Recurrent depression from midlife through late life increases the risk of vascular dementia, suggesting a progressive etiologic association with vascular disease, a large, long-term retrospective cohort study has shown.

When depression begins only in late life, it might be part of the Alzheimer’s disease prodrome, the researchers found.

Whether treatment of depression could help prevent or delay the onset of either type of dementia was not established in the study.

A growing body of evidence has shown depression to be associated with a higher risk of developing dementia; however, it is has not yet been established how the disorders relate to each other.

For their research, published in the May 2012 issue of Archives of General Psychiatry (2012;69:493-8), Deborah E. Barnes, Ph.D., of the University of California, San Francisco, and the San Francisco Veterans Affairs Medical Center, and her colleagues examined sets of records for 13,535 subjects (57.9% female, 24.2% nonwhite). All were between the ages of 40 and 55 and were members of the Kaiser Permanente health system in the years 1964 through 1973, when they participated in a voluntary health exam in San Francisco and Oakland as part of their membership.

The 1964-1973 exam asked subjects whether they often felt “unhappy or depressed,” and positive answers were considered by Dr. Barnes and her colleagues to be indicative of depression symptoms at midlife. The same patient records were screened for depression diagnoses and hospitalizations between 1990 and 2000, and then for dementia diagnoses between 2003 and 2009. None of the included study subjects had dementia at baseline or in 2003, at the onset of follow-up.

Dr. Barnes and her colleagues found that 14.1% of subjects had depressive symptoms in midlife only, 9.2% in late life only, and 4.2% in both. After the investigators adjusted for comorbidities and demographic factors, the hazard of any form of dementia increased by about 20% for people with midlife depressive symptoms only (HR, 1.19 [95% CI, 1.07-1.32]); by 70% for late-life symptoms only (1.72 [1.54-1.92]); and by 80% for people with both (1.77 [1.52-2.06]).

When vascular dementia and Alzheimer’s disease were analyzed separately, subjects with midlife depressive symptoms only did not have a significantly increased risk of Alzheimer’s disease (HR, 1.06 [95% CI, 0.85- 1.33]) or vascular dementia (HR, 1.24 [0.90-1.72]). Those with late-life depressive symptoms saw a twofold increase in Alzheimer’s risk (HR, 2.06 [95% CI, 1.67-2.55]). Those with both midlife and late-life symptoms, meanwhile, had more than a threefold increase in vascular dementia risk (HR, 3.51 [2.44-5.05]).

“There has been an ongoing debate in the field as to whether the association between depression and dementia reflects an etiologic relationship or whether depression is a prodromal symptom of dementia. Our results suggest that the answer may differ depending on the dementia subtype,” Dr. Barnes and her colleagues wrote.

The recurrence of depression in late life “may reflect a long-term process of subclinical cerebrovascular changes that may predispose toward development of [vascular dementia],” the investigators wrote; however, they acknowledged, other mechanisms could also increase vulnerability to dementia among individuals prone to depression. Future studies are needed to learn whether the treatment of depression “may help to maintain cognitive function and delay dementia onset,” Dr. Barnes and her colleagues reported.

With regard to the late-life depression patients at higher risk for Alzheimer’s disease, they wrote, future studies might examine whether patients “might benefit from monitoring for cognitive deterioration and earlier treatment with memory-enhancing agents.”

Dr. Barnes and her colleagues noted as strengths of their study its large size and 45-year time span, while acknowledging among its weaknesses its reliance on a nonspecific, self-reported measure of depression at baseline. The electronic medical record data used in the study probably were not sensitive enough to capture the true magnitude of late-life depression and dementia in the study population, they wrote.

The study was funded by the Brain and Behavior Research Foundation (formerly the National Alliance for Research on Schizophrenia and Depression), Kaiser Permanente, and the National Institutes of Health. None of its authors declared conflicts of interest.