Abstract
BACKGROUND: Late-life depression frequently co-occurs with Alzheimer's disease (AD); however, the interactive effects of amyloid-beta (Aβ) species and tau pathology on depressive symptoms remain unclear. Soluble oligomeric Aβ (OAβ) and amyloid plaques may differentially influence depression depending on tau burden. OBJECTIVES: To examine how plasma OAβ and PET-measured amyloid plaque burden are associated with depressive symptoms across varying levels of tau pathology. DESIGN: Cross-sectional analysis using generalized linear models with interaction terms, supported by stratified subgroup analyses and Johnson-Neyman procedures. SETTING: Memory disorder clinic at a university-affiliated hospital. PARTICIPANTS: A total of 103 individuals, including cognitively normal controls (n = 24), patients with mild cognitive impairment (n = 54), and amyloid-positive dementia (n = 25), all of whom underwent plasma biomarker testing and tau and amyloid PET imaging. MEASUREMENTS: Depression was evaluated using the Cornell Scale for Depression in Dementia (CSDD), Hamilton Depression Rating Scale (HAM-D), and Geriatric Depression Scale-Short Version (GDS-SV). Plasma OAβ was measured by Multimer Detection System (MDS), and PET quantified amyloid and tau burden. RESULTS: MDS-OAβ showed a significant negative interaction with tau PET SUVR on depression scores (FDR-adjusted p < 0.05). Higher OAβ levels were linked to greater depression severity in low-tau individuals, but inversely related in high-tau individuals. Amyloid plaque burden was associated with depression only in those with advanced tau pathology. CONCLUSIONS: The association between amyloid pathology and depression differs depending on tau burden. Soluble OAβ may be a key contributor to depressive symptoms in early AD stages, while plaque effects become prominent later. These findings underscore the potential utility of OAβ as an early neuropsychiatric biomarker in AD and highlight the need to consider tau pathology when evaluating amyloid-related mood disturbances.