PROJECT SUMMARY/ABSTRACT: The pathophysiological processes of Alzheimer’s disease (AD) –– beta- amyloid plaques and neurofibrillary tangles –– begin decades before objective cognitive impairment and symptoms of clinical dementia are present. This “preclinical” disease stage offers a window to understand early disease mechanisms as well as the contributions of AD pathology to cognitive aging. Although work across different research programs highlights the utility of amyloid and tau measurements in aging cohorts as important predictors of future decline, it remains difficult to predict risk at the individual subject level and mechanisms associated with the initial consequences of AD pathology in aging remain unclear. Our research program involves cutting-edge neuroimaging (MRI, PET) and cerebrospinal fluid analysis to understand the neuronal correlates of memory decline. Specifically, we propose to leverage a pre-existing baseline cohort of 199 older clinically unimpaired (CU) older adults from the Stanford Memory and Aging Study (SAMS), and additionally improve the generalizability of this cohort with 30 new participants that self-identify in an ethnoracial group that is not non-Hispanic White. SAMS participants previously completed lumbar puncture to collect cerebrospinal fluid (CSF), high-resolution functional MRI (at 3T) during a visual associative memory paradigm, ultra high- resolution structural MRI (at 7T) to assess medial temporal lobe subregion integrity, and extensive cognitive assessment including multiple measurements of hippocampal-dependent memory. This proposal will extend SAMS to include a longitudinal visit 7 years after baseline (Wave 2) that repeats baseline modalities, and incorporates tau PET with a next generation ligand 18F-PI-2620. In addition to enriching the baseline sample, we anticipate data collection on 150 of the 199 eligible participants that completed the baseline visits for SAMS. A strength of our program is the emphasis on hippocampal-dependent memory processes, given that neurofibrillary tangle pathology is common in entorhinal cortex and hippocampus, and the initial sites of cortical tau deposition are in cortical areas critical for visual associative memory recollection (angular gyrus and ventral temporal cortex). Thus, we are well positioned to understand how structural and functional measures that quantify (a) entorhinal and hippocampal integrity as well as (b) hippocampal-dependent mechanisms of memory (cortical reinstatement) predict memory decline (Aim 1) and relate to regional tau PET (Aim 2). Given that all MRI and biofluid measures previously collected at baseline will be repeated during the longitudinal Wave 2 visit proposed in this application, we will also examine regional structural and functional change in these innovative imaging measures over time (Aim 3). This proposed research program will yield critical insights regarding the specific mechanisms underlying memory failure and decline in aging ...