Objective: Several studies have reported that non-demented older adults with clinical depression show changes in amyloid-β (Aβ) levels in blood, cerebrospinal fluid and on neuroimaging that are consistent with those observed in patients with Alzheimer's disease. These findings suggest that Aβ may be one of the mechanisms underlying the relation between the two conditions. We sought to determine the relation between elevated cerebral Aβ and the presence of depression across a 54-month prospective observation period. Methods: Cognitively normal older adults from the Australian Imaging Biomarkers and Lifestyle study who were not depressed and had undergone a positron emission tomography scan to classify them as either high Aβ (n = 81) or low Aβ (n = 278) participated. Depressive symptoms were assessed using the Geriatric Depression Scale — Short Form at 18-month intervals over 54 months. Results: Whilst there was no difference in probable depression between groups at baseline, incidence was 4.5 (95% confidence interval [CI] 1.3–16.4) times greater within the high Aβ group (9%) than the low Aβ group (2%) by the 54-month assessment. Conclusions: Results of this study suggest that elevated Aβ levels are associated with a 4.5-fold increased likelihood of developing clinically significant depressive symptoms on follow-up in preclinical Alzheimer's disease. This underscores the importance of assessing, monitoring and treating depressive symptoms in older adults with elevated Aβ.