Department of Neurology, Endowed Chair in Aging and Neurodegenerative Disease, University of California San Francisco, San Francisco, CA, United States.
Handb Clin Neurol. 2020;175:261-273. doi: 10.1016/B978-0-444-64123-6.00018-7.
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.
性别生物学影响阿尔茨海默病（AD）。在这种独特的人类疾病的流行病学、影像学、生物标志物和病理学研究中存在性别差异。出于多种原因，了解 AD 等重大疾病中的性别差异是很重要的。首先，AD 是最常见的神经退行性疾病，也是一种毁灭性的疾病——表现为记忆、认知和其他大脑功能的逐渐恶化。其次，由于 AD 确实存在性别差异，对其进行准确的理解可以揭示哪些因素保护某个性别或使另一个性别易患 AD——而这种知识可以为开发新的治疗方法提供信息，使两性受益。第三，AD 在衰老的大脑中，伴随着循环性腺激素水平的降低而发展。因此，了解雄激素在男性中的特异性耗竭如何影响大脑，以及雌激素和孕激素在女性中的替代如何改变 AD 的易感性，都是相关的问题，在个性化医疗的未来具有临床意义。本综述将重点介绍人类 AD 中的性别差异研究进展，特别关注流行病学、生物标志物和临床试验。对这里回顾的性别差异进行全面而简洁的概述表明，男性和女性的脆弱性不同。本综述考察了一些最近和强有力的证据，这些证据共同表明：（1）患有 AD 的男性死亡速度更快，（2）更多的女性患有 AD，（3）男女在发展 AD 的风险上相似，直到老年时女性的风险增加，（4）男女在 AD 生物标志物负担上大致相似，但女性中具有高淀粉样蛋白的亚组中 tau 水平较高是例外，（5）女性表现出大脑储备和对 tau 病理学的适应能力，（6）男女都容易受到携带 APOE4 的遗传风险的影响，女性的风险更高，（7）迄今为止，在随机临床试验中，无论是男性还是女性都没有显示出激素替代治疗 AD 或痴呆风险的明显益处。
