Genetic and Lifestyle Determinants of Cognitive Resilience in Midlife

 描述(申请人提供)：高龄和载脂蛋白Eε4等位基因是阿尔茨海默病(AD)相关病理生理异常累积的关键决定因素，以及AD综合征的临床表现。然而，在认知老化和AD病理的积累方面存在着显著的个体间异质性，以至于一些人保持认知完好无损，即使到了老年，尽管APOE4呈阳性，但与AD相关的脑变化仍然很小。此外，尽管有可复制的证据表明阿尔茨海默病的病理生理变化和认知损害之间存在关联，但这种关系并不完美。一些人继续表现出完整的认知，尽管存在实质性的AD病理。这些发现强调了以下因素的存在：(1)年龄和载脂蛋白4对认知过程和生物标记物分布的影响，以及(2)生物标记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注册中心和威斯康星州阿尔茨海默病研究中心获得的丰富的多模式遗传、神经成像、生物标记物、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，以及体力活动。我们的研究围绕两个综合和转换的目标进行组织，旨在确定KLOTHO、BDNF和体力活动在多大程度上单独或联合修改年龄和载脂蛋白4对AD的认知轨迹(AIM 1)和AD的神经成像和体液生物标记物(AIM 2)的影响(AIM 2)在AD风险增加的中年成年人(N≈2000)中。我们还将确定这些弹性因素是否会改变生物标记物变化对认知过程的有害影响。总而言之，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关键的见解，特别是针对年龄和APOE4基因增加带来的限制。

 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.