The cholesterol-CYP46A1 axis: a promising therapeutic target to protect women at risk of Alzheimer’s disease.

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.