Although case-control studies have found elevated risk for Alzheimer disease (AD) associated with a prior psychiatric history, most of the previous research had inadequate controls for familial risk factors. Putative psychiatric risk factors were evaluated for a registry-based sample of 65 twin pairs discordant for AD. Risk ratios were calculated for psychiatric illness at any time and for episodes more than 10 years before dementia onset. Prior psychiatric illness was significantly associated with elevated risk. Most of these cases represented depressive episodes. When analyses were restricted to individuals whose mental illness commenced more than 10 years before dementia onset, the magnitude of the odds ratio decreased markedly. These findings suggest that a history of psychiatric illness, especially depression, may be associated with an elevated risk for AD. In particular, these results are consistent with an interpretation that symptoms of depression and similar complaints represent prodromal phases of dementia.