when appropriate. Result African American participants ( p <0.001) and females ( p <0.001) were more likely to live in deprived areas. African American participants had significantly lower PACC‐5 ( p <0.001) and GM volume ( p <0.001), “Other or multiple races” participants showed significantly higher amyloid burden ( p = 0.001), and White participants higher WMH ( p = 0.013). Females showed higher PACC‐5 scores ( p <0.001), while APOE4 carriers showed lower PACC‐5 ( p = 0.042) and higher amyloid burden ( p <0.001) (Table 1). Race and ADI interacted on PACC‐5 ( p = 0.043) and showed a borderline interaction on Tau ( p = 0.079), with higher ADI linked to lower PACC‐5 in White, Hispanic, and “Other or Multiple Races” and higher Tau in Hispanic. Further, there was a borderline ADI*APOE4 status interaction on WMH ( p = 0.059) and a significant ADI*APOE4 interaction on amyloid ( p = 0.001), where APOE4 carriers in deprived areas showed higher WMH and lower amyloid burden (Figure 1). No significant ADI*sex interactions were observed. Conclusion Neighborhood disadvantage was more commonly observed in African American participants, but interaction with cognition was primarily seen in other racial/ethnic groups. APOE4 carriers showed increased amyloid burden, but those from more disadvantaged neighborhoods exhibited a higher vascular component alongside lower amyloid‐driven pathology. These results may indicate varying effects of social disadvantages across groups or sample bias.

Abstract Background Neighborhood social and built environment characteristics may promote physical activity, a modifiable factor for dementia risk, which may in turn promote cognitive and brain health. We explored the associations of the U.S. National Walkability Index ‐ a nationwide geographic data resource that ranks block groups according to their relative walkability – with cognitive function, gray matter (GM) and white matter hyperintensities (WMH), neighborhood disadvantage, sedentary behavior and frequency of physical activity in cognitively unimpaired older adults at increased Alzheimer's disease (AD) risk. Method We included baseline data from 1398 older adults (68.3 ± 5.17 years, 68.3% females, 30.5% APOE4 carriers) from the U.S. POINTER trial. Walkability was classified as: least, below average, above average and most walkable. Neighborhood disadvantage (low, moderate and high) was assessed using Area Deprivation Index (ADI) ( N = 1384). Physical inactivity was assessed using the Sedentary Behavior Questionnaire (SBQ, hours sitting/week, N = 1106), and physical activity was measured with a composite score from the Community Health Activities Model Program for Seniors (CHAMPS) questionnaire. Linear and logistic regressions examined associations between walkability and (1) physical activity and sedentary behavior; and (2) cognition assessed with the Preclinical Alzheimer's Cognitive Composite (PACC‐5), GM volume and WMHs, Additionally, associations between neighborhood disadvantage and physical activity and sedentary behavior were explored. Models were adjusted for age, sex, race, APOE4 and total intracranial volume. Result More deprived areas were generally less walkable (β = ‐0.008, p < 0.001) (Figure 1). Higher walkability (Above average: β = 0.192, p = 0.011 and most walkable: β = 0.183, p = 0.032) was associated with higher PACC‐5 (Figure 2A) scores but not with more preserved GM or lower WMH. Walkability scores were not associated with physical activity and sedentary measurements, while greater neighborhood disadvantage was linked to sedentary behavior (β = 0.126, p < 0.001) (Figure 2B). Conclusion These results suggest that physical inactivity in more deprived areas is associated with neighborhood socioeconomic disadvantages rather than built environment. Additionally, walkability scores were not associated with any measure of physical activity or brain health, suggesting the need to further investigate other health effects of neighborhood disadvantage and walkability.

Abstract Background In aging and dementia research, the relationships between modifiable risk factors and biomarkers often vary across cohorts. We aim to evaluate the consistency and generalizability of the association between the area deprivation index (ADI) ‐ an indicator of socioeconomic/resource disadvantage within a specific area ‐ and cognition and Alzheimer's disease (AD) biomarkers across three distinct research cohorts, two from the U.S. (U.S. POINTER Imaging, ADNI) and one from Spain (UBRAIN). Method We included a total of 3091 participants without dementia, 1879 from U.S. POINTER Imaging, 282 from ADNI and 930 from UBRAIN (Table 1). The ADI was calculated using validated indices from the US and Spain, with neighborhood deprivation ranked as Low, Moderate, and High in the US, and Low and High in Spain. Outcomes of interest included (1) the preclinical Alzheimer's cognitive composite (PACC‐5), (2) MRI‐derived gray matter volumes in AD‐vulnerable regions and (3) PET or CSF‐derived amyloid status (+/‐). We ran logistic regression models with ADI level as predictor adjusted by sex, age, and APOE4 and considered education and race or ethnicity (only US cohorts) in our analyses. Result Participants in more deprived areas had lower education across cohorts and were more likely to be female (U.S. POINTER) and African American (U.S. POINTER and ADNI, Table 1). Independent of age, sex and APOE4 status, higher ADI was associated with lower PACC in U.S. POINTER (Moderate: β=‐0.165, p <0.001; High β=‐0.412, p <0.001) and UBRAIN (ADI: High β=‐0.096, p = 0.022) but not in ADNI (Figure 1). After controlling for education, this association remained significant in U.S. POINTER (Moderate: β=‐0.166, p = 0.002; High: β=‐0.248, p = 0.007) but not in UBRAIN (β=‐0.021, p = 0.66). In U.S. POINTER, there was a trend towards an association of higher ADI with lower GM volume in AD‐vulnerable regions (β=‐0.126, p = 0.089) that was not observed in ADNI or UBRAIN (Figure 2). No associations between ADI and amyloid status were found across cohorts. Conclusion We observed differing associations in neighborhood deprivation and cognition across US cohorts, as well as between the US and Spain cohorts. Country‐specific factors and sample representativeness must be considered when investigating the pathophysiologic mechanisms underlying social determinants and disparities in AD.

Abstract Sex and gender—biological and social constructs—significantly impact the prevalence of protective and risk factors, influencing the burden of Alzheimer's disease (AD; amyloid beta and tau) and other pathologies (e.g., cerebrovascular disease) which ultimately shape cognitive trajectories. Understanding the interplay of these factors is central to understanding resilience and resistance mechanisms explaining maintained cognitive function and reduced pathology accumulation in aging and AD. In this narrative review, the ADDRESS! Special Interest Group (Alzheimer's Association) adopted a multidisciplinary approach to provide the foundations and recommendations for future research into sex‐ and gender‐specific drivers of resilience, including a sex/gender‐oriented review of risk factors, genetics, AD and non‐AD pathologies, brain structure and function, and animal research. We urge the field to adopt a sex/gender‐aware approach to resilience to advance our understanding of the intricate interplay of biological and social determinants and consider sex/gender‐specific resilience throughout disease stages. Highlights Sex differences in resilience to cognitive decline vary by age and cognitive status. Initial evidence supports sex‐specific distinctions in brain pathology. Findings suggest sex differences in the impact of pathology on cognition. There is a sex‐specific change in resilience in the transition to clinical stages. Gender and sex factors warrant study: modifiable, immune, inflammatory, and vascular.

Abstract Sex or gender differences in the risk of Alzheimer's disease and related dementias (ADRD) differ by world region, suggesting that there are potentially modifiable risk factors for intervention. However, few epidemiological or clinical ADRD studies examine sex differences; even fewer evaluate gender in the context of ADRD risk. The goals of this perspective are to: (1) provide definitions of gender, biologic sex, and sexual orientation. and the limitations of examining these as binary variables; (2) provide an overview of what is known with regard to sex and gender differences in the risk, prevention, and diagnosis of ADRD; and (3) discuss these sex and gender differences from a global, worldwide perspective. Identifying drivers of sex and gender differences in ADRD throughout the world is a first step in developing interventions unique to each geographical and sociocultural area to reduce these inequities and to ultimately reduce global ADRD risk. Highlights The burden of dementia is unevenly distributed geographically and by sex and gender. Scientific advances in genetics and biomarkers challenge beliefs that sex is binary. Discrimination against women and sex and gender minority (SGM) populations contributes to cognitive decline. Sociocultural factors lead to gender inequities in Alzheimer's disease and related dementias (ADRD) worldwide.

AbstractBackgroundThere have been no standard definitions of successful cognitive aging (SA). Our goal was to apply different SA definitions to the 80+ population in the Mayo Clinic Study of Aging (MCSA) on the basis of (i) cross‐sectional vs longitudinal cognition (“Exceptionality” vs “Maintenance”) and (ii) memory vs global cognitive scores and explore the participant characteristics for each SA definition on the basis of baseline imaging markers and mid/late‐life health.MethodWe included 2157 participants from the MCSA, all ≥80 years at baseline and classified them into two SA definitions using memory z‐scores or global z‐scores: “Exceptionality” when high cognitive performance was observed (z‐scores ≥ 1 SD), “Maintenance” when cognitive function was preserved over time (Slope ≥ ‐0.1/year using mixed‐effect models). Our imaging markers were: PET‐based amyloid positivity (A+), MRI‐based neurodegeneration positivity (N+), WMH, FDG‐PET SUVR markers of resilience (anterior cingulate, ACC) and AD‐related areas (posterior cingulate). We also examined APOE4 status and other health characteristics. Group comparison was performed within each definition (e.g. exceptional vs non‐exceptional memory) using ANCOVA and binary logistic regressions with adjustments for age, sex, and education.ResultA lower number of participants met the “Exceptionality” criteria (10%: memory and 4%: global). A greater number met the “Maintenance” criteria (53%: memory and 32%: global). Less than 7% showed both “Exceptional” cognition and “Maintenance” over time. Participants across SA definitions were in general younger, more often women, with a higher education/occupation and less often APOE4 carriers. All SA groups showed higher ACC metabolism and lower N+ compared to the corresponding non‐SA group. More than 50% of the participants in the “Exceptional” groups were A+ (57%: memory, 50%: global). A+ frequency was significantly lower in the “Maintainers” (<42%). Better mid/late‐life health indicators were observed in the SA groups, including lower cardio‐metabolic conditions, higher mid‐life cognitive activities, lower depressive symptomatology, lower hypersomnolence and better self‐perception of health.ConclusionDifferent SA definitions identified mainly non‐overlapping 80+ groups that showed several common features including higher education/occupation, percent of women, better lifestyles, lower N+ frequency, and higher ACC metabolism. Lower A+ frequency was a key distinct feature of “Maintenance”.

AbstractIntroductionHarboring two copies of the apolipoprotein E (APOE) ε2 allele strongly protects against Alzheimer's disease (AD). However, the effect of this genotype on gray matter (GM) volume in cognitively unimpaired individuals has not yet been described.MethodsMulticenter brain magnetic resonance images (MRIs) from cognitively unimpaired ε2 homozygotes were matched (1:1) against all other APOE genotypes for relevant confounders (n = 223). GM volumes of ε2 genotypic groups were compared to each other and to the reference group (APOE ε3/ε3).ResultsCarrying at least one ε2 allele was associated with larger GM volumes in brain areas typically affected by AD and also in areas associated with cognitive resilience. APOE ε2 homozygotes, but not APOE ε2 heterozygotes, showed larger GM volumes in areas related to successful aging.DiscussionIn addition to the known resistance against amyloid‐β deposition, the larger GM volumes in key brain regions may confer APOE ε2 homozygotes additional protection against AD‐related cognitive decline.