Health of the Cholinergic System and Risk for Alzheimer's Disease in Postmenopausal Women

女性患阿尔茨海默病（AD）的风险增加。特别是在更年期，一些女性会经历 认知上的改变。然而，并非所有女性都会经历更年期对认知的负面影响。的 更年期发生的认知变化尚未与晚年病理性衰老的风险联系起来 包括AD。因此，了解与认知个体差异相关的神经生物学因素， 更年期对于理解正常认知老化和确定病理老化的风险至关重要。 理解雌激素损失对AD风险的作用的挑战是， 绝经期的激素变化和AD的临床表现。因此，确定激素 绝经后的变化与AD风险有关，将改变绝经后妇女的风险计算， 未来 本文提出的新研究将研究一种已建立的AD相关神经递质机制 这也可能是绝经后认知变化的基础。我们认为荷尔蒙环境的变化 绝经期与胆碱能系统和其他脑部病变相互作用，影响妇女患 认知能力下降临床前研究表明，雌激素是必要的正常胆碱能功能 并且其撤销导致胆碱能功能障碍和认知损害。重要的是要确定 更年期相关的认知变化与胆碱能功能完整性和AD相关 这些生物标志物预示着老年认知障碍或痴呆的风险增加。本研究将探讨 胆碱能阻断后的大脑功能，将个体分为能够补偿的个体 绝经后和未绝经者的荷尔蒙变化。我们假设那些 补偿增加了对胆碱能阻滞的敏感性，表现出认知能力差， 任务，改变大脑激活，并减少基底前脑胆碱能系统（BFCS）的体积。这些 胆碱能标记物将与认知能力差的绝经因素和AD的生物标记物相关。 具体目标1是通过测量工作记忆表现来检查胆碱能功能的“完整性”， 绝经后妇女的功能性脑激活和BFCS结构。具体目标2将审查是否 绝经相关症状和已知AD生物标志物的个体差异与认知相关， 抗胆碱能激发后的脑激活。 这项研究的公共卫生意义在于，它将确定个体差异因素， 与绝经后认知能力变化及其与结构，功能， 以及晚年认知功能障碍风险的生物标志物证据。了解这些因素将有助于 为女性提供个性化的未来风险缓解策略，包括激素，药物，认知 补救措施等，这将是进一步研究的主题。

Women are at increased risk for Alzheimer’s disease (AD). Notably at menopause, some women experience a change in cognition. However, not all women experience negative effects of menopause on cognition. The cognitive changes that occur at menopause have not yet been connected to late life risk for pathological aging including AD. Thus, understanding the neurobiological factors related to individual differences in cognition at menopause is critical for understanding normal cognitive aging and for determining risk for pathological aging. The challenge in understanding the role of estrogen loss on the risk for AD is the long lag time between the hormonal changes at menopause and the clinical manifestations of AD. Thus, identifying how the hormone changes after menopause are related to AD risk will alter the risk calculus for postmenopausal women in the future. The novel study proposed here will examine an established AD-related neurotransmitter-based mechanism that may also underlie cognitive changes after menopause. We propose that the change in the hormonal milieu at menopause interacts with the cholinergic system and other brain pathologies to influence a woman’s risk for cognitive decline. Preclinical studies have shown that estrogen is necessary for normal cholinergic functioning and its withdrawal leads to cholinergic dysfunction and cognitive impairment. It is important to determine whether menopause-related cognitive changes correlate with both cholinergic functional integrity and established AD biomarkers that portend increased risk for late-life cognitive impairment or dementia. This study will examine brain functioning following cholinergic blockade to separate individuals into those who are able to compensate for the hormone change after menopause and those who are not. We hypothesize women with poor compensation have increased sensitivity to cholinergic blockade by showing poor performance on a cognitive task, altered brain activation, and decreased basal forebrain cholinergic system (BFCS) volume. These cholinergic markers will be related to menopausal factors associated with poor cognition and biomarkers of AD. Specific Aim 1 is to examine cholinergic functional “integrity” by measuring working memory performance, functional brain activation, and BFCS structure in postmenopausal women. Specific Aim 2 will examine whether individual differences in menopause-relevant symptoms and known AD biomarkers are related to cognition and brain activation after anticholinergic challenge. The public health significance of this study is that it will identify individual difference factors that are associated with cognitive performance changes after menopause and their relationship to structural, functional, and biomarker evidence of risk for later life cognitive dysfunction. Knowledge of these factors will serve to advance personalized future risk-mitigation strategies for women including hormonal, medication, cognitive remediation, etc. that will be the subject of further research.