Project Summary Late life depression (LLD) is one of the strongest and most consistently identified risk factors for accelerated cognitive decline and dementia but the mechanisms contributing to these relationships have not yet been adequately clarified. Compelling evidence suggests that progressive cortico-limbic atrophy may act as a primary mechanism of accelerated cognitive decline in LLD. However, a significant barrier has been differentiating the effects of incipient and undiagnosed Alzheimer’s disease (AD) from those of LLD. In our parent award we partnered with the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to begin to address this challenge. We created an adjunct arm of ADNI for individuals with LLD in order to collect genetic, cognitive, and neuroimaging data, including Positron Emission Tomography (PET) measures of amyloid (Aβ) and Magnetic Resonance Imaging (MRI) measures of neurodegeneration that characterize AD. Our results have shown that: 1) Accelerated cognitive decline is evident in LLD compared to Non-Depressed (ND) older adults over 30 months after accounting for Aβ, AD genetic risk (Apolipoprotein ε4 alleles; APOE), and measures of cerebrovascular disease (white matter lesions; WML), 2) Neurodegeneration in key regions implicated in depression across the lifespan, including the lateral orbitofrontal cortex (OFC), superior temporal lobe (STL), temporal pole (TP) hippocampus (HC), amygdala (AMG) and accumbens area (AA) were characteristic of LLD independent of Aβ, APOE, and WML, 3) LLD was associated with focal regions of abnormal cerebral blood flow (CBF) but not increased Aβ or WML relative to ND, and 4) Baseline cortico-limbic volumes were the strongest neurobiological factors associated with baseline cognition and subsequent cognitive decline and worse course of depression. However the parent study had only one neuroimaging evaluation. As such, we could not evaluate progression of atrophy in LLD which is essential to determine neurodegenerative mechanisms of cognitive decline in LLD. Additionally, we did not obtain tau PET data which is critical given recent evidence that suggests LLD is associated with increased cortico-limbic tau deposition even in absence of elevated Aβ and that tau is more strongly linked to atrophy and cognitive decline than Aβ in ND. This study will: 1) Determine the association of LLD with progressive cortico-limbic atrophy independent of Aβ, 2) Determine the association of LLD with increased cortico-limbic tau deposition and the relationship of tau with neurodegeneration in LLD, and 3) Determine the association of cortico-limbic atrophy and tau deposition with 7-year cognitive and 9-year depression outcomes in LLD. These goals will be achieved by conducting additional evaluations of 100 participants from the parent study. We will conduct a second neuroimaging evaluation (MRI, PET) 5 years after their initial scans, complete clinical evaluations (psychiatric, cognitive) at 5- years and 7-years...