Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis

CONTEXT: A history of depression may increase risk for developing Alzheimer disease (AD) later in life. Clarifying this relation might improve understanding of risk factors for and disease mechanisms in AD. OBJECTIVE: To systematically review and complete a meta-analysis on the relation of depression and AD. DATA SOURCES: We conducted electronic bibliographic searches of MEDLINE, PsychLit, EMBASE, and BIOSIS using search terms sensitive to studies of etiology combined with searches on terms related to depression and AD and reviewed reference lists of articles. STUDY SELECTION: Studies with data contrasting depressed vs nondepressed patients who did and did not later develop AD were included. Studies that related continuous measures of depression and cognitive status were excluded. DATA EXTRACTION: Numerical data were independently extracted by 3 reviewers. They also rated studies on a scale that assessed quality indicators for observational studies. Data on the interval between observation of depression and the diagnosis of AD were collected when available. DATA SYNTHESIS: Meta-analytic evaluation with random-effects models resulted in pooled odds ratios of 2.03 (95% confidence interval, 1.73-2.38) for case-control and of 1.90 (95% confidence interval, 1.55-2.33) for cohort studies. Findings of increased risk were robust to sensitivity analyses. Interval between diagnoses of depression and AD was positively related to increased risk of developing AD, suggesting that rather than a prodrome, depression may be a risk factor for AD. CONCLUSIONS: A history of depression may confer an increased risk for later developing AD. This relation may reflect an independent risk factor for the disease.