Sex difference in Alzheimer's disease: An updated, balanced and emerging perspective on differing vulnerabilities

Sex biology influences Alzheimer's disease (AD). Sex differences exist in the epidemiologic, imaging, biomarker, and pathology studies of this uniquely human condition. The mandate to understand sex differences in major diseases like AD is important for many reasons. First, AD is the most common neurodegenerative condition and a devastating disease—experienced as an insidious and progressive erosion of memory, cognition, and other brain functions. Second, since true sex differences in AD exist, their precise understanding could reveal what protects one sex or makes the other vulnerable—and this knowledge could inform development of new therapeutic approaches to benefit both sexes. Third, AD develops in the aging brain in a milieu of decreased circulating gonadal hormones. Thus, how sex-specific depletion affects the brain along with how replacement of androgens in men and estrogens and progestins in women alters vulnerability to AD are relevant questions, with clinical implications in a future of personalized medicine. This review will highlight advances in sex differences in AD in human populations with a focused perspective on epidemiology, biomarkers, and clinical trials. A thorough and concise overview of sex differences reviewed here indicates varying vulnerabilities in men and women. This review examines several lines of recent and strong evidence that collectively indicate the following: (1) men die faster with AD, (2) more women live with AD, (3) both sexes show similar risk of developing AD until advanced ages when women show increased risk, (4) both sexes show largely similar AD biomarker burden with notable exceptions for higher tau levels in subgroups of women with high amyloid, (5) women show brain reserve and resilience to tau pathology, (6) both sexes are vulnerable to the genetic risk of carrying APOE4, with women showing higher risk, and (7) neither sex has shown clear benefit of hormone replacement for AD or dementia risk in randomized clinical trials to date.