PROJECT SUMMARY: Episodic memory declines during healthy aging and is an early symptom of Alzheimer’s disease (AD). However, the nature of memory changes that occur during the prolonged preclinical course of AD are poorly understood and ill defined. The concept of an asymptomatic, preclinical stage has gained importance in AD research due to the recognition that AD pathological processes begin years before appearance of pronounced memory deficits. Consequently, individuals at this stage often perform normally on standard neuropsychological tests designed to detect more overt memory and cognitive impairments. We propose a single, highly powered study to identify the memory processes that are most sensitive to this asymptomatic stage of AD pathologic change. The proposed study combines a continuous report item-location associative memory task with advanced behavioral (Aim 1) and neural (Aim 2) modelling to estimate subtle changes in memory precision that are independent of more traditional measures of retrieval success. The behavioral analyses in Aim 1 will allow us to test the prediction that subtle changes in memory precision can reliably differentiate between healthy aging and preclinical AD. Plasma biomarkers of amyloid, tau, and neurodegeneration will be used to classify cognitively unimpaired older adults into healthy (biomarker negative) and preclinical (biomarker positive) subgroups. This will allow us to validate and compare the predictive efficacy of memory precision against more traditional measures of retrieval success and ‘gold-standard’ standardized memory assessments. For Aim 2, we will use high-resolution functional magnetic resonance imaging (fMRI) to examine the neural computations that enable individuals to encode and retrieve precise memories. Critically, our approach will allow us to focus on how AD risk status affects local computations in hippocampal subfields as well as functional connectivity between larger cortico-hippocampal memory networks. The expected outcome of the proposed research is a novel behavioral assay that is sensitive to the earliest stages of AD pathologic change, when early detection and intervention have the highest likelihood of success. Moreover, the fMRI data collected as part of Aim 2 will provide novel mechanistic insights into the types of neural computations that enable older individuals to encode precise, high-fidelity memories. Finally, the insights gained from this project can inform future large-scale longitudinal studies aimed at clarifying the effects of healthy and pathological aging processes on episodic memory.