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Women account for two-thirds of individuals suffering from Alzheimer’s Disease (AD). Women with early menopause and those carrying the APOE4 gene are at higher risk for AD. Menopause-related estrogen loss and dysregulated brain cholesterol metabolism may contribute to AD and represent therapeutic targets, particularly for women. Our data show that activation of the brain enzyme CYP46A1 (responsible for converting excess cholesterol into the oxysterol 24SOH) enhances memory and estrogen signaling in female mice during aging and in menopausal-like conditions.We propose todetermine whether CYP46A1 is a druggable axis for women at higher risk for AD. We will induce menopausal-like conditions and activate CYP46A1 (through genetic and pharmacological approaches) in AD mouse models (App knock-in and APOE4/E3) and study disease mechanisms in depth in vitro. establish whether 24SOH levels can serve as an early blood biomarker to predict higher vulnerability to AD in women, possibly offering a time window for prevention. We will analyze data from the Women Health Initiative Study including levels of oxysterols, sex hormones, APOE genotype, CYP46A1 polymorphisms, reproductive history in women, and AD outcomes. The findings from this project could be revolutionary and lead to novel interventions to increase brain-specific estrogen activity in women at risk. This could be an alternative to hormone therapies, which have led to controversial results until now, including side effects.

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.