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Background: Although depression is very common in the preclinical stage of Alzheimer's disease (AD), it is still unclear whether depression moderates the progression of AD or not. In the present study, we aimed to investigate the moderation of depression on the relationship between β‐amyloid (Aβ) deposition and progression of hippocampal atrophy and cognitive decline in cognitively normal (CN) older adults. Method: Two‐hundred eighty nine CN older adults (55–90 years; 48.4% female; 14.2% Aβ+) from an ongoing prospective cohort study, the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE), were followed up for 24 months. All participants underwent annual clinical assessments on depressive symptoms and cognitive function, and biennial [11C] Pittsburgh compound B‐PET and three‐dimensional MRI scans. Depression was defined based on the following: 1) depression diagnosed by a psychiatrist, 2) Geriatric Depression Scale score ≥ 11, or 3) the presence of any depressive symptom on Neuropsychiatric Inventory. Result: Among the subjects, 73.4% (n = 212) were followed up for two years and twelve converted to mild cognitive impairment. Association between Aβ and depression was not observed at baseline. There was a significant Aβ positivity x Depression x Time interaction effect on hippocampal volume (F = 4.252, p = 0.042) and verbal memory (F = 7.488, p = 0.007) even after controlling for age, sex, educational level, APOE genotype, subjective memory complaint, and baseline white matter hyper intensity volume. Aβ positive individuals with depression showed faster decline of hippocampal atrophy and verbal memory decline than those in other subgroups for two years. Conclusion: The findings indicate that the presence of depression may accelerate hippocampal atrophy and episodic memory loss in older adults with preclinical AD. [ABSTRACT FROM AUTHOR]