Role of estrogen in women's Alzheimer's disease risk as modified by APOE

Alzheimer's disease (AD) is characterized by numerous sexual dimorphisms that impact the development, progression, and probably the strategies to prevent and treat the most common form of dementia. In this review, we consider this topic from a female perspective with a specific focus on how women's vulnerability to the disease is affected by the individual and interactive effects of estrogens and apolipoprotein E (APOE) genotype. Importantly, APOE appears to modulate systemic and neural outcomes of both menopause and estrogen-based hormone therapy. In the brain, dementia risk is greater in APOE4 carriers, and the impacts of hormone therapy on cognitive decline and dementia risk vary according to both outcome measure and APOE genotype. Beyond the CNS, estrogen and APOE genotype affect vulnerability to menopause-associated bone loss, dyslipidemia and cardiovascular disease risk. An emerging concept that may link these relationships is the possibility that the effects of APOE in women interact with estrogen status by mechanisms that may include modulation of estrogen responsiveness. This review highlights the need to consider the key AD risk factors of advancing age in a sex-specific manner to optimize development of therapeutic approaches for AD, a view aligned with the principle of personalized medicine.