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

晚发性阿尔茨海默病(AD)是年龄相关性痴呆最常见的形式。创伤后应激障碍 与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基因可能影响AD和PTSD的风险。最强的APOE AD遗传风险因素也被认为是战斗相关创伤后应激障碍的风险因素。这个 这些基因的最初影响可能在中年时明显，比通常的AD发病年龄更早。 我们最近的核磁共振研究发现，AD多基因风险评分(PRS；全基因组总结) 通过轻度创伤性脑损伤(MTBI)的交互作用与 平均年龄为35岁的VA样本的皮质厚度和记忆表现。在这个项目中， 我们将使用百万退伍军人项目的数据来检查AD风险基因和早期 认知功能缺陷和创伤后应激障碍症状学。我们的AD遗传风险措施将包括 阿尔茨海默病风险(PR)、载脂蛋白E基因类型和AD相关变异的全基因组测量 在ABCA7、CLU和TNXRD1等基因中。我们将评估潜在的基因x环境。 (GxE)AD基因与颅脑损伤及战斗创伤暴露的关系。作为AD的早期检测 风险可能是治疗的关键，我们将特别感兴趣的是识别认知 与AD风险相关的表型早于典型的发病年龄。因此，我们将表演 三个年龄层次的分析：中年早期(45-54岁)、中年晚期(55-)和老年 (65+)。我们对认知表现的测量将包括认知能力的存在/不存在 病历中的损害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功能进行验证 医疗记录中的测试数据(例如MMSE和MOCA)。接下来，我们将研究一下潜在的 AD基因对创伤后应激障碍风险的影响以及与创伤和脑外伤相关的潜在GxE相互作用。 最后，我们将使用回溯性纵向设计来确定AD基因xTBI与创伤 相互作用会影响到AD的进展。近一半的退伍军人年龄在65岁以上，还有许多人 面临认知损害和随后的阿尔茨海默病的风险，关键是改进早期治疗方法 认知症状和痴呆的识别和治疗。了解互动 遗传风险和军事创伤病史之间的关系对于早期发现至关重要 方法给退伍军人群体。好了！

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. !