Paes, Vítor Ribeiro

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.

A bstract Alzheimer’s disease (AD) presents with substantial clinical and anatomical heterogeneity, including both typical amnestic and atypical variants such as posterior cortical atrophy and logopenic primary progressive aphasia. Although neurofibrillary tangle (NFT) burden is a defining pathological feature of AD, its regional distribution varies across clinical phenotypes, suggesting that selective neuronal vulnerability may shape disease presentation. However, the cellular and molecular determinants underlying this vulnerability remain incompletely understood. Here, we profiled single-nucleus transcriptomes across multiple brain regions, including hippocampal (CA1) and neocortical (superior temporal gyrus and occipital cortex) regions, from individuals with typical and atypical AD and healthy controls. Integrative analysis identified major cell classes and resolved diverse excitatory and inhibitory neuronal subpopulations that were reproducibly observed across regions and individuals. Using quasi-binomial regression models to assess compositional changes, we quantified subtype-specific vulnerability associated with AD pathology. We identified a distinct excitatory neuronal subpopulation characterized by NRGN and BEX1 expression, which showed reproducible depletion across multiple regions, with the strongest evidence in amnestic AD and in neocortical regions in lvPPA. This vulnerable population showed concordance with previously reported AD-associated excitatory neuron signatures, supporting a conserved transcriptional program of susceptibility. Genes enriched in this population were associated with chemical synaptic transmission and regulation of synaptic plasticity and formed interconnected networks in protein-protein interaction analyses. These findings suggest that intrinsic properties related to synaptic function may predispose specific neuronal populations to degeneration in AD. Together, our results define a conserved, transcriptionally distinct excitatory neuron subpopulation that is selectively vulnerable across AD phenotypes and brain regions. This work provides a framework for linking regional pathology to cell-type-specific susceptibility and highlights synaptic regulatory pathways as potential contributors to neuronal degeneration in Alzheimer’s disease.

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.

BACKGROUND: Cerebrovascular disease is prevalent in older adults and is associated with cognitive impairment. Although the association between brain infarcts and cognition has been widely investigated, the contribution of vascular disease to cognitive impairment has been less studied, particularly in non-White populations. We investigated the epidemiological and clinical characteristics of vascular disease phenotypes and their association with cognitive abilities in a diverse population. METHODS: In a Brazilian population–based clinicopathological study (recruitment between 2004 and 2024), inclusion criteria were age at death ≥18 years and the availability of an informant. Clinical information and cognitive abilities were assessed through informant interviews. Hyaline arteriolosclerosis (HA) was evaluated in 13 brain areas and categorized as absent, mild, moderate, or severe. Moderate/severe HA defined microvascular disease (Micro[+]). Intracranial atherosclerosis in the circle of Willis was similarly classified, with moderate/severe cases defining macrovascular disease (Macro[+]). Four vascular profiles were compared: Micro[+]/Macro[+], Micro[−]/Macro[+], Micro[+]/Macro[−], and Micro[−]/Macro[−]. Linear regression models adjusted for sociodemographic, clinical, and cerebrovascular/neurodegenerative lesions evaluated the association of cognition with vascular profiles, and microvascular and macrovascular diseases separately. RESULTS: Of 2418 participants, 834 with missing data were excluded, yielding a final sample of 1584 individuals (mean age, 74.3±13.4 years; 776 [49%] women; 982 [62%] White). Microvascular disease was slightly more frequent (31%) than macrovascular (29%). Regarding vascular profiles, 788 (50%) participants were Micro[−]/Macro[−], 334 (21%) Micro[+]/Macro[−], 301 (19%) Micro[−]/Macro[+], and 161 (10%) Micro[+]/Macro[+]. Micro[+] participants were older and more frequently women, and had worse cognitive abilities. Vascular groups were similar regarding most clinical comorbidities. HA (β, 0.81 [95% CI, 0.25–1.36]; P =0.004) and Micro[+]/Macro[+] phenotype (β, 1.25 [95% CI, 0.38–2.12]; P =0.005) were associated with worse cognitive abilities compared with HA-negative and Micro[−]/Macro[−] participants, respectively. CONCLUSIONS: HA was as frequent as intracranial atherosclerosis. HA and the vascular phenotype with both microvascular and macrovascular diseases were associated with worse cognition.

Abstract INTRODUCTION Apolipoprotein E allele 4 (APOE ε4) is the main genetic risk factor for late‐onset Alzheimer's disease (AD), but most evidence comes from White populations in high‐income countries. We investigated APOE and AD pathology in an ethnically diverse Brazilian autopsy cohort. METHODS This cross‐sectional study used Biobank for Aging Studies (BAS) data. AD pathology was evaluated with Braak, Consortium to Establish a Registry for Alzheimer's Disease, and Thal criteria. APOE genotypes were obtained from blood or brain tissue. Regression models were adjusted for age, sex, race, and education; interaction with race was tested. RESULTS Among 1391 participants (mean age 75.1 ± 12.4 years, 50% women, 64% White), APOE ε4showed a dose response with greater AD pathological burden and higher odds of AD diagnosis, while APOE ε2/X was protective. APOE ε4/ε4 did not show full penetrance across age groups. Associations were similar in White and Black individuals. DISCUSSION APOE ε4was strongly associated with AD pathology, with consistent associations across racial groups. Highlights APOE ε4 increased AD neuropathological burden in Brazilians. APOE ε2/εX was protective against AD pathology. APOE ε4/ε4did not show full penetrance across age groups. Associations between APOE and AD pathology were similar by race. Large multiethnic autopsy study expands evidence beyond high‐income country studies.