A MULTINATIONAL cohort study of 4,592 individuals has revealed significant sex and ancestry-based differences in how the APOE-ε4 gene influences Alzheimer’s disease biomarkers, with women of African and European ancestry showing stronger associations between APOE-ε4 and tau pathology compared to men.
Alzheimer’s disease risk is profoundly influenced by age, sex, and the APOE-ε4 allele, but interactions between these factors across diverse populations remain poorly understood. This study, analysing cerebrospinal fluid (CSF) biomarkers from 20 cohorts spanning 1985–2020, provides critical insights into how sex and ancestry modulate APOE-ε4’s impact on amyloid-β and tau pathology. The findings challenge one-size-fits-all approaches to Alzheimer’s risk assessment and highlight the need for personalised diagnostic strategies.
The research included 4,592 participants (mean age 70.8; 52.8% female) grouped by genetic ancestry: African (2.6%), Asian (1.1%), and European (96.3%). APOE-ε4 dosage correlated with lower CSF amyloid-β1-42 levels (β=−0.58, p<0.001), indicating greater amyloid pathology. This association was stronger in European men (β=−0.63) than women (β=−0.52; interaction p=0.01). Conversely, APOE-ε4’s link to phosphorylated tau (p-tau) was more pronounced in women, particularly among African ancestry groups (women: β=0.66, p<0.001 vs men: β=0.10, p=0.57; interaction p=0.03). Total tau levels also showed sex disparities, with European women exhibiting stronger APOE-ε4 associations (β=0.36 vs men: β=0.27; p=0.053). No significant interactions were observed in the smaller Asian cohort. Sensitivity analyses excluding APOE-ε2 carriers confirmed these trends, underscoring the specificity of ε4 effects.
These findings necessitate sex- and ancestry-tailored approaches in Alzheimer’s research and clinical practice. For clinicians, assessing APOE-ε4’s risk should account for patients’ sex and genetic background, particularly when interpreting tau pathology biomarkers. Future studies must prioritise larger, diverse cohorts to validate these interactions and explore biological mechanisms driving observed disparities. Public health strategies should integrate ancestry-specific risk models to improve early detection and personalised interventions, ensuring equitable advances in Alzheimer’s care.
Reference
Xu X et al. Sex differences in apolipoprotein e and alzheimer disease pathology across ancestries. JAMA Netw Open. 2025;8(3):e250562.
