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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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