AbstractBackgroundDepressive symptoms are a known risk factor for dementia, and higher concentrations of glial fibrillary acid protein (GFAP) is associated with a faster rate of cognitive decline. However, it is unknown whether the two risk factors increase the risk of cognitive decline additively.MethodThis investigation is based on 1,169 participants from the Chicago Health and Aging Project (CHAP), a population‐based cohort study, who completed at least two cognitive performance assessments with baseline serum GFAP measurement. Depressive symptoms were determined utilizing a modified version of the Center for Epidemiologic Studies‐Depression Scale. A composite global cognitive function score was calculated using cognitive performance testing. Linear mixed effects regression models were conducted to examine the association of depressive symptoms and GFAP concentrations on baseline global cognitive function and the annual rate of cognitive decline. Regression models also adjusted for age, race, sex, education, chronic medical conditions, and their interactions with time.ResultOur study sample consisted of 60% African American participants and 63% female participants and had an average age of 77 (SD = 6.0) years. In our sample, 21% had few depressive symptoms (0‐2), and the remaining 79% had more depressive symptoms (3‐10). We found a statistically significant interaction between depressive symptoms and GFAP (β = ‐111 (SE = .039), p = .005) on global cognitive function. Stratified analysis showed that the associations between the log of GFAP and global cognitive function were statistically significant for participants with few (0‐2) depressive symptoms (β = ‐.223 (SE = .087), p = .010) and more (3‐10) depressive symptoms (β = ‐.781 (SE = .198), p = .000). Statistically significant associations were also observed between the log of GFAP and global cognitive decline for participants with few (β = ‐.069 (SE = .017), p = .000) and more (β = ‐.100 (SE = .040), p = .012) depressive symptoms.ConclusionOur findings show additive effects of depressive symptoms in the association between the log of GFAP with baseline global cognitive function and rate of cognitive decline. Prevention and treatment of depression in old age can significantly impact the risk of progressive cognitive decline, especially among individuals with higher concentrations of GFAP.