Geriatric depression is not only a common and disabling condition in the elderly, but it is also often a predictor of major medical disorders such as stroke. Depression itself is due to a variety of factors, including personality factors (e.g., neuroticism) and vascular factors. Recent meta-analyses have shown that depression predicts stroke occurrence with significant heterogeneity across studies, which is not well explained by current understanding. For this reason, a hypothesis-based validation study was conducted by Radboud M. Marijnissen et al. from the Netherlands. The investigators hypothesized that the effect of depression on the risk of stroke occurrence is conditional, i.e., in specific patients may be dependent on the contribution of vascular disease and the underlying neuroticism of depression. The investigators aimed to clarify whether depression would also increase the risk of stroke in patients with low neuroticism characteristics and no prior cardiac disease. The findings suggest that depression independently predicts stroke without relying on neuroticism in patients with a history of heart disease; whereas in patients without a history of heart disease, depression only predicts stroke in people with low levels of neuroticism. The study was published in a recent issue of Neurology. This was a population-based cohort study with a total of nine years of follow-up and included 2050 subjects aged ≥55 years, 52% of whom were women). The incidence of stroke was clarified by self-reported data as well as from general practitioners and death certificates. Neuroticism was detected by the Dutch Personality Questionnaire and depression was assessed using the Center for Epidemiological Studies Depression Scale. All data were analyzed using Cox proportional risk regression. A total of 117 patients had a stroke during the follow-up. In patients with a history of cardiac disease (n = 401), depression was predictive of stroke occurrence independently of neuroticism levels, with a risk ratio (HR) of 1.05. In patients without a history of cardiac disease (n = 1649), there was a significant interaction between depression and neuroticism in predicting stroke occurrence. Stratified analysis showed that in those with low levels of neuroticism, depression predicted stroke with an HR of 1.05; in those with higher levels of neuroticism, the HR was 1.01. The study concluded that in those without a history of heart disease, depression predicted stroke only in the absence of high levels of neuroticism. The investigators explained that there is a hypothesis that depression in older adults occurring at low neuroticism levels is a marker of subclinical vascular disease, and this hypothesis may partially explain the study’s findings.