Women's midlife: the front line of Alzheimer prevention.

Abstract

Nearly two-thirds of patients with Alzheimer disease (AD) are women, most of them postmenopausal. While sex differences in AD have historically been attributed to women's relative longevity, accumulating evidence challenges that view, pointing to female sex-specific biological underpinnings. In particular, neuroendocrine aging and the hormonal shifts that accompany the menopause transition have emerged as potentially modifiable AD risk factors in women. Yet, key neuroendocrine aging-related factors linked to increased AD and dementia risk, such as early menopause, premenopausal bilateral oophorectomy, frequent vasomotor symptoms, and midlife cognitive and mood disturbances, remain underinvestigated. Additionally, although a growing evidence base highlights the potential of menopause hormone therapy for AD prevention, particularly in women undergoing oophorectomy, progress remains hindered by a lack of clinical trials and biomarker-driven studies. This Review calls for a paradigm shift: from viewing AD risk as a byproduct of generalized aging to validating midlife neuroendocrine aging as a distinct window of vulnerability, and an opportunity for prevention. By 2050, over 1.2 billion women worldwide will be in or approaching menopause. The stakes are global, and the opportunity is urgent: to redefine AD prevention through sex-specific, time-sensitive, and biologically informed strategies that translate science into scalable, actionable care.