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

总结 女性可能更容易患阿尔茨海默病（AD）-病理学，然而，在AD的早期阶段， 在非文字记忆测试中的表现比病理水平相似的男性更好。尽管如此，尽管如此， 早期语言记忆优势，随着疾病的进展，女性表现出更快的认知能力下降。因此更 需要进行研究以更好地描述AD生物标志物进展中的性别差异， 认知弹性或易受AD病理学影响的机制。解决 这些关键的知识差距，我将利用我们正在进行的纵向生物标志物研究， 常染色体显性AD家系由于早老素-1基因（PSEN 1）中的单一突变（E280 A）。PSEN1 突变携带者在遗传上决定了他们会患上早发性痴呆，伴有轻度认知障碍 中位年龄为44岁，痴呆年龄为49岁。这一非凡的群体提供了机会， 研究AD的性别差异，几乎没有年龄相关的混淆和方法学挑战。为此中央 候选人建议：（1）培养目标建立性生物学专业知识，纵向和多元 建模和多模式神经成像数据，这些数据将进一步推动职业发展， AD的独立临床研究者;（2）研究目的是检查累积的性别差异 AD相关病理、神经退行性变和认知能力下降的可能性，以及类固醇激素在 常染色体显性AD;（3）导师和顾问团队，以确保候选人的成功， 在常染色体显性AD（Yakeel Quiroz博士）、生物学性别差异（Jill Goldstein博士）、散发性AD（Jill Goldstein博士）中， Reisa Sperling）、多模式神经影像学（Chen博士）、AD的性别特异性差异和风险（Michelle博士 Mielke），以及纵向和多变量建模（Hui Zheng博士）。拟议的具体目标是 确定：（1）性别对PSEN 1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PSEN 1突变携带者认知功能下降的影响;（3）类固醇激素的影响 PSEN 1突变携带者的AD生物标志物积累和认知能力下降。这项拟议的研究是 采用多模式研究常染色体显性AD的纵向性别差异 神经成像和检查类固醇激素在AD生物标志物异常和认知下降中的作用。 这项拟议中的研究意义重大，因为进一步了解性别差异对提供信息至关重要 预防研究、早期发现、临床试验设计和治疗开发。总体而言，这 项目和培训计划将促进候选人的职业发展， 一项研究计划，检查AD的性别差异，并阐明AD风险和恢复力的机制， 为精确干预和治疗提供信息。

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.