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

Menopause hormone therapy (MHT) has been studied for decades, but its implications for cognitive aging remain unclear. The authors suggest this may be because prior work has not sufficiently considered MHT type—despite notable pharmacokinetic differences across formulations—and has given limited attention to individual differences that may worsen cognitive risk.

To address this, they examined neurocognitive outcomes by APOEε4 status, the strongest genetic predictor of Alzheimer's disease, and by MHT formulation in a sample of older females over age 70 (N=8,741). Neuroimaging analyses were available for a subset of participants (N=930).

Results suggested formulation- and domain-specific associations between MHT and cognition, with evidence that estradiol-based MHT provided more benefits for APOEε4 carriers relative to conjugated equine estrogens use. In the imaging subset, APOEε4 carriers taking estradiol-based MHT showed a consistent pattern of more favorable associations, including higher volume, greater cortical thickness, and less white matter damage. The authors say these results reframe mixed MHT findings as an issue of exposure definition and support formulation- and genetic-risk-aware approaches to menopause care.