Early Cognitive Impairment as a Function of Alzheimer’s Disease Genes and Trauma

阿尔茨海默病基因和创伤导致的早期认知障碍

• 批准号: 10355411
• 负责人: MARK W LOGUE
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355411
• 关键词: Age; Age of Onset; Aging; Algorithms; Alzheimer' s Disease; Alzheimer' s disease risk; Brain region; Candidate Disease Gene; Cognitive; Cox Proportional Hazards Models; Data; Dementia; Development; Diagnosis; Diagnostic; Early Diagnosis; Early identification; Early treatment; Environment; Environmental Exposure; Genes; Genetic; Genetic Risk; Genotype; Impaired cognition; Individual; Intervention; Investigation; Late Onset Alzheimer Disease; Lead; Life Style; Magnetic Resonance Imaging; Measures; Medical Records; Memory; Methods; Molecular; Neurobehavioral Manifestations; Neurologic Effect; Onset of illness; Participant; Pathology; Patient Self-Report; Performance; Phenotype; Post-Traumatic Stress Disorders; Price; Protein Isoforms; Psychiatry; Recording of previous events; Risk; Risk Factors; Sampling; Severities; Stress; Surveys; Symptoms; Testing; Thick; Time; Trauma; Traumatic Brain Injury; Variant; Veterans; age related; apolipoprotein E-4; base; cognitive function; cognitive performance; cognitive testing; combat; combat trauma; comorbidity; dementia risk; design; detection method; disorder risk; effective therapy; gene environment interaction; gene function; genetic risk factor; genetic variant; genome wide association study; genome-wide; human old age (65+); improved; interest; longitudinal design; middle age; mild cognitive impairment; mild traumatic brain injury; military trauma; military veteran; polygenic risk score; risk variant; symptomatology; trauma exposure; traumatic stress

Late-onset Alzheimer’s disease (AD) is the most common form of age-related dementia. PTSD and dementia co-occur more often than expected by chance. One potential reason for this comorbidity is that AD genes may influence the risk for both AD and PTSD. APOE, the strongest AD genetic risk factor, has also been implicated as a risk factor for combat-related PTSD. The initial effects of these genes may be apparent in middle age, ahead of the usual age of AD onset. Our recent MRI study found that an AD polygenic risk score (PRS; a genome-wide summary measure of genetic risk) by mild traumatic brain injury (mTBI) interaction was associated with cortical thickness and memory performance in a VA sample with mean age 35. In this project, we will use Million Veterans Project data to examine association between AD risk genes and early cognitive function deficits and PTSD symptomatology. Our AD genetic risk measures will include a genome-wide measure of AD risk (PRS), APOE genotypes, and AD GWAS implicated variants in genes such as ABCA7, CLU, and TNXRD1. We will evaluate the potential gene x environment (GxE) effects between AD genes and TBI and combat trauma exposure. As early detection of AD risk may be critical for treatment, we will be especially interested in identifying cognitive phenotypes associated with AD risk ahead of the typical age of onset. Hence, we will perform analyses within three age strata: early middle age (45-54), late middle age (55-64), and old age (65+). Our measures of cognitive performance will include the presence/absence of a cognitive impairment diagnosis in the medical record and factor scores computed from self-reported cognitive impairment (MVP Lifestyle Survey Items) which we will validate using available cognitive testing data from the medical record (e.g. MMSE and MOCA). Next, we will examine the potential impact of AD genes on PTSD risk as well as potential GxE interactions involving trauma and TBI. Finally, we will use a retrospective longitudinal design to determine if AD gene x TBI and trauma interactions impact the progression to AD. With nearly half of all veterans over age 65, and many at risk for cognitive impairment and subsequent AD, it is critical to advance methods for early identification and treatment of cognitive symptoms and dementia. Understanding the interaction between genetic risk and history of military trauma will be essential for tailoring early detection methods to a veteran population. !

晚期的阿尔茨海默氏病（AD）是与年龄有关的痴呆症最常见的形式。 PTSD 和痴呆症同时发生的频率比偶然的预期更频繁。一个潜在的原因 合并症是AD基因可能会影响AD和PTSD的风险。 Apoe，坚强 AD遗传危险因素也已被视为与战斗有关的PTSD的危险因素。 这些基因的初始影响在中年可能是显而易见的，紧随AD发作的年龄。 我们最近的MRI研究发现AD多基因风险评分（PRS；全基因组摘要 轻度创伤性脑损伤（MTBI）相互作用的遗传风险度量与 平均年龄35岁的VA样本中的皮质厚度和记忆性能。在此项目中， 我们将使用数百万退伍军人项目数据来检查广告风险基因与早期之间的关联 认知功能定义了PTSD症状学。我们的AD遗传风险措施将包括 全基因组风险（PRS），APOE基因型和AD GWAS实施变体的测量 在诸如ABCA7，CLU和TNXRD1之类的基因中。我们将评估潜在的基因X环境 （GXE）AD基因与TBI和战斗创伤暴露之间的影响。作为AD的早期检测 风险可能对治疗至关重要，我们将特别有兴趣识别认知 在典型发作时代之前，与AD风险相关的表型。因此，我们将表演 三个年龄阶段的分析：中年早期（45-54），中年晚期（55-64）和老年 （65+）。我们的认知表现衡量标准将包括存在/不存在认知能力 病历中的损伤诊断和根据自我报告计算的因素得分 认知障碍（MVP生活方式调查项目）我们将使用可用的认知验证 从病历（例如MMSE和MOCA）中测试数据。接下来，我们将研究潜力 AD基因对PTSD风险以及涉及创伤和TBI的潜在GXE相互作用的影响。 最后，我们将使用回顾性纵向设计来确定AD基因X TBI和创伤是否是否 相互作用会影响AD的发展。在65岁以上的所有退伍军人中，几乎一半 面临认知障碍和随后的广告的风险，提前进步的方法至关重要 认知症状和痴呆症的鉴定和治疗。了解互动 在遗传风险和军事创伤历史之间对于调整早期发现至关重要 资深人口的方法。