Examining the impact of sex and hormones on the progression of autosomal dominant Alzheimer's disease

摘要 女性可能更容易患阿尔茨海默病(AD)-病理，然而，在AD的早期阶段，女性 在言语记忆测试中，与病理水平相近的男性相比，男性表现得更好。尽管如此，尽管如此， 早期的言语记忆优势，随着疾病的进展，女性表现出更快的认知衰退。因此，更多 需要研究来更好地表征AD生物标记物进展中的性别差异，并阐明潜在的 整个疾病谱的认知恢复力或对AD病理的易感性的机制。致信地址 这些关键的知识差距，我将利用我们正在进行的最大规模的纵向生物标志物研究 常染色体显性遗传性AD家系源于早老素-1基因(PSEN1)的单一突变(E280A)。PSEN1 基因突变携带者会患上早发性痴呆，并伴有轻度认知障碍 出现的年龄中值为44岁，痴呆症的年龄中值为49岁。这一非凡的群体提供了一个机会 检查AD患者的性别差异，很少有与年龄相关的混淆和方法学挑战。为此， 候选人建议：(1)培训目标：建立纵向和多变量的性生物学专业知识 建模和多模式神经成像数据，这些共同将进一步发展为 AD的独立临床研究人员；(2)研究目的：检验性别差异在AD中的积累 与AD相关的病理、神经退行性变和认知能力下降，以及类固醇激素在 常染色体显性AD；(3)确保候选人成功的导师和顾问团队，具有专业知识 常染色体显性AD(Yakeel Quiroz博士)、生物学性别差异(Jill Goldstein博士)、散发性AD(Dr. Reisa Sperling)，多模式神经成像(陈博士)，性别差异和AD风险(米歇尔博士 Mielke)，以及纵向和多变量模型(郑辉博士)。拟议的具体目标是 确定：(1)性别对PSEN1突变携带者AD相关病理和神经变性的影响；(2) 性别和AD生物标志物对PSEN1突变携带者认知功能减退的影响；(3)类固醇激素的影响 PSEN1突变携带者AD生物标志物积聚与认知功能减退的研究这项拟议的研究是 用多模式研究常染色体显性AD纵向性别差异的创新 神经成像和研究类固醇激素在AD生物标记物异常和认知功能下降中的作用。 这项拟议的研究意义重大，因为进一步了解性别差异对于了解 研究预防、早期发现、临床试验设计和治疗方法的开发。总体而言，这 项目和培训计划将促进候选人的职业发展，通过促进独立 研究项目考察AD的性别差异，阐明AD的风险和抗逆机制 告知精准干预和治疗。

Summary Females may be more susceptible to Alzheimer’s disease (AD)-pathology, yet, in the early stages of AD, females perform better on verbal memory tests than males with similar levels of pathology. Nonetheless, despite this early verbal memory advantage, as disease progresses, females show faster cognitive decline. Thus, more research is needed to better characterize sex differences in AD biomarker progression, and to clarify potential mechanisms of cognitive resiliency or vulnerability to AD-pathology across the disease spectrum. To address these critical knowledge gaps, I will capitalize on our ongoing longitudinal biomarker study with the largest autosomal dominant AD kindred due to a single mutation (E280A) in the Presenilin-1 gene (PSEN1). PSEN1 mutation carriers are genetically determined to develop early-onset dementia, with mild cognitive impairment emerging at a median age of 44 and dementia at age 49. This extraordinary cohort offers the opportunity to examine sex differences in AD with few age-related confounds and methodological challenges. To this end, the candidate proposes: (1) training objectives to establish expertise in sex biology, longitudinal and multivariate modeling, and multimodal neuroimaging data, which together will further career development into an independent clinical researcher in AD; (2) a research objective to examine sex differences in the accumulation of AD-related pathology, neurodegeneration, and cognitive decline, and the potential role of steroid hormones in autosomal dominant AD; (3) a team of mentors and advisors to ensure the candidate’s success, with expertise in autosomal dominant AD (Dr. Yakeel Quiroz), biological sex differences (Dr. Jill Goldstein), sporadic AD (Dr. Reisa Sperling), multimodal neuroimaging (Dr. Chen), sex-specific differences and risk in AD (Dr. Michelle Mielke), and longitudinal and multivariate modeling (Dr. Hui Zheng). The proposed specific aims are to determine the: (1) effect of sex on AD-related pathology and neurodegeneration in PSEN1 mutation carriers; (2) effect of sex and AD biomarkers on cognitive decline in PSEN1 mutation carriers; (3) effect of steroid hormones on AD biomarker accumulation and cognitive decline in PSEN1 mutation carriers. This proposed research is innovative for investigating longitudinal sex differences in autosomal dominant AD using multimodal neuroimaging and examining the role of steroid hormones in AD biomarker abnormalities and cognitive decline. The proposed research is significant because further understanding of sex differences is crucial to inform research on prevention, early detection, design of clinical trials, and development of treatments. Overall, this project and training plan will promote the candidate’s career development by facilitating an independent program of research examining sex differences in AD and elucidating mechanisms of AD risk and resilience to inform precision interventions and treatments.