The episodic autobiographical memory hypothesis of preclinical Alzheimer's disease: Developing a new approach for early cognitive detection and measurement of Alzheimer's disease

神经心理测试是检测阿尔茨海默病(AD)的核心，但目前 现有的测试对AD神经病理不够敏感，直到疾病进展到 好几年了。我们最近介绍并为一部插曲自传体提供了初步支持 临床前AD的记忆(EAM)假说。这一假说表明，由于eAM将 对AD、EAM测试的初始阶段所针对的神经网络的需求可以改进 阿尔茨海默病的“临床前”(即早期)认知检测。这份R03提案建立在我们的新假设之上 并试图通过填补当前的两个空白来推进临床前AD的EAM测试的开发 知识。具体地说，我们提出这一建议的目的是为了更好地理解(1)认知亚 对临床前AD敏感的EAM成分以及(2)临床前AD的哪个阶段(轻度 与严重相比)可以检测到EAM中断。为了实现这些目标，我们成立了一个团队， 在自传体记忆和衰老的神经心理学方面有专长的研究人员(Pi Grilli) 默认模式网络(DMN)和休眠状态功能连接(RSFC)(Co-I Andrews- 和认知老化的神经成像(Co-I Ryan)。我们的方法是研究EAM和 在认知正常的老年人中调查EAM与DMN RSFC的关系，其中一半是 载脂蛋白Eε4等位基因携带者，这增加了临床前AD的风险。我们有两个具体的 目的：(1)揭示认知正常的老年ε4携带者eAM核心亚成分受损 以及(2)证明eAM中断与DMN RSFC改变有关。在第一个目标下， 我们将研究已建立的和新的行为任务，每个任务强调不同的EAM认知 我们假设的亚成分在临床前AD中受到损害。在第二个目标下，我们将 调查是否与目标1中研究的任何eAM任务表现较差有关 在DMN已被确定为特别敏感的区域中具有高和/或低RSFC 临床前阿尔茨海默病我们的推理是，如果认知正常的ε4运营商表现出更差的eAM性能 在与非携带者相关的行为任务上，我们深入了解了eAM认知子任务。 易受临床前AD影响的组件。此外，通过研究EAM与DMN RSFC的关系， 我们可以阐明受损的EAM对轻度还是重度临床前AD敏感，并通过 扩展，EAM对两个关键AD过程的敏感度。这项研究具有重要意义，因为它 最终可能导致神经心理测试和认知结果测量的发展 可以检测到目前尚不存在的临床前AD。这项研究具有创新性，因为 EAM假说是临床前AD认知检测的一种新思路，本项目将是 首先测试EAM是否与轻度或重度临床前AD的RSFC信号有关。

Neuropsychological tests are central to the detection of Alzheimer’s disease (AD), but currently available tests are not sufficiently sensitive to AD neuropathology until the disease has progressed for years. We recently introduced and provided preliminary support for an episodic autobiographical memory (EAM) hypothesis of preclinical AD. This hypothesis states that because EAM places high demands on a neural network that is targeted by the initial stages of AD, EAM testing can improve “preclinical” (i.e., early) cognitive detection of AD. This R03 proposal builds on our novel hypothesis and seeks to advance the development of EAM tests for preclinical AD by filling two gaps in current knowledge. Specifically, our objectives for this proposal are to better understand (1) the cognitive sub- components of EAM that are sensitive to preclinical AD and (2) at what stage of preclinical AD (mild versus severe) EAM disruption is detectable. To achieve these objectives, we formed a team of researchers with expertise in the neuropsychology of autobiographical memory and aging (PI Grilli), the default mode network (DMN) and resting state functional connectivity (RSFC) (Co-I Andrews- Hanna), and the neuroimaging of cognitive aging (Co-I Ryan). Our approach is to study EAM and investigate the relation of EAM to DMN RSFC in cognitively normal older adults, half of whom are carriers of the apolipoprotein E ε4 allele, which increases risk for preclinical AD. We have two specific aims: (1) to reveal that core EAM sub-components are disrupted in cognitively normal older ε4 carriers and (2) to demonstrate that EAM disruption is associated with altered DMN RSFC. Under the first aim, we will investigate established and novel behavioral tasks, each emphasizing a different EAM cognitive sub-component that we hypothesize is compromised in preclinical AD. Under the second aim, we will investigate whether poorer performance on any of the EAM tasks studied under Aim 1 is associated with hyper- and/or hypo-RSFC in regions of the DMN that have been identified as particularly sensitive to preclinical AD. Our reasoning is that if cognitively normal ε4 carriers exhibit worse EAM performance on the behavioral tasks relative to non-carriers, we have gained insight into EAM cognitive sub- components that are vulnerable to preclinical AD. Also, by studying the relation of EAM to DMN RSFC, we can shed light on whether disrupted EAM is sensitive to mild or severe preclinical AD, and by extension, the sensitivity of EAM to two key AD processes. This research is significant because it ultimately could lead to the development of neuropsychological tests and cognitive outcome measures that can detect preclinical AD, which currently do not exist. This research is innovative because the EAM hypothesis is a novel idea for cognitive detection of preclinical AD, and this project will be the first to test whether EAM is related to RSFC signatures of mild or severe preclinical AD.