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Abstract：
Despite decades of extensive research efforts, efficacious therapies for Alzheimer\'s disease (AD) are lacking. The multi-factorial nature of AD neuropathology and symptomatology has taught us that a single therapeutic approach will most likely not fit all. Women constitute ~70% of the affected AD population, and pathology and rate of symptoms progression are 2-3 times higher in women than men. Epidemiological data suggest that menopausal estrogen loss may be causative of the more severe symptoms observed in AD women, however, results from clinical trials employing estrogen replacement therapy are inconsistent. AD pathological hallmarks-amyloid β (Aβ), neurofibrillary tangles (NFTs), and chronic gliosis-are laid down during a 20-year prodromal period before clinical symptoms appear, which coincides with the menopause transition (peri-menopause) in women (~45-54-years-old). Peri-menopause is marked by widely fluctuating estrogen levels resulting in periods of irregular hormone-receptor interactions. Recent studies showed that peri-menopausal women have increased indicators of AD phenotype (brain Aβ deposition and hypometabolism), and peri-menopausal women who used hormone replacement therapy (HRT) had a reduced AD risk. This suggests that neuroendocrine changes during peri-menopause may be a trigger that increases risk of AD in women. Studies on sex differences have been performed in several AD rodent models over the years. However, it has been challenging to study the menopause influence on AD due to lack of optimal models that mimic the human process. Recently, the rodent model of accelerated ovarian failure (AOF) was developed, which uniquely recapitulates human menopause, including a transitional peri-AOF period with irregular estrogen fluctuations and a post-AOF stage with low estrogen levels. This model has proven useful in hypertension and cognition studies with wild type animals. This review article will highlight the molecular mechanisms by which peri-menopause may influence the female brain vulnerability to AD and AD risk factors, such as hypertension and apolipoprotein E (APOE) genotype. Studies on these biological mechanisms together with the use of the AOF model have the potential to shed light on key molecular pathways underlying AD pathogenesis for the development of precision medicine approaches that take sex and hormonal status into account.
摘要：
尽管进行了数十年的广泛研究，阿尔茨海默病（AD）缺乏有效的治疗方法。AD神经病理学和症状学的多因素性质告诉我们，单一的治疗方法很可能不适合所有人。女性占受影响AD人口的约70％，女性的病理和症状进展率是男性的2-3倍。流行病学数据表明，更年期雌激素流失可能是导致AD女性出现更严重症状的原因。然而,使用雌激素替代疗法的临床试验结果不一致.AD病理标志-淀粉样β(Aβ),神经原纤维缠结（NFT），和慢性神经胶质增生-在临床症状出现之前的20年前驱期，这与女性（〜45-54岁）的更年期过渡（围更年期）相吻合。围绝经期的特点是雌激素水平波动很大，导致激素-受体相互作用不规则。最近的研究表明，围绝经期妇女的AD表型指标（脑Aβ沉积和低代谢）增加，使用激素替代疗法(HRT)的围绝经期女性AD风险降低.这表明围绝经期的神经内分泌变化可能是增加女性AD风险的触发因素。多年来，已经在几种AD啮齿动物模型中进行了性别差异研究。然而,由于缺乏模拟人类过程的最佳模型，因此研究更年期对AD的影响一直具有挑战性。最近,建立了加速卵巢功能衰竭（AOF）的啮齿动物模型，独特地概括了人类更年期，包括AOF周围的过渡性雌激素波动不规则和AOF后阶段雌激素水平低。该模型已被证明可用于野生型动物的高血压和认知研究。本文将重点介绍围绝经期可能影响女性大脑对AD的易感性和AD危险因素的分子机制。如高血压和载脂蛋白E（APOE）基因型。对这些生物学机制的研究以及AOF模型的使用有可能揭示AD发病机理的关键分子途径，以开发考虑性别和激素状态的精准医学方法。
