Accelerated Cognitive Decline in Late Life Depression: The Role of Amyloid-beta, Cortico-Limbic Volume, and White Matter Hyperintensities

Am J Geriatr Psychiatry. 2025 Aug 29:S1064-7481(25)00453-1. doi: 10.1016/j.jagp.2025.08.008. Online ahead of print.

ABSTRACT

OBJECTIVES: Late life depression (LLD) is associated with cognitive impairment and dementia, but studies of cognitive decline in LLD have been confounded by underlying Alzheimer’s disease (AD). We evaluated longitudinal cognition in LLD against nondepressed (ND) older adults with equivalent AD risk and pathology and assessed relative contributions of clinical and neuroimaging characteristics to cognitive change.

DESIGN: Longitudinal.

SETTING: Outpatient psychiatry program.

PARTICIPANTS: Participants (120 LLD, 240 ND) were matched on demographics, global cognition, mild cognitive impairment diagnosis, and Amyloid-β (Aβ) positivity.

MEASUREMENTS: Participants underwent genetic testing, 3T MRI, and Aβ PET at baseline, and serial neuropsychological assessment extending up to 36 months postbaseline.

RESULTS: After accounting for demographics, MCI diagnosis, and AD risk and pathology, LLD showed accelerated decline on tests of global cognition, verbal memory, and attention/processing speed. Lower baseline cortico-limbic volume was associated with greater decline in global cognition, verbal memory, and attention/processing speed regardless of LLD diagnosis. Baseline Aβ positivity predicted greater decline on tests of global cognition and verbal learning and memory regardless of LLD diagnosis. White matter hyperintensity burden predicted faster decline in attention/processing speed and verbal learning in LLD. MCI diagnosis did not predict cognitive decline in either group.

CONCLUSIONS: These findings demonstrate significant cognitive decline in LLD independent of Aβ pathology and highlight the importance of identifying causal mechanisms for cortico-limbic volume abnormalities in this patient population.

PMID:40973605 | DOI:10.1016/j.jagp.2025.08.008