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:
- 金额:$ 74.13万
- 依托单位:
- 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:
- 关键词:AddressAlzheimer&aposs DiseaseAlzheimer&aposs disease diagnosisAlzheimer&aposs disease related dementiaAustraliaAutopsyBrainCerebral Amyloid AngiopathyCerebrovascular TraumaClinicClinicalCommunitiesComplexComplex MixturesDataData AnalysesData SetDementiaDiagnosticDiseaseElderlyEuropeGenesGeneticGenetic DiseasesGenetic Predisposition to DiseaseGenetic VariationGenetic studyGenomic approachGenomicsGenotypeGoalsHeritabilityImpaired cognitionIndividualInjuryJapanKnowledgeLesionLewy Body DiseaseMolecularNeurofibrillary TanglesPathologicPersonsPhenotypePopulationSample SizeSamplingSenile PlaquesTechniquesTestingVariantclinical diagnosiscomorbiditydensitygenetic variantgenome sequencinggenome-widehippocampal sclerosisneuropathologynext generation sequence datanovelprotein distributionresponse to injurytooltraitvariant of interestwhole 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
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
AI-enabled in silico immunohistochemical characterization for Alzheimer's disease.
- DOI:10.1016/j.crmeth.2022.100191
- 发表时间:2022-04-25
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Gary Wayne Beecham其他文献
Gary Wayne Beecham的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Gary Wayne Beecham', 18)}}的其他基金
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 - 财政年份:2023
- 资助金额:
$ 74.13万 - 项目类别:
Genomic Characterization of Alzheimer Disease Risk in Admixed Populations with Native American and Southern European Genetic Ancestry
美洲原住民和南欧遗传血统混合人群阿尔茨海默病风险的基因组特征
- 批准号:
10615046 - 财政年份:2021
- 资助金额:
$ 74.13万 - 项目类别:
Genomic Characterization of Alzheimer Disease Risk in Admixed Populations with Native American and Southern European Genetic Ancestry
美洲原住民和南欧遗传血统混合人群阿尔茨海默病风险的基因组特征
- 批准号:
10335250 - 财政年份:2021
- 资助金额:
$ 74.13万 - 项目类别:
Dissecting the Genomic Etiology of non-Mendelian Early-Onset Alzheimer Disease and Related Phenotypes
剖析非孟德尔早发性阿尔茨海默病的基因组病因学及相关表型
- 批准号:
10412088 - 财政年份:2019
- 资助金额:
$ 74.13万 - 项目类别:
Dissecting the Genomic Etiology of non-Mendelian Early-Onset Alzheimer Disease and Related Phenotypes
剖析非孟德尔早发性阿尔茨海默病的基因组病因学及相关表型
- 批准号:
10667461 - 财政年份:2019
- 资助金额:
$ 74.13万 - 项目类别:
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
- 批准号:
10372972 - 财政年份:2019
- 资助金额:
$ 74.13万 - 项目类别:
Dissecting the Genomic Etiology of non-Mendelian Early-Onset Alzheimer Disease and Related Phenotypes
剖析非孟德尔早发性阿尔茨海默病的基因组病因学及相关表型
- 批准号:
9811242 - 财政年份:2019
- 资助金额:
$ 74.13万 - 项目类别:
National Institute on Aging Alzheimer's Disease Family-Based Study (NIA-AD FBS)
国家老年阿尔茨海默病家庭研究研究所 (NIA-AD FBS)
- 批准号:
10355812 - 财政年份:2017
- 资助金额:
$ 74.13万 - 项目类别:
Genetic Epidemiology of Early-Onset Alzheimers disease in Caribbean Hispanics and non-Hispanic Whites
加勒比西班牙裔和非西班牙裔白人早发性阿尔茨海默病的遗传流行病学
- 批准号:
9194817 - 财政年份:2016
- 资助金额:
$ 74.13万 - 项目类别:
Genomic Characterization of Alzheimer's Disease Risk in the Puerto Rican Population
波多黎各人群阿尔茨海默病风险的基因组特征
- 批准号:
9194733 - 财政年份:2016
- 资助金额:
$ 74.13万 - 项目类别: