Reproductive risk factors for Alzheimer's disease dementia and pathology

项目概要/摘要 最近的估计表明，几乎三分之二的人被诊断患有阿尔茨海默病[AD]。 是女性美国国立卫生研究院和阿尔茨海默氏症协会强调了 了解AD危险因素和临床进展的性别差异。生殖和激素 这些因素对妇女可能特别重要。妊娠期高血压疾病[HPD]一直是 与HPD后5至10年的主观认知主诉或白色病变相关，但 HPD对大脑结构和认知功能的长期影响尚不清楚。基于人口的研究是 需要评估HPD和亚型的贡献（即，先兆子痫）与认知能力下降，AD， 以及β淀粉样蛋白[Aβ]、神经变性和脑血管病变的神经影像学测量。 此外，观察性研究和临床试验已经检查了早期绝经（自然或 药物诱导）和激素治疗[HT]对AD和其他痴呆症风险的影响。但不 目前已知是否影响早期绝经，HT的使用，以及它们与APOE基因型的相互作用， 与特定类型的脑病理学有关（即，Aβ、神经变性、脑血管），因为 尚未进行多模式成像研究。本提案的总体目标是阐明 两个与生殖相关的性别特异性因素对女性的影响，怀孕（例如，怀孕次数， HPD）和绝经（绝经诱导或自然），对认知能力下降、AD和神经影像学的风险 Aβ、神经变性和脑血管病理学指标。因为文学和我们的 初步数据表明，心血管疾病和痴呆症的风险评分对女性的预测性较低， 与男性相比，我们还建议纳入这些性别特异性因素，以开发更具预测性的风险 女性轻度认知障碍和AD评分。为了实现我们的目标，我们将利用现有的两个 马约诊所的基础设施：马约诊所衰老研究（MCSA; U 01 AG 006786）和罗切斯特 流行病学项目病历-链接系统（REP; R 01 AG 034676）。使用REP，我们将新 2,370名参加MCSA的妇女的妊娠和绝经摘要信息。因为很少 评估妊娠和绝经的研究也调整了假定的混杂变量，我们将 我还使用REP来提取这些数据，以确定这些性别特异性条件是否是独立的 认知能力下降、AD和特定脑病理的神经影像学指标的预测因子。成功 完成这些目标将是理解这些性别特异性因素是否 与女性AD风险相关，以了解这些因素是否与特定类型有关 脑病理学（即，Aβ、神经变性、脑血管），并制定更好的风险评分， 预测女性认知障碍、痴呆症和特定的大脑变化。

PROJECT SUMMARY/ABSTRACT Recent estimates suggest that almost two-thirds of the individuals diagnosed with Alzheimer’s disease [AD] are women. The National Institutes of Health and the Alzheimer’s Association have highlighted the critical need to understand sex differences in the risk factors and clinical progression of AD. Reproductive and hormonal factors may be particularly important for women. Hypertensive pregnancy disorders [HPD] have been associated with subjective cognitive complaints or white matter lesions five to ten years after the HPD, but the long-term effects of HPD on brain structure and cognitive function are unknown. Population-based studies are needed to assess the contribution of HPD and subtype (i.e., preeclampsia) to the risk of cognitive decline, AD, and neuroimaging measures of amyloid-beta [Aβ], neurodegeneration, and cerebrovascular pathologies. Further, observational studies and clinical trials have examined the effects of early menopause (natural or surgically-induced) and hormonal therapy [HT] on the risk of AD and other dementias. However, it is not currently known whether the effects of early menopause, HT use, and their interactions with APOE genotype, are associated with specific type(s) of brain pathology (i.e., Aβ, neurodegeneration, cerebrovascular) because multi-modal imaging studies have not been conducted. The overall aims of this proposal are to elucidate the impact of two hormonally-related sex-specific factors for women, pregnancy (e.g., number of pregnancies, HPD) and menopause (surgically-induced or natural), on the risk of cognitive decline, AD, and neuroimaging measures of Aβ, neurodegeneration, and cerebrovascular pathologies. Because the literature and our preliminary data suggest that risk scores for cardiovascular disease and dementia are less predictive in women compared to men, we also propose to incorporate these sex-specific factors to develop a more predictive risk score of mild cognitive impairment and AD for women. To accomplish our goals, we will utilize two existing infrastructures at the Mayo Clinic: the Mayo Clinic Study of Aging (MCSA; U01 AG006786) and the Rochester Epidemiology Project medical records-linkage system (REP; R01 AG034676). Using the REP, we will newly abstract information on pregnancy and menopause for 2,370 women enrolled in the MCSA. Because few studies assessing pregnancy and menopause have also adjusted for putative confounding variables, we will also abstract this data using the REP to determine whether these sex-specific conditions are independent predictors of cognitive decline, AD, and neuroimaging measures of specific brain pathologies. Successful completion of these aims will be a key step towards understanding whether these sex-specific factors are associated with the risk of AD in women, to understanding whether these factors are related to a specific type of brain pathology (i.e., Aβ, neurodegeneration, cerebrovascular), and to developing a better risk score for predicting cognitive impairment, dementia, and specific brain changes in women.