Background: It is generally accepted that depression can be associated with significant cognitive deficits and that depression can be comorbid with dementia. Objective: This review seeks to go further and ask whether depression earlier in life can be a risk factor for subsequent dementia or for cognitive decline. Methods: A review was made of the epidemiological evidence from case-control and prospective studies that depression is a risk factor. The literature was also reviewed in relation to six hypotheses that might explain an association: (1) depression treatments are a risk factor for dementia, (2) dementia and depression share common risk factors, (3) depression is a prodrome of dementia, (4) depression is an early reaction to cognitive decline, (5) depression affects the threshold for manifesting dementia, and (6) depression is a causal factor in dementia. Results: A meta-analysis found that depression was associated with an increased risk of subsequent dementia in both case-control studies (95% CI for relative risk: 1.16–3.50) and prospective studies (95% CI: 1.08–3.20). There was little support for hypotheses 1 and 2. The other hypotheses have limited support, but warrant further research. Conclusion: There is sufficient evidence to take seriously the possibility that depression is a risk factor for dementia and cognitive decline. Further work is needed to examine depression as a prodrome of vascular dementia, depression as an early reaction to perceived cognitive decline, the effects of depression on the threshold for manifesting dementia, and depression as a source of hippocampal damage through a glucocorticoid cascade.
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