OBJECTIVES:To investigate the association between cognitive decline and cortical atrophy in individuals with mild cognitive impairment (MCI) and chronic subsyndromal symptoms of depression (SSD) over a 4-year period. DESIGN:Prospective cohort study. SETTING:Multicenter, clinic-based. PARTICIPANTS:Within the Alzheimer's Disease Neuroimaging Initiative repository, the Neuropsychiatric Inventory was used to identify individuals with MCI and stable endorsement (SSD group N = 32) or no endorsement (non-SSD group N = 69) of depressive symptoms across time points. MEASUREMENTS:Repeated measures of cognitive outcomes, cortical atrophy, and their associations were evaluated with mixed effects models adjusting for age, education, sex, and APOE genotype. RESULTS:The SSD group demonstrated accelerated decline on measures of global cognition (Alzheimer Disease Assessment Scale; df = 421, t = 2.242, p = 0.025), memory (Wechsler Memory Scale-Revised Logical Memory II; df = 244, t = -2.525, p = 0.011), information processing speed (Trail Making Test Parts A [df = 421, t = 2.376, p = 0.018] and B [df = 421, t = 2.533, p = 0.012]), and semantic fluency (Category Fluency; df = 424, t = -2.418, p = 0.016), as well as accelerated frontal lobe (df = 341, t = -2.648, p = 0.008) and anterior cingulate (df = 341, t = -3.786, p < 0.001) atrophy. No group differences were observed for rate of decline on measures of attention, learning, and confrontation naming or for rate of atrophy in any other regions. Accelerated frontal lobe and anterior cingulate atrophy was associated with cognitive decline on measures of global cognition, information processing speed, and semantic fluency (all p < 0.05), but not memory. CONCLUSIONS:Individuals with chronic SSD may represent an MCI subgroup that is highly vulnerable to accelerated cognitive decline, an effect that may be governed by frontal lobe and anterior cingulate atrophy.