Previous results have been mixed regarding the role of the apolipoprotein E e4 (APOE e4) allele in later-life depression: some studies note that carriers experience greater symptoms and increased risk while others find no such association. However, there are few prospective, population-based studies of the APOE e4-depression association and fewer that examine depressive symptom trajectory and depression risk longitudinally. We examined the association between APOE e4 allele status and longitudinal change in depressive symptoms and depression risk in later-life, over a 12-year follow-up period.

We used data from 690 participants of the Lothian Birth Cohort 1936 who took part in the Scottish Mental Survey 1947 (aged 11) and were followed-up in later-life over five waves from 2004 to 2019 (aged 70–82). We used APOE e4 allele status to predict longitudinal change in depressive symptom scores and risk of depression (defined by a symptom score threshold or use of depression-related medication). Models were adjusted for sex, childhood cognitive ability, childhood social class, education, adult social class, smoking status and functional limitations at baseline.

Depressive symptom scores increased with age. Once adjusted for covariates, APOE e4 allele status did not significantly predict symptom score trajectories or depression risk. Greater functional limitations at baseline significantly predicted poorer symptom score trajectories and increased depression risk (defined by medications). APOE e4 allele status did not significantly moderate the contribution of sex, education or functional limitations.

There was no evidence that APOE e4 carriers experience an increased risk for later-life depression.

The apolipoprotein E ε4 allele (APOE*ε4) is indicated as a risk for Alzheimer's disease and other age-related diseases. The risk attributable to APOE*ε4 for depression is less clear and may be because of confounding of the relationship between dementia and depression.

We examined the risk of APOE* ε4 for incident depression and depressive symptomology over a 12-year period across the adult lifespan.

Participants were from the Personality and Total Health Through Life study, aged 20 to 24 (n = 1420), 40 to 44 (n = 1592) or 60–64 (n = 1768) at baseline, and interviewed every 4 years since 1999. Ethnicities other than White, those without genotyping and those with depression at baseline, or who reported strokes and scores on the Mini-Mental State Examination <27 at any observation, were excluded.

Over the study period, there was no evidence that APOE*ε4+ was a risk factor for depression, including any depression (odds ratio (OR) = 0.94, 95% CI 0.77–1.16, P = 0.573), major depression (OR = 0.96, 95% CI 0.60–1.53, P = 0.860), minor depression (OR = 0.94, 95% CI 0.67–1.30, P = 0.695) or depressive symptomology (incidence rate ratio (IRR) = 1.02, 95% CI 0.97–1.08, P = 0.451). APOE*ε4 was unrelated to incident depression. Findings were consistent for all age cohorts.

Among cognitively intact Australian adults who were free of depression at baseline, there was little evidence that APOE*ε4+ carriers are at increased risk for depression over a 12-year period among those who are cognitively intact.