In JCP this month, Locke and colleagues7 publish an article that advances our understanding in this important area. In a cleverly designed study, they address whether depressive symptomatology escalates preclinically concurrent with accelerated memory decline. Using the Arizona APOE Cohort, the investigators compared cognitively and functionally normal subjects who were free of major depression at study entry. All included participants remained cognitively and functionally normal at subsequent follow-up visits. Longitudinal changes in depression measures were assessed in APOE e4 carriers as compared to noncarriers. Incident depression was estimated using accepted clinical cutoffs on depression measures and initiation of antidepressant medications. The same group of investigators previously showed that age-related cognitive decline accelerates preclinically in heterozygote and homozygote APOE e4 carriers who remain cognitively normal.8 Consequently, a similar accelerated increase in depressive symptoms would be anticipated if depression is intrinsic to the Alzheimer’s disease syndrome. The 2 study groups were well balanced for most baseline characteristics. There were more Hispanic/Latino participants in the noncarrier group and, as expected, a higher percentage of reported family history of Alzheimer’s disease in the APOE e4 carrier group. Adjusting the statistical models for those differences did not change the results. Longitudinal analyses of depression scale scores did not differ between the APOE e4 carriers and noncarriers. Slight increase in depressive scores was seen with age, regardless of genotype. There was also no significant difference between the groups in emergence of incident depression. These findings remained consistent using different statistical approaches and adjustments. In conclusion, the investigators found no difference in measures of depression between APOE e4 carriers and noncarriers who remained cognitively and functionally normal during the observation period. Previously, in the same cohort, the APOE e4 carriers were shown to have accelerated age-related memory decline despite not crossing the boundary to abnormal cognitive function.8 If depression is intrinsic to Alzheimer’s disease, we would expect a gradual increase in depressive symptoms and incident depression even at this preclinical stage and that this change would happen in tandem with the cognitive changes. It remains possible that depressive symptomatology may accelerate later in the preclinical course or prodromal course when memory decline becomes symptomatic (MCI). Not enough participants in the Arizona APOE Cohort had Submitted: September 10, 2013; accepted September 10, 2013. Corresponding author: Anton P. Porsteinsson, MD, University of Rochester School of Medicine, 435 East Henrietta Rd, Rochester, NY 14620 (anton_porsteinsson@urmc.rochester.edu).