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Genetic Architecture of Alzheimer’s disease Proteinopathies

阿尔茨海默病的遗传结构蛋白质病

基本信息

批准号：
10581599
负责人：
Carlos Cruchaga
金额：
$ 189.59万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581599
关键词：
Acceleration Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid Amyloid beta-42 Amyloid beta-Protein Apolipoprotein E Automobile Driving Autopsy Bioinformatics Biological Biological Markers Brain Brain Diseases Cell model Cell physiology Cerebrospinal Fluid Clinical Data Data Set Dementia Disease Etiology Gene Expression Genes Genetic Genetic Variation Genetic study Genome Scan Genomics Genotype Goals Impaired cognition In Vitro Individual Intervention Magnetic Resonance Imaging Measures Mediation Mendelian randomization Methods Myeloid Cells National Institute on Aging Nature Nerve Degeneration Neurofibrillary Tangles Neuronal Injury Outcome Pathogenesis Pathologic Pathologic Processes Pathology Pathway interactions Persons Phase Phenotype Plasma Positron-Emission Tomography Preventive measure Proxy Public Health Quantitative Trait Loci Recommendation Research Research Subjects Risk Role Sampling Senile Plaques Signal Transduction Symptoms Testing Variant abeta deposition amyloid pathology biomarker validation clinical diagnosis comorbidity diagnostic value effective therapy endophenotype experimental study extracellular fluorodeoxyglucose positron emission tomography follow-up genetic architecture genetic association genetic information genetic variant genome sequencing genome wide association study improved interest neuroimaging neuropathology novel personalized medicine polygenic risk score population based pre-clinical prevent rare variant tau Proteins tau-1 whole genome

项目摘要

Project Summary/Abstract In order to enhance and focus research on Alzheimer's disease (AD)-specific proteinopathies, the 2018 research framework proposed by the National Institute on Aging and Alzheimer's Association (NIA-AA) recommends that AD be defined by its specific biological signatures that can be documented at autopsy or in living people by biomarkers rather than by its non-specific neurodegenerative and clinical syndromic features. Of the three proposed biomarkers by the NIA-AA research framework in living people (amyloid-beta (Aβ), pathologic tau and neurodegeneration), only the two AD-specific proteinopathies (Aβ and pathologic tau) are considered obligatory for the biological definition of AD, while neurodegeneration, although contribute to cognitive impairment and is part of the fully manifested disease, can also occur in other brain disorders and thus is not specific to AD. The purpose of this harmonized biological definition of AD in living people that includes the preclinical phase is to distinguish AD from other types of brain disorders and dementia, to accelerate and focus research on AD-specific proteinopathies that manifest decades before the clinical manifestation of first symptoms of AD, to enhance better understanding in the underlying mechanisms of AD clinical expression, and to use (and discover) targeted disease modifying interventions that can prevent or delay the onset of AD symptoms. Our ongoing and long-term research interest coincides well with the NIA-AA research framework in living people where we have already performed genome-wide association studies (GWAS) on CSF Aβ42/tau levels and Aβ deposition in the brain measured by amyloid-PET and identified known and novel associations in the APOE and non-APOE regions. However, the identified signals do not explain all of the phenotypic variation in the two AD-specific proteinopathies or endophenotypes. Here we propose a collaborative study between leading experts in the field to extend our ongoing efforts to delineate the complete genetic basis of the two AD- specific proteinopathies (Aβ and pathologic tau) by whole genome sequencing (WGS) using well-characterized and large amyloid-PET and CSF Aβ42/tau datasets with clinical outcomes of dementia followed by testing the effects of identified significant variants on downstream neurodegeneration markers, and performing extensive bioinformatics and functional studies. The primary objective of this application is to perform and analyze WGS in adequately powered large discovery samples with well-characterized Aβ and tau data along with clinical outcomes of dementia to identify putative functional variants associated with Aβ and tau pathologies followed by replications in independent and large samples with Aβ and tau data (Aims 1-2). We will integrate genetic information to create polygenic risk scores in order to predict Aβ and tau pathologies and will also examine the role of AD pathology-associated variants with downstream neurodegeneration, neuropathologies that coexist with AD and the risk and age-at-onset of AD (Aim3). Finally, we will functionally characterize genetic association using bioinformatics, causality tests and in vitro experiments to understand their roles in affecting gene expression as being expression quantitative traits loci, affecting intracellular and extracellular APP/Aβ and tau levels, and in myeloid cell function. The successful completion of this study will help to identify novel AD-related genes and pathways, and to uncover underlying possible mechanisms for AD.

项目总结/文摘