Associations of menopause hormone therapy with late-life cognition and brain health vary by formulation and APOEε4 presence

Implications of menopause hormone therapy (MHT) for cognitive aging remain unclear despite decades of research. Potential reasons include insufficient consideration of MHT type, despite notable pharmacokinetic differences across formulations, and limited attention to individual differences that may exacerbate cognitive risk. We examined late-life neurocognitive outcomes as a function of APOEε4 status, the strongest genetic predictor of Alzheimer’s disease, and MHT formulation (N=8,741). Results suggest formulation- and domain-specific association between MHT and cognition, with evidence of estradiol-based MHT providing more benefits for APOEε4 carriers relative to conjugated equine estrogens use. Neuroimaging analyses available for a subset of participants (N=930) revealed a consistent pattern of more favourable associations (higher volume, cortical thickness; less white matter damage) in APOEε4 carriers taking estradiol-based MHT. These results reframe mixed MHT findings as an issue of exposure definition and support formulation- and genetic-risk-aware approaches to menopause care.