Highlights
Female individuals demonstrated significantly higher neuritic plaque burden compared with male individuals, with an adjusted odds ratio of 1.65 after controlling for sociodemographic factors, vascular comorbidities, and apolipoprotein E ε4 (APOE ε4) status. APOE ε4 carriers of both sexes exhibited approximately four-fold greater odds of amyloid plaques compared with noncarriers. The protective effect of African ancestry against high plaque burden—observed in Black noncarriers and those without African ancestry—was substantially weakened among APOE ε4 carriers. Among individuals with moderate-to-frequent neuritic plaques (CERAD score ≥2), women were 25% more likely than men to reach advanced Braak stage V-VI tau pathology.
Background: Unraveling Disparities in Alzheimer’s Disease
Alzheimer disease (AD) represents the most common cause of dementia worldwide, affecting an estimated 50 million individuals globally. While sex-based and racial disparities in AD incidence and outcomes have been documented extensively in clinical and epidemiological studies, the underlying neuropathological mechanisms driving these differences remain incompletely characterized. Autopsy-based investigations that integrate amyloid pathology, tau staging, genetic factors, and population diversity are particularly scarce, limiting the development of precision medicine approaches for historically underrepresented groups.
The Biobank for Aging Studies at the University of São Paulo, Brazil, provides a unique platform for addressing these knowledge gaps. Brazil’s historically admixture population—resulting from centuries of genetic mixing among European, African, and indigenous populations—offers a natural experiment for examining how race, ancestry, and genetics interact to influence AD neuropathology. Understanding these relationships is critical for establishing culturally appropriate biomarker thresholds and equitable clinical trial enrollment strategies.
Study Design and Population
This cross-sectional study analyzed postmortem neuropathological data from 2,268 autopsies collected between April 2004 and March 2025. The sample included 1,152 male (51%) and 1,116 female (49%) participants, with 802 individuals (35%) identified as Black and 1,466 (65%) as White by informant-reported race. The median age was 74.8 years (interquartile range, 63.8–83.3 years). Female participants were significantly older than male participants and demonstrated higher rates of cognitive impairment at death (Clinical Dementia Rating global score ≥0.5).
The primary exposures examined included sex, informant-reported race, African ancestry proportion, and APOE ε4 carrier status. The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) scoring system quantified neuritic plaque burden, while the Clinical Dementia Rating-Sum of Boxes (CDR-SB) assessed cognitive function. Ordinal logistic regression models evaluated associations between sex and CERAD scores, incorporating 2-way and 3-way interaction terms among sex, race, ancestry, and APOE ε4 status. All models adjusted for age, educational attainment, vascular risk factors, and Braak stages. Linear regression models examined relationships between pathology markers and CDR-SB scores, with secondary analyses incorporating copathologies.
Key Findings
The principal finding confirms that female sex is independently associated with greater amyloid pathology. In unadjusted analyses, women exhibited nearly double the odds of higher neuritic plaque burden compared with men (odds ratio [OR], 1.97; 95% CI, 1.67–2.29; P < .001). This association persisted after comprehensive adjustment for age, education, vascular factors, and APOE ε4 status (adjusted OR, 1.65; 95% CI, 1.33–2.20; P < .001), indicating that female sex confers approximately 65% increased odds of elevated amyloid burden independent of genetic and vascular confounders.
APOE ε4, the strongest genetic risk factor for sporadic AD, demonstrated its expected profound effect on amyloid pathology. Carriers of this allele showed approximately four-fold greater odds of neuritic plaques regardless of sex, underscoring the central role of APOE ε4 in amyloidogenesis and providing a biological anchor for understanding differential vulnerability across genetic subgroups.
Critically, the study identified significant 2-way interactions between sex, APOE ε4 status, race, and African ancestry on CERAD scores. Black individuals who were APOE ε4 noncarriers demonstrated the lowest likelihood of high plaque burden (OR, 0.47; 95% CI, 0.47–0.67), as did individuals without African ancestry (OR, 0.57; 95% CI, 0.43–0.76). However, these protective associations were substantially attenuated among APOE ε4 carriers, suggesting that the allele may overwhelm race- or ancestry-based protective factors. No significant 3-way interaction was detected, indicating that the combined effects of sex, APOE ε4, and race or ancestry operate through largely independent pathways rather than synergistic triple interactions.
Among individuals with moderate-to-frequent neuritic plaques (CERAD score ≥2), female subjects were 25% more likely than male subjects to exhibit advanced Braak stage V-VI tau pathology (probability ratio, 1.25; 95% CI, 1.13–1.38; P = .002). This finding suggests that excess amyloid burden in women may drive accelerated tau propagation, providing a mechanistic link between sex-based differences in initial amyloid deposition and subsequent downstream neurodegeneration.
The addition of Braak stage to multivariable models substantially attenuated the female-male difference in plaques, and the interaction between sex and plaque burden on CDR-SB scores lost statistical significance after tau staging adjustment. This suggests that the cognitive consequences of amyloid pathology in women are substantially mediated through accelerated tau accumulation rather than amyloid burden per se.
Expert Commentary and Clinical Implications
The findings from Abu Raya and colleagues represent a significant advance in understanding the intersectionality of sex, race, and genetics in AD neuropathogenesis. The observation that female sex confers independent risk for both amyloid and tau pathology has profound implications for biomarker development and therapeutic targeting. Current amyloid PET thresholds and cerebrospinal fluid cutoff values derived predominantly from male-dominated cohorts may underestimate pathology burden in women, potentially delaying diagnosis and treatment initiation.
The attenuation of racial and ancestry-based protective effects by APOE ε4 carriage merits particular attention. In clinical practice, this finding suggests that APOE ε4 status may be a more powerful predictor of amyloid burden than self-reported race or genetically inferred ancestry in certain populations. This observation challenges simplistic interpretations of racial disparities in AD and emphasizes the need for polygenic risk scoring approaches that integrate multiple susceptibility loci.
Several limitations warrant consideration. The reliance on informant-reported race introduces potential classification bias, though the use of genetically inferred African ancestry proportions provides a complementary quantitative approach. The cross-sectional design precludes causal inference regarding the temporal sequence of amyloid and tau accumulation differences. Additionally, the Brazilian population’s unique admixture patterns may limit generalizability to other geographic or ancestral populations. Selection bias inherent in autopsy-based studies—where participation may correlate with disease severity or healthcare access—should also be acknowledged.
The biological mechanisms underlying female susceptibility to amyloid accumulation remain incompletely understood but may involve hormonal influences on microglial function, differences in amyloid clearance mechanisms, or X-chromosome-linked genetic factors. Estrogen withdrawal following menopause has been hypothesized to accelerate amyloidogenesis, though randomized trials of hormone replacement therapy have yielded mixed results.
Conclusion
This large-scale autopsy study provides compelling evidence that sex, race, African ancestry, and APOE ε4 jointly influence amyloid pathology burden in an admixed Brazilian population. Female sex confers independent risk for both amyloid and tau pathology, with approximately 65% increased adjusted odds of neuritic plaques and 25% greater probability of advanced tau staging among amyloid-positive individuals. The protective effects of African ancestry against amyloid burden appear contingent on APOE ε4 noncarrier status, highlighting the importance of genetic context in interpreting racial disparities.
These findings carry substantial implications for precision medicine approaches in AD prevention and treatment. Biomarker threshold development must incorporate sex-specific considerations, and clinical trial enrichment strategies should account for differential vulnerability across genetic and ancestral subgroups. As the field moves toward amyloid-targeting therapies and secondary prevention strategies, equitable application of these interventions will require understanding and addressing the biological and social determinants underlying observed disparities.
References
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