Elucidating the role of endocrine aging as a risk factor for Alzheimer's Disease

项目摘要 女性占阿尔茨海默病(AD)人口的三分之二。而特定性别的生物 女性患病率上升的机制尚不清楚，越来越多的证据表明 更年期是一种神经过渡状态，可能会影响AD的风险。在过去的四分之一世纪里，浩瀚的 大多数脑成像研究已经研究了老年人与年龄相关的认知能力下降的神经基础。 65岁及以上。这一惯例忽略了女性一生中最重要的神经内分泌变化之一- 更年期的过渡--在关键的中年时期，我们对老化的大脑的理解存在差距 好几年了。更年期过渡的标志是性激素的产生全面下降--高达 在17b-雌二醇和黄体酮的情况下，90%。动物研究提供了强有力的证据表明雌二醇和 黄体酮在易受神经变性影响的脑区发挥神经保护作用，包括 前额叶皮质和内侧颞叶。然而，女性生殖老化导致的程度 人脑形态、内在脑网络连通性和AD易感性的变化 流行率代表着尚未充分调查的重大知识差距。这项提议将 确认性类固醇激素在绝经过渡期间的下降是否与易感性有关 与阿尔茨海默病有关的大脑回路。在F99阶段(目标1)，我将探讨生殖老化对 健康女性(N=90，年龄45-55岁)的大脑，研究中年神经老化的内分泌基础。这个 特征良好的样本得到丰富，包括绝经前、围绝经期和绝经期后的均衡分布 妇女在有限的年龄范围内，以便将生殖老龄化的影响与时间上的老龄化区分开来。 我将首先确定中年性激素的枯竭如何改变大规模的大脑功能网络。 使用静息状态功能磁共振成像和复杂系统分析的计算方法。然后我会用高- 对海马体和周围内侧颞叶进行分辨率解剖成像，以确定 性激素的枯竭影响到特定的海马区(CA1-3、齿状回、下丘)和 内嗅皮层、周围皮质和海马旁皮质，这些区域富含性激素受体。在K00 阶段(目标2)，我将学习从F99阶段学到的技能和见解，包括 神经内分泌学和脑成像，并用它们来建立女性生殖之间的关系 衰老和病理性AD生物标志物(b-淀粉样蛋白，tau)。要做到这一点，我将利用两个大型社区队列 (n~620，60%女性)，提供相关的激素、认知和分子正电子发射断层扫描 (PET)来自中年受试者(40-65岁)的数据，并建立AD风险的神经内分泌模型。总而言之，这 一项提案将确定更年期在女性阿尔茨海默氏症易感性中所起的作用 疾病，这是认知神经科学中一个研究严重不足的领域，对妇女的健康具有明显的影响。

Project Summary Women constitute two-thirds of the Alzheimer’s disease (AD) population. While the sex-specific biological mechanisms underlying women’s increased prevalence are unclear, accumulating evidence points to menopause as a neurological transition state that may influence AD risk. Over the last quarter century, the vast majority of brain imaging studies have studied the neural basis of age-related cognitive decline in adults aged 65 and older. This convention overlooks one of the most significant neuroendocrine changes in a woman’s life— the transition to menopause—and leaves a gap in our understanding of the aging brain during the critical midlife years. The menopausal transition is marked by a sweeping decline in the production of sex hormones—up to 90% in the case of 17b-estradiol and progesterone. Animal studies provide powerful evidence that estradiol and progesterone play a neuroprotective role in brain regions vulnerable to neurodegeneration, including the prefrontal cortex and medial temporal lobes. However, the degree to which female reproductive aging leads to changes in human brain morphology, intrinsic brain network connectivity, and susceptibility to increased AD prevalence represents a significant knowledge gap that has yet to be adequately examined. This proposal will establish whether the decline in sex steroid hormones over the menopausal transition relates to vulnerability in brain circuits implicated in AD. In the F99 phase (Aim 1), I will probe the effects of reproductive aging on the brain in healthy women (N=90, ages 45–55), investigating the endocrine basis of neural aging in midlife. The well-characterized sample is enriched to include a balanced distribution of pre, peri, and post-menopausal women across a limited age range in order to isolate the effects of reproductive aging from chronological aging. I will first determine how the depletion of sex hormones in midlife alters large-scale functional brain networks using resting-state fMRI and computational approaches from complex systems analysis. I will then use high- resolution anatomical imaging of the hippocampus and surrounding medial temporal lobe to determine whether the depletion of sex hormones impacts specific hippocampal subfields (CA1-3, dentate gyrus, subiculum) and entorhinal, perirhinal, and parahippocampal cortices, regions enriched with sex hormone receptors. In the K00 phase (Aim 2), I will take the skills and insights gained from the F99 phase, including fundamental training in neuroendocrinology and brain imaging, and use them to establish the relationship between female reproductive aging and pathological AD biomarkers (b-amyloid, tau). To do this, I will leverage two large community cohorts (N~620, 60% female) that provide relevant hormonal, cognitive, and molecular positron emission tomography (PET) data from midlife subjects (ages 40-65) and build a neuroendocrine model of AD risk. Together, this proposal will identify the role menopause plays in contributing to female-specific vulnerability to Alzheimer’s disease, a severely understudied area in cognitive neuroscience with clear implications for women’s health.