Genetic and neuroanatomical basis of neuropsychiatric symptoms in Alzheimer's disease in populations of diverse ancestry

不同血统人群中阿尔茨海默病神经精神症状的遗传和神经解剖学基础

• 批准号: 10567606
• 负责人: Gary Wayne Beecham
• 金额: $ 79.06万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567606
• 关键词: Acceleration; Address; Adverse effects; African American; African American population; Aggressive behavior; Agitation; Alzheimer' s Disease; Alzheimer' s disease patient; Anxiety; Asian; Awareness; Biological Markers; Brain imaging; Candidate Disease Gene; Cognitive; Cohort Studies; Collection; Complement; Data; Data Set; Dementia; Ethnic Population; Etiology; Family; Follow-Up Studies; Future; Genes; Genetic; Genetic Determinism; Genetic Risk; Genomic Segment; Genomic approach; Genomics; Goals; Heritability; Hispanic; Hispanic Americans; Home; Individual; Knowledge; Latino; Mendelian randomization; Mental Depression; Mental disorders; Modeling; Molecular; Neuroanatomy; Not Hispanic or Latino; Pathway Analysis; Pathway interactions; Patients; Pharmacological Treatment; Phenotype; Population; Population Heterogeneity; Process; Psychiatric Diagnosis; Psychoses; Research Personnel; Resources; Risk; Role; Sampling; Severities; Sleep disturbances; Structure; Underserved Population; United States National Institutes of Health; Variant; admixture mapping; cohort; cost; data harmonization; disabling symptom; druggable target; ethnic diversity; genetic architecture; genetic risk factor; genetic variant; genome resource; genome-wide; genomic data; health disparity; improved; in silico; mortality; neuropathology; neuropsychiatric symptom; neuropsychiatry; novel; pharmacologic; racial diversity; racial population; repetitive behavior; response; segregation; trait; whole genome

PROJECT SUMMARY This application is in response to PAR-21-212, Alzheimer’s Disease Sequencing Project Follow-Up Study 2.0 (ADSP FUS 2.0): The Diverse Population Initiative. Neuropsychiatric Symptoms (NPS) (e.g. aggression, psychosis, anxiety, apathy, depression, agitation, sleep disturbances, repetitive behaviors) occur in 85% of AD patients, and are associated with accelerated decline, out-of-home placement, increased costs, and greatly increased suffering of patients and families. Despite this, our understanding of the etiology of NPS in AD is inadequate, with treatments for NPS often being ineffective and associated with serious adverse effects (including increased mortality). This knowledge gap is particularly egregious in underserved racial and ethnic groups such as Hispanics and African-Americans, which historically have had limited genetic and phenotypic studies of AD, although AD is up to twice as prevalent in these ethnic groups compared to non-Hispanic Whites. To begin addressing this lack of diversity in AD genomics studies, the NIH/NIA has begun a number of diverse genomics initiatives, among these the Alzheimer Disease Sequencing Project (ADSP) and its Follow-Up-Study (ADSP-FUS) which have assembled and whole-genome sequenced ~60,000 individuals of diverse ancestral background (Hispanic, African American, Asian, non-Hispanic White) and are now in the process of harmonizing cognitive, brain imaging, neuropathological and biomarker data on these individuals. There is, however, no plan to collect, harmonize, or analyze the important AD-associated NPS data that has been collected for these samples. This is a critical oversight, as a better understanding of the genetic basis of NPS in AD, informed by ancestral background, is vital to infer the mechanistic pathways underlying these highly disabling symptoms and develop more effective pharmacological targets. To begin addressing this gap, we propose to (1) expand the racially and ethnically diverse datasets of the ADSP-FUS and related efforts to include harmonized NPS data, creating the largest and most diverse genomic resource on NPS in AD to date (n=61,343) allowing researchers to assess a wide range of additional critical hypotheses through these resources; (2) utilize these harmonized data to identify and describe genetic determinants, pathways, and polygenic effects underlying specific NPS in AD; (3) explore the shared genetic architecture across AD-associated NPS and with primary psychiatric disorders; and (4) disentangle the role of ancestry in NPS genetic risk.

项目概要 此应用程序是为了响应 PAR-21-212（阿尔茨海默病测序项目后续研究 2.0） (ADSP FUS 2.0)：多样化人口倡议 (NPS)（例如攻击性、 85% 的 AD 患者会出现精神病、焦虑、冷漠、抑郁、烦躁、睡眠障碍、重复性行为 患者，并与加速衰退、外出安置、成本增加以及极大的 尽管如此，我们对 AD 中 NPS 病因的理解仍然是增加的。 不充分，NPS 治疗往往无效，并伴有严重的不良反应 （包括死亡率增加）。这种知识差距在服务不足的种族和民族中尤其严重。 西班牙裔和非裔美国人等群体在历史上的遗传和表型有限 尽管 AD 在这些族裔群体中的患病率是非西班牙裔白人的两倍。 为了开始解决 AD 基因组学研究缺乏多样性的问题，NIH/NIA 已经开始了一系列不同的研究 基因组学计划，其中包括阿尔茨海默病测序项目 (ADSP) 及其后续研究 （ADSP-FUS）已组装了约 60,000 个不同祖先的个体并进行了全基因组测序 背景（西班牙裔、非裔美国人、亚洲人、非西班牙裔白人），目前正在协调中 然而，目前还没有关于这些人的认知、脑成像、神经病理学和生物标志物数据的计划。 收集、协调或分析为这些目的收集的与 AD 相关的重要 NPS 数据 这是一个重要的疏忽，因为可以更好地了解 AD 中 NPS 的遗传基础。 祖先背景对于推断这些高度致残症状背后的机制途径至关重要 为了开始解决这一差距，我们建议（1）扩大范围。 ADSP-FUS 的种族和族裔多样化数据集以及纳入统一 NPS 数据的相关工作， 创建迄今为止 AD 领域 NPS 上最大、最多样化的基因组资源 (n=61,343)，使研究人员能够 (2) 利用这些统一的 识别和描述特定 NPS 背后的遗传决定因素、途径和多基因效应的数据 AD；(3) 探索 AD 相关 NPS 和原发性精神病学的共同遗传结构 (4) 理清血统在 NPS 遗传风险中的作用。