Health of the cholinergic system and risk for Alzheimer's disease in post-menopausal 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风险相关，将改变绝经后妇女的风险计算。 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。 这种补充申请将在两个主要方面提高父母补助金。首先，它将使 获得药用美加明（我们的抗胆碱能药物）已变得非常困难 在过去的两年里。 第二，它将增加一种新的体内胆碱能分子成像生物标志物，其可以反映细胞的完整性/功能。 胆碱能神经传递系统这种方法将使用一种新的正电子发射断层扫描（PET） 放射性示踪剂，[18 F]氟乙氧基苯并维沙霉素（[18 F]FEOBV），开发用于脑的体内评估 胆碱能功能，因为它对突触前囊泡乙酰胆碱表现出高结合亲和力和特异性 转运蛋白（VAChT）。[18F]FEOBV PET成像将用于大大提高我们评估 早期临床前AD病理对胆碱能完整性、早期认知功能 改变和生殖史。 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. 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 supplemental application will enhance the parent grant in two primary ways. First it will enable the acquisition of medicinal mecamylamine (our anticholinergic challenge drug) that has become exceedingly difficult to obtain in the last two years. Second, it will add a novel in-vivo cholinergic molecular imaging biomarker of the integrity/function of the cholinergic neurotransmission system. This approach will use a novel positron emission tomography (PET) radiotracer, [18F]Fluoroethoxybenzovesamicol ([18F]FEOBV), that was developed for in-vivo assessment of brain cholinergic function as it exhibits high binding affinity and specificity for the presynaptic vesicular acetylcholine transporter (VAChT). [18F]FEOBV PET imaging will be used to greatly enhance our abilities to evaluate the impact of early preclinical AD pathologies on the relationship between cholinergic integrity, early cognitive alterations, and reproductive history. 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.