Gene-behavior interaction of depressive symptoms and the apolipoprotein e ε4 allele on cognitive decline

Depression is common in older age; in fact, it has been estimated that up to 49% of older adults have clinically-relevant depression (1) and depressive symptoms are also common (2-6), persistent (7), and have been associated with increased co-morbidities (8) and even mortality (9). Depression is a known risk factor for neurodegenerative outcomes, such as Alzheimer's disease (AD) and dementia, cognitive impairment, and cognitive decline (10-13). The causal link of depression and dementia is postulated to occur due to a neurotoxic mechanism, such as cortisol-induced hippocampus atrophy or lower levels of brain-derived neurotrophic factor (14-15). Moreover, there might be genetic links between depressive symptoms and cognitive decline through the Apolipoprotein E (APOE) e4 allele that is associated with accelerated deposition of beta amyloid consequently leading to a greater risk of AD (16). However, the relationship between the APOE genotype and late-life depressive symptoms is less clear. For example, some studies have found a positive association between the APOE e4 allele and depressive symptoms (17-18), whereas other studies have reported no association (19-20). Previous studies have investigated the genetic link of the APOE e4 allele with depressive symptoms and several cognitive outcomes, but the findings have been inconsistent. For example, Niti et al. showed that depressive symptoms were not associated with a decline in the Mini-Mental State Examination (MMSE) scores among participants with no copies of the APOE e4 allele; however, depressive symptoms were related to increased cognitive decline among participants with one or more copies of the APOE e4 allele (21). On the contrary, Dean et al. reported that depressive symptoms predicted the time to incident MCI among participants with no copies of the APOE e4 allele, but the prediction was not significant among participants with one or more copies of the APOE e4 carriers (22). However, other studies also found a synergistic interaction between depressive symptoms and the APOE genotype on incident MCI (23) and dementia (24). Using a one-wave 6-year follow-up study, Corsentino et al. showed that the association of depressive symptoms with cognitive decline was higher among individuals with the APOE e4 allele (25). Freiheit et al. (2012) found an increased rate of cognitive decline among patients with both persistent depressive symptoms and the APOE e4 allele compared to patients with either one or neither (26). Given the inconsistency in the literature and the fact that some older adults may be genetically susceptible to an increased risk of cognitive decline via presence of the APOE e4 allele, the scientific hypothesis of interest is to test whether the presence of both depressive symptoms and the APOE e4 allele increase cognitive decline jointly rather than each individually. Hence, we tested this hypothesis using the Chicago Health and Aging Project (CHAP), a large population-based cohort of 4,150 participants with APOE genotype and at least two follow-up assessments yielding an average of 9.2 years of follow-up (maximum 18.7 years). In addition to the key genetic and depressive symptoms measures, this study also includes other relevant demographic and health measures that might confound the association of depressive symptoms and the APOE e4 allele on cognitive decline in older adults.