The interaction between APOE, menopause, and estrogen in Alzheimer’s disease

APOE variant 4 is the most common genetic risk factor for late-onset Alzheimer’s disease (AD), and it is well known that women carrying APOE4 run a 4-fold higher risk of AD than male carriers. Nevertheless, the cause of this sex difference is still enigmatic.

In this project, we address the hypothesis that the drop of female sex hormone estrogen and metabolic changes at menopause impact on APOE4 regulation and downstream factors, and that this contributes to sex differences in AD.

Our preliminary results support this hypothesis by suggesting that the estrogen receptor beta (ERβ) to be an important link between menopause and APOE levels.

Selective ERβ activation protects against AD pathology in an AD mouse model and can regulate APOE levels in a sex-specific manner.

Making use of a multidisciplinary collaboration between experts in neuroendocrinology, AD, epidemiology, biostatistics, and genetics, we will:address the relationship between age at menopause, hormone replacement therapy, APOE4 and other genetic variants, and AD diagnosis in human cohorts,validate such relationships in an AD mouse model where menopause is simulated, andin a data-driven approach identify causative molecular networks underlying these relationships using human APOE4 brain organoid models.The outcome of this project will provide new mechanistic insights into the sex differences in AD and how such knowledge can be used for preventive clinical measures, especially for APOE4-positive women.