Age-related deficits in episodic memory for the content and structure of naturalistic events - PROJECT SUMMARY/ABSTRACT The exact process of episodic memory loss in aging and Alzheimer’s disease (AD) is not understood. The long- term goal is to refine our understanding of this process, and its links to pathology in the brain. Critically, our current ways of assessing memory decline are sufficient to detect frank dementia, but are largely insufficient to identify those at risk before significant pathology has already accumulated. In part, this lack of sensitivity stems from the fact that laboratory tests use simplistic, arbitrary stimuli that do not reflect the complexity of the real world. That is, existing cognitive evaluations are limited due to a failure to capture a central feature of human memories: they are not unitary, but rather feature representations of specific content in a structured fashion. These components of memories rely on different brain networks. The objective of this proposal is to determine the way aging distinctly affects the content (Aim 1) and structure (Aim 2) of memory representations, and how this relates to dysfunction in different brain networks based on their susceptibility to AD pathology (via plasma biomarker status, Aim 3). The central hypothesis is that aging will be associated with distinct profiles of memory deficits for event content and structure, linked to unique brain networks. The rationale underlying this proposal is that completion of the project will identify two distinct cognitive and neural targets for characterizing, clinically assessing, and eventually treating AD in at-risk older adults. Our specific aims will test the following hypotheses: (Aim 1) Aging disproportionately affects memory for local perceptual information, such as people and objects, which will coincide with dysfunction in an anterior-temporal brain network. (Aim 2) Older adults will show a shift in brain networks involved in representing event memories and poor differentiation between events compared to younger adults, leading to a bias toward remembering information at a gist-level and a susceptibility to confusion. (Aim 3) Plasma biomarkers will predict the extent of age-related dysfunction in memory networks. Specifically, tau burden will relate to anterior-temporal network dysfunction and memory loss for local perceptual content in memories, whereas amyloid burden will relate to dysfunction in a posterior-medial brain network and more widespread memory deficits related to context and structure. This work uses an innovative combination of novel behavioral testing techniques, as well as cutting-edge brain imaging and plasma proteomic tools. The proposed research makes a significant contribution, because it will provide foundational evidence that memory loss is not a monolith, but rather a nuanced process with different components that are uniquely vulnerable to the presence of pathological biomarkers in AD. Results of this project will have a positive impact on basic research in memory and aging in that they will provide important evidence for the way the human brain supports the content and structure of memories, and how this changes across the lifespan. Moreover, this work will inform future clinical investigations and interventions by refining their targets for understanding and treating specific memory deficits.
