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 该应用是对PAR-21-212的响应，阿尔茨海默氏病测序项目后续研究2.0 （ADSP FUS 2.0）：多样化的人口倡议。神经精神症状（NP）（例如侵略性， 精神病，焦虑，冷漠，抑郁，躁动，睡眠障碍，重复行为）发生在85％的AD 患者，并且与加速下降，室外安置，成本增加以及大大相关 患者和家庭的苦难增加。尽管如此，我们对AD中NP的病因的理解是 不充分 （包括死亡率增加）。在服务不足的赛车和种族中，这种知识差距尤其明显 西班牙裔和非裔美国人等群体，历史上的遗传和表型有限 与非西班牙裔白人相比，在这些种族中，AD的研究最多是这些族裔的两倍。 为了开始解决AD基因组学研究中缺乏多样性，NIH/NIA已经开始了许多潜水员 在这些阿尔茨海默氏病测序项目（ADSP）及其后续研究中，基因组学计划 （adsp-fus）组装和全基因组，测序了约60,000个潜水员的个体 背景（西班牙裔，非裔美国人，亚洲人，非西班牙裔白色），现在正在和谐 这些个体的认知，脑成像，神经病理学和生物标志物数据。但是，没有计划 收集，协调或分析已收集的重要AD相关的NPS数据 样品。这是一个关键的监督，作为对AD中NP遗传基础的更好理解， 祖先背景对于推断这些高度残疾症状和的机械途径至关重要 开发更有效的药物目标。为了开始解决这一差距，我们建议（1）扩展 种族和种族多样性的ADSP-FU的数据集以及相关的努力，包括统一的NPS数据， 迄今为止，在广告中创建最大和最潜水员的基因组资源（n = 61,343）允许研究人员 通过这些资源评估广泛的额外关键假设； （2）利用这些协调 数据以识别和描述遗传决定剂，途径和多基因效应 广告; （3）探索跨广告相关的NP和主要精神病学的共享遗传结构 疾病； （4）解除祖先在NPS遗传风险中的作用。