Alzheimer’s is not sex-neutral: nearly two-thirds of people with Alzheimer’s are women, a gap that goes far beyond simple life expectancy and has sparked a scientific debate over sex-specific mechanisms. Recent studies suggest that biological factors particularly the hormonal changes associated with menopause may increase the female brain’s vulnerability.

Estrogen, a central hormone in female reproductive biology, exerts multiple effects on the brain: it modulates synapses, protects neurons from oxidative stress, and regulates immune and metabolic processes. When its production drops abruptly during menopause, those protective networks may weaken, leaving neurons and myelin more exposed to the processes that precede Alzheimer’s disease. Reviews and laboratory studies have outlined these pathways and propose the hypothesis of a post-menopausal “critical window” in which hormone replacement could have real biological impact.

Clinical evidence, however, is complex and sometimes contradictory. Older trials and their interpretations led to caution regarding hormone therapy (HT); but more recent meta-analyses and cohort studies show that timing matters: starting HT near the onset of menopause may be associated with a reduced risk of dementia, while beginning it years later may be not only ineffective but potentially harmful. That nuance explains why the medical community calls for prudence and more detailed research on formulation, dosage, and method of administration.

Beyond estrogen, other factors contribute to the sex gap: genetic differences (such as the interaction between the APOE4 gene and sex), variations in immune response, vascular factors, and social inequalities that shape exposure to risks and access to care. Emerging research even points to distinct lipid and metabolic profiles in women with Alzheimer’s, suggesting sex-specific therapeutic pathways.

What does this mean for prevention and clinical practice? In the short term, experts advocate for personalized approaches that incorporate reproductive history (age of menopause, contraceptive use or HT), genetics, and cardiovascular factors. On the policy and regulatory front, recommendations are shifting: the debate over regulatory warnings and the use of HT has returned to the forefront, underscoring the need to evaluate risks and benefits on a case-by-case basis.

In sum, the heavier burden of Alzheimer’s on women stems from an intersection of longevity, hormonal biology, and social determinants. Understanding the role of estrogen is not merely an academic question it is key to designing prevention and treatment strategies that recognize sex-based differences in brain aging.