# Characterizing Cognitive Decline in Late Life Depression: The ADNI-D Project

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $1,419,298

## Abstract

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...

## Key facts

- **NIH application ID:** 10681480
- **Project number:** 5R01MH098062-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Robert Scott Mackin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $1,419,298
- **Award type:** 5
- **Project period:** 2013-08-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10681480

## Citation

> US National Institutes of Health, RePORTER application 10681480, Characterizing Cognitive Decline in Late Life Depression: The ADNI-D Project (5R01MH098062-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10681480. Licensed CC0.

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