Variation in the apolipoprotein E (APOE) genotype is associated with cognitive decline in normal aging. Increased symptoms of depression are also associated with greater cognitive impairment and risk of dementia in old age. Unlike APOE, where the direction of the effect is from genotype to cognitive decline, the causal relationship between depressed mood and cognitive impairment is not known. Rather than being a reaction to worsening cognitive performance with age, depressive symptoms might be a risk factor for age-related cognitive decline. The study by Rajan and colleagues (published in this issue of Psychosomatic Medicine) speaks to this possibility and, importantly, considers the association between depressive symptoms and age-related cognitive decline in the context of APOE variation. This editorial discusses these findings in relation to causal pathways and highlights how longitudinal studies of this nature will improve our understanding of the biological underpinnings of cognitive decline and classification of its risk in the general population.