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

检查性别和激素对常染色体显性阿尔茨海默病进展的影响

• 批准号: 10449410
• 负责人: Clara Vila Castelar
• 金额: $ 13.51万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10449410
• 关键词: Address; Age; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Atrophic; Biological Markers; Biology; Blood; Brain; Brain Pathology; Brain region; Clinical; Clinical Trials Design; Cognitive; Data; Dementia; Development Plans; Disease; Early Diagnosis; Ensure; Estrogens; Exhibits; Family member; Female; Genes; Glucose; Goals; Gonadal Steroid Hormones; Hippocampus (Brain); Hormonal Change; Hysterectomy; Impaired cognition; Individual; Knowledge; Link; Medial; Mediating; Memory; Menopause; Mentors; Methodology; Modeling; Mutation; Nerve Degeneration; Ovariectomy; Pathology; Precision therapeutics; Predisposition; Prevention; Progesterone; Research; Research Personnel; Risk; Risk Factors; Role; Sex Differences; Strategic Planning; Symptoms; Temporal Lobe; Testing; Testosterone; Thick; Training; United States National Institutes of Health; Women' s Health; age related; autosomal dominant Alzheimer' s disease; base; biological sex; career; career development; cognitive performance; cohort; dementia risk; early onset; female sex hormone; follow up assessment; hippocampal atrophy; innovation; kindred; male; mild cognitive impairment; mortality; multidisciplinary; multimodal neuroimaging; mutation carrier; personalized intervention; pre-clinical; presenilin-1; programs; progression marker; protective factors; resilience; sex; steroid hormone; success; tau Proteins; tau aggregation; therapy development; virtual; β-amyloid burden

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.

概括 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，女性 尽管如此，在言语记忆测试中，男性的表现仍优于具有相似病理水平的男性。 早期语言记忆有优势，随着疾病的进展，女性表现出更快的认知衰退。 需要研究来更好地描述 AD 生物标志物进展中的性别差异，并阐明潜在的 整个疾病谱中 AD 病理学的认知弹性或脆弱性机制。 这些知识上的关键差距，我将利用我们正在进行的最大的纵向生物标志物研究 由于 Presenilin-1 基因 (PSEN1) 的单一突变 (E280A)，常染色体显性 AD 家族。 基因突变携带者会患上早发性痴呆，并伴有轻度认知障碍 中位年龄为 44 岁，痴呆症发病年龄为 49 岁。这个非凡的群体提供了机会 研究 AD 中的性别差异，几乎没有与年龄相关的混淆和方法学挑战。 候选人建议：（1）培训目标是建立性生物学、纵向和多元方面的专业知识 建模和多模态神经影像数据，这些数据共同将进一步推动职业发展 AD 的独立临床研究者；（2）研究目标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研究，以及类固醇激素在 常染色体显性 AD；(3) 拥有专业知识的导师和顾问团队，以确保候选人的成功 常染色体显性 AD（Yakeel Quiroz 博士）、生物性别差异（Jill Goldstein 博士）、散发性 AD（Dr. Reisa Sperling）、多模式神经影像学（陈博士）、AD 中的性别特异性差异和风险（米歇尔博士） Mielke）以及纵向和多元建模（郑辉博士）提出的具体目标是 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； 性别和 AD 生物标志物对 PSEN1 突变携带者认知能力下降的影响 (3) 类固醇激素的影响； 这项研究是关于 PSEN1 突变携带者 AD 生物标志物积累和认知能力下降的研究。 使用多模式研究常染色体显性 AD 的纵向性别差异的创新 神经影像学并检查类固醇激素在 AD 生物标志物异常和认知能力下降中的作用。 拟议的研究意义重大，因为进一步了解性别差异对于提供信息至关重要 总体而言，这涉及预防、早期检测、临床试验设计和治疗开发的研究。 项目和培训计划将通过促进独立的候选人的职业发展 一项研究 AD 性别差异并阐明 AD 风险机制和恢复力的研究计划 为精准干预和治疗提供信息。