Genetic and Lifestyle Determinants of Cognitive Resilience in Midlife

 描述（由申请人提供）：年龄增长和载脂蛋白E ε4（APOE 4）等位基因是阿尔茨海默病（AD）相关病理生理异常累积以及AD综合征临床表现的关键决定因素。然而，在认知老化和AD病理学的累积中存在显著的个体间异质性，使得一些个体即使到老年仍然保持认知完整并且具有最小的AD相关脑变化，尽管是APOE 4阳性。此外，虽然有可重复的证据表明AD的病理生理变化和认知功能障碍之间的关联，这种关系是不完美的。一些人继续表现出完整的认知，尽管窝藏大量的AD病理。这些发现强调了赋予以下恢复力的因素的存在：（i）年龄和APOE 4对认知过程和生物标志物谱的影响，以及（ii）生物标志物改变对认知轨迹的影响。在这个项目中，我们利用在威斯康星州阿尔茨海默病预防登记处和威斯康星州阿尔茨海默病研究中心获得的丰富的多模态遗传、神经影像、生物标志物、认知和生活方式数据来研究三个这样的因素：衰老抑制基因KLOTHO及其系统表达、神经可塑性促进基因脑源性神经营养因子（BDNF）及其系统表达和身体活动。我们的研究是围绕两个综合和翻译的目的，旨在确定在多大程度上KLOTHO，BDNF和体力活动单独或联合修改年龄和APOE 4对认知轨迹（目的1）和AD的神经影像学和流体生物标志物（目的2）在中年人（N/N 2000）在AD风险增加的影响。我们还将确定这些弹性因素是否会改变生物标志物变化对认知过程的有害影响。总之，这组互补的研究将为促进大脑和认知健康的假定途径提供重要见解，特别是针对年龄增长和APOE 4基因型所带来的限制。

 DESCRIPTION (provided by applicant): Advancing age and the apolipoprotein E ε4 (APOE4) allele are key determinants of the accumulation of pathophysiological abnormalities related to Alzheimer's disease (AD), as well as the clinical manifestation of AD syndrome. However, there is substantial interindividual heterogeneity in cognitive aging and the accrual of AD pathology such that some individuals remain cognitively intact and harbor minimal AD-related brain changes even into old age, and despite being APOE4 positive. Further, although there is replicable evidence for an association between AD pathophysiological changes and cognitive impairment, this relationship is imperfect. Some individuals continue to exhibit intact cognition despite harboring substantial AD pathology. These findings underscore the existence of factors that confer resilience to (i) the influence of age and APOE4 on cognitive course and biomarker profile, and (ii) the impact of biomarker alterations on cognitive trajectory. In this project, we leverage the wealth of multimodal genetic, neuroimaging, biomarker, cognitive, and lifestyle data acquired in the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center to study three such factors: the aging-suppressor gene KLOTHO and its systemic expression, the neuroplasticity-promoting gene brain-derived neurotrophic factor (BDNF) and its systemic expression, and physical activity. Our investigations are organized around two integrative and translational aims that seek to ascertain the extent to which KLOTHO, BDNF, and physical activity singly or jointly modify the effect of age and APOE4 on cognitive trajectory (Aim 1) and neuroimaging and fluid biomarkers of AD (Aim 2) in middle-aged adults (N ≈ 2000) at increased risk for AD. We will also determine whether these resilience factors alter the pernicious influence of biomarker changes on cognitive course. Together, this complementary set of studies will provide critical insights into putative avenues for promoting brain and cognitive health, particularly against the constraints imposed by advancing age and APOE4 genotype.