Rodriguez, Roberta Diehl

Abstract INTRODUCTION Sex differences in dementia‐related neuropathology are understudied in diverse populations. METHODS We analyzed sex differences in neuropathological and cognitive data from the Brazilian Biobank for Aging Studies. Cognitive performance was evaluated with the Clinical Dementia Rating–Sum of Boxes (CDR‐SOB). Linear and logistic regression models were conducted, including interaction terms for age, race, and education. RESULTS In 2229 participants (50.7% female, mean age ± SD 75.4 ± 12.3 years, 62.1% White), female sex was associated with a higher odds of AD pathology (Braak: odds ratio [OR] = 1.42, 95% confidence interval [CI] = 1.17–1.72; Consortium to Establish a Registry for Alzheimer's Disease (CERAD): OR = 1.58, 95% CI = 1.27–1.98), and trans‐activation response (TAR) DNA‐binding protein 43 (TDP‐43) (OR = 1.77, IC 95% = 1.22–2.59), and lower odds of Lewy body disease (OR = 0.69, 95% CI = 0.51–0.95). Female participant had worse cognitive performance ( β = 1.56, 95% CI = 1.03–2.10). Sex modified associations of Braak, CERAD, TDP‐43, and cerebral amyloid angiopathy with cognition. Age also interacted with sex and pathology on CDR‐SOB. DISCUSSION Sex differences in the associations between sex and neuropathology suggest the need for sex‐informed dementia research.

Abstract INTRODUCTION We integrate visual and quantitative metrics in white matter and medial temporal lobe to examine relationships with neuropathology in a community cohort. METHODS Postmortem in situ MRI (T1, T2, DWI) was performed in 25 human brains, followed by visual ratings (Fazekas, MTA, ERICA, Koedam). Neuropathology included ADNC, LATE-NC, hippocampal sclerosis, PART, ARTAG, Lewy pathology, and CAA. RESULTS Increased Fazekas score was linked to aging, lower education, hypertension, higher basilar artery wall thickness, and greater Braak NFT stage. WMH volume also correlated with lacunes, Thal phase, and CERAD score that was not observed using Fazekas. Hippocampal volumes were lower in elderly, less educated people and were associated with higher atrophy scores and higher Braak NFT stage. Higher amygdala volume was only associated with higher CERAD score. DISCUSSION Quantitative MRI may detect neuropathologic associations more sensitively than visual ratings. Tau pathology is a key predictor of WMH burden and hippocampal atrophy.

Importance Sex and racial or ancestral disparities in Alzheimer disease remain incompletely understood; autopsy studies that examine amyloid, tau, and genetic factors are scarce. Objective To test whether neuritic plaque burden and cognitive outcomes differ by sex and whether sex modifies the effects of apolipoprotein E ε4 ( APOEε4 ), informant-reported race, and African ancestry. Design, Setting, and Participants This was a cross-sectional study using postmortem neuropathological data from the Biobank for Aging Studies, University of São Paulo, São Paulo, Brazil. A total of 2268 autopsies from a population-based, diverse clinicopathological sample were collected between April 2004 and March 2025. Exposures Sex, informant-reported race (Black, White), African ancestry proportion, and APOEε4 carrier status. Main Outcomes and Measures Neuritic plaque burden (Consortium to Establish a Registry for Alzheimer’s Disease [CERAD] score), and cognitive function (Clinical Dementia Rating–Sum of Boxes [CDR-SB]). Ordinal logistic regression examined association of sex with CERAD scores and 2- and 3-way interactions among sex, race, ancestry, and APOEε4 ; adjusting for age, education, vascular factors, and Braak stages. Linear models related pathology to CDR-SB, adding copathologies. Results The analysis included 2268 autopsies (median [IQR] age, 74.8 [63.8-83.3] years; 1152 [51% male] and 1116 [49%] female; 802 [35%] Black and 1466 [65%] White; other race groups not included owing to small numbers); female individuals were older than male individuals and more likely to exhibit cognitive impairment (CDR global score ≥0.5). Female individuals had higher plaque burden than male individuals (unadjusted odds ratio [OR], 1.97; 95% CI, 1.67-2.29; P < .001), and this association remained significant in adjusted models for sociodemographic and vascular factors and APOEε4 status (adjusted OR, 1.65; 95% CI, 1.33-2.20; P < .001). APOEε4 carriers of both sexes had an approximately 4-fold greater odds of plaques. Significant 2-way interactions were found between sex, APOEε4 status, race, and ancestry on CERAD scores. Black noncarriers (OR, 0.47; 95% CI, 0.34-0.67) and noncarriers of African ancestry (OR, 0.57; 95% CI, 0.43-0.76) were least likely to have high plaque burden, whereas this protection was weakened in ε4 carriers. No significant 3-way interaction was detected. Among individuals with a CERAD score of 2 or higher, female individuals were more likely than male individuals to reach Braak stage V-VI than male individuals (probability ratio, 1.25; 95% CI, 1.13-1.38; P = .002). Adding Braak stage to multivariable models attenuated the female-male difference in plaques and interaction of sex and plaque on CDR-SB was no longer significant. Conclusions and Relevance The findings indicate that female sex, APOEε4 , and both race and African ancestry were jointly associated with amyloid in this study population. Excess amyloid among women may partly explain their greater tau burden and steeper cognitive decline. These findings highlight the importance of incorporating sex, race, and ancestry into biomarker thresholds, risk stratification, and the design of preventive or disease-modifying trials for Alzheimer disease.

Abstract Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease linked to repetitive traumatic brain injury, but its prevalence and risk factors in the general population remain poorly defined. We investigated CTE neuropathological changes (CTE-NC) in an admixed, population-based clinicopathological cohort. Neuropathological evaluation was conducted on brain samples from 1151 individuals in the University of São Paulo Biobank for Aging Studies collected from 2004 to 2022. CTE-NC and aging-related tau astrogliopathy (ARTAG) were assessed across 14 963 histological slides using p-tau immunostaining. Clinical, cognitive, and neuropsychiatric data were obtained via informant interviews; information on sports exposure and traumatic brain injury history was limited. Seven cases (0.6%) met criteria for CTE-NC, mean age at death 73.4 ± 12.5 years; 1 was female. Dementia was present in 43% of CTE-NC cases; 57% exhibited neuropsychiatric symptoms. Most common co-pathologies were Alzheimer disease-type changes, ARTAG, and argyrophilic grain disease. Comprehensive exposure histories were unavailable for most cases; 2 had documented soccer involvement. These findings indicate that CTE-NC is rare in this population-based Brazilian cohort and predominantly affects males with frequent coexisting neuropathologies. Findings align with reports from high-income countries and support prioritizing primary prevention by reducing exposure to repetitive head impacts in sport and other settings.