Highlight
- Female individuals exhibited a significantly higher neuritic plaque burden compared to male individuals (aOR 1.65), even after adjusting for age, education, vascular factors, and APOEε4 status.
- The protective effect against amyloid accumulation observed in individuals of Black race and African ancestry was significantly attenuated in the presence of the APOEε4 allele.
- Among those with high amyloid burden, women were more likely than men to progress to advanced neurofibrillary tangles (Braak stages V-VI), potentially explaining steeper cognitive decline in females.
- The findings advocate for the integration of sex and ancestry-specific thresholds in Alzheimer’s disease (AD) biomarker interpretation and clinical trial recruitment.
Introduction: The Intersectionality of Alzheimer Disease Pathology
Alzheimer disease (AD) is not a monolithic condition; its phenotypic expression and pathological progression are deeply influenced by a complex interplay of biological sex, genetic risk factors, and social constructs such as race. While it is well-established that women represent a disproportionate share of AD cases globally, the underlying reasons—ranging from longevity to biological vulnerability—remain a subject of intense investigation. Similarly, while epidemiological data often point to higher dementia prevalence among Black and Hispanic populations in the United States, the precise neuropathological substrates of these disparities are frequently obscured by a lack of diverse autopsy data.
Historically, the majority of AD neuropathology research has relied on cohorts of European ancestry, which limits the generalizability of findings to more admixed populations. A recent landmark study by Abu Raya et al., published in JAMA Neurology, addresses this gap by utilizing a large-scale, population-based autopsy sample from Brazil. By examining sex differences through the lens of race, African ancestry, and the APOEε4 genotype, the researchers provide a nuanced look at how these factors jointly contribute to amyloid-beta deposition and cognitive decline.
Study Design and Methodology
The USP Biobank Cohort
The study utilized postmortem data from the Biobank for Aging Studies at the University of São Paulo, Brazil. This unique cohort is particularly valuable due to the high degree of genetic admixture in the Brazilian population and the population-based nature of the sample, which reduces the selection bias often found in specialized memory clinic cohorts. The analysis included 2,268 autopsies collected between April 2004 and March 2025.
Analytical Framework
The primary exposures were sex, informant-reported race (categorized as Black or White), genomic African ancestry proportion, and APOEε4 carrier status. The main outcomes were:
1. Neuritic plaque burden, measured using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) score.
2. Cognitive function, assessed via the Clinical Dementia Rating-Sum of Boxes (CDR-SB).
3. Tau pathology progression, measured by Braak stages.
Statistical models employed ordinal logistic regression to examine the associations between sex and CERAD scores, incorporating 2-way and 3-way interactions between sex, race, ancestry, and APOEε4. Adjustments were made for age, education, vascular risk factors (such as hypertension and diabetes), and Braak stages to isolate the specific impact of amyloid pathology.
Key Findings: Sex as a Primary Driver of Amyloid Load
The study population was balanced by sex (51% male, 49% female) with a median age of 74.8 years. A significant racial representation was achieved, with 35% identifying as Black and 65% as White. Initial observations confirmed that female participants were generally older and exhibited higher rates of cognitive impairment (CDR global score ≥0.5) at the time of death compared to their male counterparts.
Differential Plaque Burden
The most striking finding was the pronounced sex difference in amyloid pathology. Women had nearly double the unadjusted odds of a higher neuritic plaque burden (OR 1.97; 95% CI, 1.67-2.29). Even after rigorous adjustment for sociodemographic variables, vascular health, and APOEε4 status, the association remained robust (aOR 1.65; 95% CI, 1.33-2.20). This suggests that the female predisposition to amyloid accumulation is not merely a byproduct of living longer or having different vascular risk profiles, but may be driven by intrinsic biological sex differences.
The Interaction of APOEε4, Race, and Ancestry
The APOEε4 allele remains the strongest genetic risk factor for sporadic AD, and this study confirmed that carriers of both sexes faced a fourfold increase in the odds of high plaque burden. However, the study revealed critical nuances when race and ancestry were considered:
1. Protection in Non-Carriers: Black individuals who did not carry the APOEε4 allele, and those with a high proportion of African ancestry without the allele, were the least likely to exhibit high neuritic plaque burden (OR 0.47 and 0.57, respectively).
2. Loss of Protection: This apparent “protection” associated with African ancestry was significantly weakened in the presence of the APOEε4 allele. This highlights that the risk conferred by APOEε4 may be more aggressive in certain ancestral backgrounds or that the baseline lower risk in these groups is erased by the presence of the ε4 allele.
3. Sex Modifiers: Significant 2-way interactions were detected between sex and APOEε4, as well as between sex and race. The data suggests that the amyloid-promoting effect of APOEε4 may be particularly potent in women, further compounding their risk.
Progression to Tau Pathology and Cognitive Decline
The study also explored why women often experience steeper cognitive decline than men for the same level of amyloid. Among individuals with moderate to high neuritic plaque burden (CERAD score ≥ 2), women were significantly more likely to reach Braak stages V-VI—the stages associated with widespread neurofibrillary tangles and severe clinical dementia (probability ratio 1.25). Interestingly, when Braak stage was added to the multivariable models, the sex difference in plaque burden was attenuated, suggesting that the higher amyloid load in women serves as a catalyst for more advanced tau pathology, which in turn drives the cognitive symptoms.
Expert Commentary: Mechanistic Insights and Clinical Implications
Biological Plausibility
Several mechanisms may explain the observed sex differences. Estrogen has long been hypothesized to be neuroprotective; the sharp decline in estrogen during menopause may trigger a cascade of amyloid accumulation. Furthermore, the X-chromosome contains several genes involved in immune function and protein degradation, and incomplete X-inactivation in females could lead to differential expression of pathways related to amyloid clearance. The findings regarding African ancestry also point toward the importance of the genetic “background.” The APOEε4 allele may interact with other ancestral variants (localized on the same chromosome) that modify its effect on the blood-brain barrier or lipid metabolism.
Clinical Trial Design and Biomarker Thresholds
From a clinical perspective, these results have immediate implications for the use of amyloid PET scans and CSF biomarkers. If women and individuals of different ancestries accumulate amyloid at different rates or have different “tolerances” for plaque burden before tau pathology accelerates, then a single universal threshold for “amyloid positivity” may be inappropriate.
For example, if Black non-carriers have lower baseline amyloid, they might be excluded from clinical trials for anti-amyloid therapies despite having early-stage disease. Conversely, women might benefit from earlier intervention if their amyloid burden is more likely to trigger rapid tau spread. Precision medicine in AD must move toward sex- and ancestry-adjusted risk scores.
Conclusion: A Mandate for Inclusive Neurosciences
The study by Abu Raya and colleagues provides compelling evidence that sex, race, and ancestry are not merely peripheral variables but are central to the neuropathological architecture of Alzheimer disease. The finding that women harbor a higher amyloid burden, which subsequently facilitates more severe tau pathology, offers a clear biological pathway for the sex disparities observed in clinical practice.
Furthermore, the complex interaction between the APOEε4 allele and African ancestry underscores the necessity of studying diverse populations to truly understand the genetic underpinnings of AD. As the medical community moves toward a new era of disease-modifying therapies, ensuring that these treatments are developed and deployed with an understanding of these fundamental biological differences is not just a scientific necessity—it is a matter of health equity.
References
- Abu Raya M, Suemoto CK, Paes VR, et al. Sex Differences in Amyloid Pathology by Race, Ancestry, and Apolipoprotein E ε4 in an Admixed Autopsy Sample. JAMA Neurol. 2026;23:e260054. doi:10.1001/jamaneurol.2026.0054.
- Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413-446.
- Belloy ME, Napolioni V, Greicius MD. A Quarter Century of APOE and Alzheimer’s Disease: Progress to Date and the Path Forward. Neuron. 2019;101(5):820-838.
