NEURAL PHENOTYPES OF RESISTANCE AND RESILIENCY TO AD AND ADRD IN THE OLDEST OF THE OLD

项目4的摘要 以前的工作已经描述了几个因素，这些因素赋予了开发风险的脆弱性或对开发风险的保护 阿尔茨海默病(AD)和相关疾病(ADRD)的风险，包括人口和社会决定因素 健康(例如，社会经济地位和教育质量/技能)、全身和器官健康(包括疾病 从中年开始，例如高血压和肥胖症；在项目1中检查)、生活方式和健康因素(例如 体力活动和睡眠质量；在项目2中检查)，更年期的表现(例如血管运动 症状；在项目3中检查)，以及精神疾病(例如抑郁症)和社会学(例如社会网络 密度)域1。一些因素在青壮年和中年就开始影响ADRD的风险， 促进相对较早的老年认知障碍。因此，老年人在功能上有很大的不同， 早年表现出认知能力减退的“不成功的”个体。这些人处于赤裸裸的状态 与最近几十年生活中存在认知风险因素但成功抵抗的人形成对比 病理或表现出对认知损害的韧性，当病理存在时。来自大型数据库的发现 Rush Memory Aging项目的尸检队列显示认知和认知之间经常不一致 他指出，有必要研究认知复原力的机制2。在这里，我们的目的是阐明这些因素 与生命最新阶段的“成功衰老”(最低限度的大脑病理和最佳认知)有关。 研究已经确定了有助于非常大的3，4岁儿童相对保留功能的神经因素。 患有AD病理的队列，表现良好的个体的海马体体积相对较大而不是较低 表演个人5.这种对大脑结构的保护可能会赋予某些人认知韧性。 我们和其他人已经发现，血管病变调节了给定水平所需的AD病理水平 临床损害的6，7，血管损害负担与海马区萎缩有关8。因此，它是 更好的血管健康(即保存好的血管生理和较低的血管病变负担) 保护免受AD早期病理的损害。在拟议的工作中，我们将研究 衰老对群体中结构和功能脑连接、神经化学和认知能力的影响 按认知表现(认知综合指数的高/典型表现)和认知风险分层 (根据已知的风险因素，高/典型；“不平衡负荷”)。目标1.确定大脑连接的模式 和神经化学，赋予高龄(80岁以上)成年人卓越的认知能力。目标2.确定 脑血管健康、连通性、性能和寿命风险与保护因素之间的关系。 目标3.进一步定义在非常老的基础上的优越表现，基于对 病理的发展(淀粉样蛋白、tau和神经退行性变‘A-T-N’；通过血浆淀粉样蛋白β42/40进行索引； P-tau、NFL和海马区萎缩)，或在面对现有病理时的认知“弹性”。成功 这项工作的完成将揭示与晚期衰老的完整认知相关的神经机制。

ABSTRACT FOR PROJECT 4 Prior work has described several factors that confer vulnerability for or protection against risk for the development of Alzheimer's disease (AD) and related disorders (ADRD), including demographic and social determinants of health, (e.g., socioeconomic status and education quality/skill), systemic and organ health (including conditions beginning at midlife, e.g. hypertension and obesity; examined in Project 1), lifestyle and wellness factors (e.g. physical activity and sleep quality; examined in Project 2), manifestations of menopause (e.g. vasomotor symptoms; examined in Project 3), as well as psychiatric (e.g. depression), and sociological (e.g. social network density) domains1. Some factors begin to influence risk for ADRD early in young adulthood and mid-life and promote cognitive impairment in relatively early old age. Thus, older adults vary greatly in function, with certain `unsuccessful' individuals exhibiting a reduction of cognitive abilities earlier in life. These individuals are in stark contrast to individuals in the latest decades of life who harbor cognitive risk factors but have successfully resisted pathology or exhibit resilience against cognitive impairment when pathology is present. Findings from the large autopsy cohort in the Rush Memory Aging Project demonstrated frequent discordance between cognition and pathology and noted the need to examine mechanisms of cognitive resilience2. Here, we aim to elucidate factors related to `successful aging' (minimal brain pathology and optimal cognition) in the latest stages of life. Studies have identified neural factors that contribute to relatively preserved functioning in the very-old3,4. In cohorts with AD pathology, high performing individuals have relatively larger hippocampal volumes than lower performing individuals5. This preservation in brain structure may confer cognitive resilience in certain individuals. We and others have found that vascular lesions modulate the level of AD pathology necessary for a given level of clinical impairment6,7 and that vascular lesion burden is associated with hippocampal atrophy8. It is therefore possible that superior vascular health (i.e., preserved vascular physiology and low vascular lesion burden) protects against impairment from early AD pathology. In the proposed work, we will examine the impact of advanced aging on structural and functional brain connectivity, neurochemistry, and cognitive abilities in groups stratified by cognitive performance (high/typical performance on a cognitive composite index), and cognitive risk (high/typical based on known risk factors; `allostatic load'). Aim 1. To determine patterns of brain connectivity and neurochemistry that confer superior cognitive performance in very-old (80+) adults. Aim 2. To determine associations among cerebrovascular health, connectivity, performance and lifespan risk and protective factors. Aim 3. To further define superior performance in the very-old based on patterns of `resistance' against the development of pathology (amyloid, tau, and neurodegeneration `A-T-N'; indexed via plasma amyloid β 42/40, p-tau, NfL, and hippocampal atrophy), or cognitive `resilience' in the face of existing pathologies. Successful completion of this work would uncover neural mechanisms associated with intact cognition in advanced aging.