Reproductive risk factors for Alzheimer's disease dementia and pathology

项目摘要/摘要 最近的估计表明，几乎三分之二的阿尔茨海默病患者[AD] 都是女人。美国国立卫生研究院和阿尔茨海默氏症协会强调了这一迫切需要 了解阿尔茨海默病的危险因素和临床进展的性别差异。生殖和荷尔蒙 这些因素对女性来说可能特别重要。高血压妊娠障碍[HPD]一直是 与主观认知主诉或白质损害有关，但HPD后5至10年 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(即先兆子痫)对认知功能下降、AD、 以及淀粉样β蛋白[Aβ]、神经退行性变和脑血管病理的神经成像测量。 此外，观察性研究和临床试验检验了早期绝经(自然或绝经)的影响。 手术诱导的)和激素治疗[HT]对AD和其他痴呆症的风险。然而，它并不是 目前已知的是，绝经早期的影响，羟色胺的使用，以及它们与载脂蛋白E基因的相互作用， 与特定类型(S)的脑病理(即Aβ、神经退行性变、脑血管病变)有关，因为 尚未进行多模式成像研究。这项建议的总体目标是澄清 两个与荷尔蒙相关的性别特定因素对妇女的影响，怀孕(如怀孕次数， HPD)和绝经(手术引起或自然绝经)对认知衰退、AD和神经成像风险的影响 Aβ、神经退行性变和脑血管病理的测量。因为文学和我们的 初步数据显示，女性患心血管疾病和痴呆症的风险分数较低。 与男性相比，我们还建议纳入这些性别特有的因素，以开发更具预测性的风险 女性轻度认知功能障碍和AD评分。为了实现我们的目标，我们将利用现有的两个 梅奥诊所的基础设施：梅奥老年诊所研究(MCSA；U01 AG006786)和罗切斯特 流行病学项目病历-链接系统(REP；R01 AG034676)。使用代表，我们将全新 2,370名参加妇幼保健服务的妇女的怀孕和更年期信息摘要。因为很少有人 评估怀孕和更年期的研究也调整了假定的混杂变量，我们将 还可以使用REP来抽象此数据，以确定这些特定性别的条件是否独立 认知衰退、阿尔茨海默病和特定大脑病理的神经成像测量的预测因子。成功 完成这些目标将是了解这些特定性别的因素是否 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(即，β、神经变性、脑血管)的风险，并制定更好的风险评分 预测女性的认知障碍、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.