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Identifying the Genetic Etiology of Neuropathology for Alzheimer Disease and Related Dementias

确定阿尔茨海默病和相关痴呆症神经病理学的遗传病因

基本信息

批准号：
10612832
负责人：
Gary Wayne Beecham
金额：
$ 74.13万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612832
关键词：
Address Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease related dementia Australia Autopsy Brain Cerebral Amyloid Angiopathy Cerebrovascular Trauma Clinic Clinical Communities Complex Complex Mixtures Data Data Analyses Data Set Dementia Diagnostic Disease Elderly Europe Genes Genetic Genetic Diseases Genetic Predisposition to Disease Genetic Variation Genetic study Genomic approach Genomics Genotype Goals Heritability Impaired cognition Individual Injury Japan Knowledge Lesion Lewy Body Disease Molecular Neurofibrillary Tangles Pathologic Persons Phenotype Population Sample Size Sampling Senile Plaques Techniques Testing Variant clinical diagnosis comorbidity density genetic variant genome sequencing genome-wide hippocampal sclerosis neuropathology next generation sequence data novel protein distribution response to injury tool trait variant of interest whole genome

项目摘要

PROJECT SUMMARY Multiple population and community based studies conducted across the US, Europe, Japan, and Australia all have repeatedly observed complex neuropathologic changes in individuals with a clinical diagnosis of Alzheimer's disease (AD) dementia. Although usually including neuritic plaques (NP) and neurofibrillary tangles (NFT), the regional levels and extent of distribution of these hallmark lesions are variable. Additionally, more than half of individuals with AD dementia have other comorbid lesions in brain that when present in isolation can be diagnostic of dementia—the AD-Related Dementias (ADRDs). These include cerebral amyloid angiopathy (CAA), vascular brain injury (VBI), Lewy body disease (LBD), and hippocampal sclerosis of the elderly (HS), among others. Indeed, individuals with a clinical diagnosis of AD dementia frequently show a complex mix of AD lesions and comorbid lesions, making it unclear the extent to which each contributed to cognitive decline and dementia in that person. We hypothesize that the mechanisms of injury and response to injury that produce these different disease-specific brain lesions are influenced by differing genetic factors. With few exceptions, genetic studies for AD have associated genetic variants with a clinical diagnosis of AD dementia. The comorbid complexity described above is a serious limitation to interpreting these data. Are the associations with AD dementia related to the hallmark lesions of AD (common assumption), the variably present comorbid lesions, or both? Only two studies have attempted to address this limitation. As a core analysis of the Alzheimer Disease Genetics Consortium (U01AG032984), our study of AD neuropathologic changes was the larger of these studies with approximately 4900 brain autopsies. However, even this initial study was limited by sample size, platform, and less sophisticated analysis tools. To address these limitations and to advance our knowledge of the full spectrum of dementia neuropathology, we propose a genomics study of hallmark AD lesions together with comorbid lesions associated with ADRDs. This study will expand the sample size of neuropathology subjects, will expand efforts to include next-generation sequence data, and will implement more advanced statistical techniques to better understand the relationships between traits. When successfully completed, our results will point to novel, relevant molecular contributors for each of the pathologic lesions of AD or ADRDs, either alone or in combination. To accomplish these goals we propose four Specific Aims. SA1: Identify genetic variants associated with hallmark AD lesions by whole genome sequencing and genome-wide genotyping; SA2: Identify genetic variants associated with comorbid lesions commonly present in brains of older individuals; SA3: Determine the inter-trait genetic landscape by assessing confounding and genetic correlations across traits; and, SA4: Determine regional, cellular, and lesion distribution of protein products of selected genes identified in SA1-2.

项目总结