Exploring the Relationship Between Amyloid Burden and Depression in Pre-clinical Alzheimer’s Disease

Background Alzheimer's disease (AD) is a form of dementia, marked by amyloid-β plaques, neurofibrillary tangles, and neuronal loss. The amyloid burden has been associated with cognitive impairment and depression, suggesting a potential link between these conditions. Objective This study investigates the relationships between amyloid burden, cognitive impairment, and depression in the preclinical stages of AD. Methods Data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study, involving 4486 cognitively unimpaired individuals aged 65-85, was analyzed. The amyloid burden was assessed using positron emission tomography (PET) standardized uptake value ratio (SUVR), cognitive function via cognitive function index (CFI) and tests, and depression via the short-form geriatric depression scale. Mediation analyses, adjusted for age, sex, and education, were employed to measure the impact of amyloid deposition on depression into direct and cognition-mediated indirect effects. Results No significant direct correlation between amyloid burden and depression was found (p=0.2935). Significant indirect effects were observed in cognition measures: CFI (0.3203, 95% CI: (0.2382, 0.4010)), digit symbol substitution test (0.0401, 95% CI: (0.0180, 0.0683)), and immediate recall (0.0169, 95% CI: (0.0014, 0.0354)). However, free and cued selective reminding (0.0056, 95% CI: (-0.0078, 0.0268)) and delayed recall (0.0105, 95% CI: (-0.0009, 0.0259)) showed no significant indirect effects. Conclusions The findings indicate significant mediation by CFI, digit symbol substitution test, and immediate recall in the relationship between amyloid burden and depression while free and cued selective reminding and delayed recall showed no significant mediation. These results underscore the importance of further research using longitudinal data and a broader range of confounders to fully understand cognition's mediating role.