ABSTRACT Better understanding the interface of depression and Alzheimer’s Disease (AD) pathology could lead to new strategies to prevent or slow cognitive decline, with significant public health impact. Depression has historically been neglected and/or excluded in observational cohort and clinical trial research on AD– so we have limited knowledge about its relationship with pathological hallmarks of AD and cognitive decline. Our data suggest an association between tau and depression that may potentiate cognitive decline in preclinical stages of AD—when amyloid are below PET positivity thresholds--and confer dementia risk. Currently, the model of tau- associated depressive symptoms needs to be validated across the full spectrum of depressive symptom severity, including major depressive disorder (MDD). The current study was designed to address this critical gap. Our overarching goal is to investigate the relationships between tau and depressive symptoms over time in cognitively unimpaired older adults using both longitudinal tau PET (with spatiotemporal resolution) and novel plasma tau measures (with greater potential for clinical translation than PET or CSF) that are gaining rapid readiness for clinical translation). Achieving this goal will help characterize risk of cognitive decline for older adults with clinically significant depressive symptoms, optimize approaches to depression evaluation, and provide potential opportunities for early recognition and prevention of AD. Our primary hypothesis is that tau in temporal brain regions will predict more severe depressive symptoms, and that greater depressive symptoms will potentiate tau-associated cognitive decline. We will test these hypotheses in 150 cognitively unimpaired older adults across the spectrum of depression (subclinical to Major Depressive Disorder [MDD]) integrating longitudinal affective and cognitive symptom characterization, tau PET, and tau plasma biomarker assessments.This is the first study to our knowledge to investigate longitudinal tau PET and plasma measures in a cohort of older adults across the full range of depressive symptom severity. Better understanding of the mechanisms underlying depressive symptoms in preclinical AD could inform prevention efforts, including tau measurement as a means of identifying risk in older adults with late life depression. Thus, we will address the FOA goal “to encourage biomedical, behavioral and social sciences research that will enhance knowledge of mechanisms underlying neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) or Alzheimer's disease-related dementias (ADRD) so as to enable novel treatment development.”