# Sex Differences in Amyloid Pathology by Race, Ancestry, and Apolipoprotein E ε4 in an Admixed Autopsy Sample

## TL;DR

Women had higher amyloid plaque and tau levels than men, and ancestry influenced Alzheimer's risk linked to APOEε4, suggesting personalized risk assessments are needed.

## Contribution

Identified sex-specific and ancestry-modulated effects of APOEε4 on amyloid pathology in an admixed population.

## Key findings

- Female sex was independently associated with higher neuritic plaque burden, especially in White women.
- Black individuals and those with African ancestry had lower plaque burden among APOEε4 noncarriers.
- Women with moderate/frequent plaques were more likely to reach high tau stages than men.

## Abstract

Do male and female individuals differ in neuritic plaque deposition, and does sex modify the influence of apolipoprotein E ε4, informant-reported race, or African genetic ancestry on plaque burden?

In this cross-sectional study of 2268 autopsied adults, female sex was independently associated with greater neuritic plaque burden, especially White female individuals; among participants with moderate/frequent plaques, female individuals were more likely to reach high tau stages than male individuals, but sex did not modify the APOEε4 effect. The association between APOEε4 and neuritic plaque burden varied by race and African ancestry, with lower plaque burden observed in Black individuals and those with African ancestry only among ε4 noncarriers; among ε4 carriers, plaque burden did not differ by race or ancestry.

In this study, amyloid and tau burdens were higher in women, and ancestry modulated APOEε4-related risk, underscoring the need for sex- and ancestry-specific thresholds in Alzheimer disease risk assessment and targeted interventions.

This cross-sectional study evaluates associations of neuritic plaque burden and cognitive outcomes with sex, apolipoprotein E ε4 status, race, and ancestry.

Sex and racial or ancestral disparities in Alzheimer disease remain incompletely understood; autopsy studies that examine amyloid, tau, and genetic factors are scarce.

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.

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.

Sex, informant-reported race (Black, White), African ancestry proportion, and APOEε4 carrier status.

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.

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.

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.