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.

项目摘要 本申请是对PAR-21-212，阿尔茨海默病测序项目随访研究2.0的回应 (ADSP FUS 2.0：多样化人口倡议。神经精神症状（Neuropsychiatric Symptoms）（例如攻击性， 精神病、焦虑、冷漠、抑郁、激越、睡眠障碍、重复行为）发生在85%的AD中 患者，并与加速下降，离家安置，增加成本，大大 增加了患者和家属的痛苦。尽管如此，我们对AD患者的病因学的理解是， 不充分，对腹泻的治疗往往无效，并伴有严重的不良反应 （包括死亡率上升）。这种知识差距在服务不足的种族和族裔群体中尤为严重。 像西班牙裔和非洲裔美国人这样的群体，历史上他们的遗传和表型都很有限， 虽然AD在这些种族群体中的流行率是非西班牙裔白人的两倍。 为了开始解决AD基因组学研究中缺乏多样性的问题，NIH/NIA已经开始了许多不同的研究。 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）已经组装和全基因组测序了约60，000个不同祖先的个体， 背景（西班牙裔，非洲裔美国人，亚洲人，非西班牙裔白色），现在正在协调的过程中 这些个体的认知、脑成像、神经病理学和生物标志物数据。然而，没有计划 收集、协调或分析已收集的与广告相关的重要广告数据， 样品这是一个关键的疏忽，因为更好地了解AD中的遗传基础， 祖先的背景，是至关重要的，以推断这些高度致残的症状， 开发更有效的药理学靶点。为了开始解决这一差距，我们建议（1）扩大 ADSP-FUS的种族和族裔多样性数据集以及为纳入统一的可持续发展数据而作出的相关努力， 创建了迄今为止最大和最多样化的AD基因组资源（n= 61，343）， 通过这些资源评估广泛的其他关键假设;（2）利用这些统一的 识别和描述遗传决定因素、途径和多基因效应的数据， （3）探讨AD相关性脑卒中和原发性精神病患者共有的遗传结构 疾病;（4）解开祖先在遗传风险中的作用。