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: 9899737
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899737
• 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; Military Personnel; Molecular; Neurobehavioral Manifestations; Neurologic Effect; Onset of illness; Participant; Pathology; Patient Self-Report; Performance; Phenotype; Population; 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; comorbidity; dementia risk; design; 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; 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. !

晚发性阿尔茨海默病 (AD) 是最常见的与年龄相关的痴呆症。创伤后应激障碍 和痴呆症同时发生的几率比预期的要高。造成这种情况的一个潜在原因 共病是 AD 基因可能会影响 AD 和 PTSD 的风险。 APOE最强 AD 遗传风险因素也被认为是与战斗相关的创伤后应激障碍 (PTSD) 的风险因素。这 这些基因的最初影响可能在中年时显现出来，早于 AD 的通常发病年龄。 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）相互作用与遗传风险的测量）相关 平均年龄 35 岁的 VA 样本中的皮质厚度和记忆表现。在该项目中， 我们将使用百万退伍军人项目数据来检查 AD 风险基因与早期疾病之间的关联 认知功能缺陷和 PTSD 症状。我们的 AD 遗传风险措施将包括 AD 风险 (PRS)、APOE 基因型和 AD GWAS 相关变异的全基因组测量 存在于 ABCA7、CLU 和 TNXRD1 等基因中。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 的早期发现 风险可能对治疗至关重要，我们对识别认知能力特别感兴趣 在典型发病年龄之前与 AD 风险相关的表型。因此，我们将执行 三个年龄段的分析：中年早期（45-54岁）、中年晚期（55-64岁）和老年 （65+）。我们对认知表现的衡量将包括认知能力的存在/不存在 病历中的损伤诊断和根据自我报告计算的因素评分 认知障碍（MVP 生活方式调查项目），我们将使用可用的认知进行验证 来自医疗记录的测试数据（例如 MMSE 和 MOCA）。接下来我们将考察潜力 AD 基因对 PTSD 风险的影响以及涉及创伤和 TBI 的潜在 GxE 相互作用。 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 相互作用影响 AD 的进展。近一半的退伍军人年龄超过 65 岁，而且许多人 由于存在认知障碍和随后的 AD 风险，因此推进早期预防方法至关重要 认知症状和痴呆症的识别和治疗。了解交互 遗传风险和军事创伤史之间的关系对于制定早期检测至关重要 退伍军人群体的方法。 ！