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.

项目总结 这项申请是对PAR-21-212，阿尔茨海默病测序项目后续研究2.0的响应 (ADSP FUS 2.0)：人口多样化倡议。神经精神症状(NPS)(如攻击性、 精神病、焦虑、冷漠、抑郁、烦躁、睡眠障碍、重复行为)出现在85%的AD患者中 患者，并与加速下降，家庭外安置，增加成本，并大大 增加了患者和家属的痛苦。尽管如此，我们对AD中NPS的病因的理解是 不足，NPS的治疗往往无效，并与严重的不良反应有关 (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为严重 拉美裔和非裔美国人等群体，历史上遗传和表型有限 对AD的研究，尽管AD在这些种族中的流行程度是非西班牙裔白人的两倍。 为了开始解决AD基因组研究中缺乏多样性的问题，NIH/NIA已经开始了许多不同的 基因组学倡议，其中包括阿尔茨海默病测序项目(ADSP)及其后续研究 (ADSP-FUS)已组装并全基因组测序，来自不同祖先的约60,000个个体 背景(西班牙裔、非裔美国人、亚洲人、非西班牙裔白人)，现在正在协调过程中 这些人的认知、脑成像、神经病理和生物标记物数据。然而，目前还没有计划 收集、协调或分析为以下项目收集的与AD相关的重要NPS数据 样本。这是一个关键的疏忽，因为更好地理解AD中NPS的遗传基础，由 祖先背景，对于推断这些高度致残症状和 开发更有效的药理靶点。为了开始解决这一差距，我们建议(1)扩大 不同种族和族裔的ADSP-FUS数据集以及包括协调的核动力源数据的相关努力， 创建迄今为止AD中NPS上最大和最多样化的基因组资源(n=61,343)，使研究人员能够 通过这些资源评估广泛的附加批判性假设；(2)利用这些协调一致的资源 识别和描述特定NPS潜在的遗传决定因素、途径和多基因效应的数据 AD；(3)探索与AD相关的NPS和与初级精神病患者共享的遗传结构 疾病；以及(4)阐明血统在NPS遗传风险中的作用。