Brain ageing is thought to be related to geriatric depression, but the relationship between ageing and depression among middle aged individuals is unknown. The present study aimed to evaluate whether the age-related reduction of brain cortical thickness (CT) can be found in adult first-episode MDD patients, as well as to identify the possible genetic effect of the ANK3 gene polymorphism age-relates CT reduction. This study recruited 153 first-episode MDD patients with a disease duration < 2 years and 276 healthy controls (HC), and the CT of 68 whole brain regions and two ANK3 SNPs (rs1994336 and rs10994359) were analyzed. The results showed that although the CT of both groups was negative correlated with age, the MDD group had significant greater age-related decrease in CT than the HC group (–9.35 × 10−3 mm/year for MDD vs. –1.23 × 10−3 mm/year for HC in the left lateral orbitofrontal lobe). The multivariate analysis of covariance (MANCOVA) results yielded significant interactions of diagnosis × age, genotype × age and diagnosis × genotype interaction for rs10994359. In HC, the C allele showed a protective effect on age-related CT reduction. The reduction in CT with age was several times as greater in non-C carriers as in C carriers (–3.54 × 10−3 vs.–0.15 × 10−3 mm/year in left supramarginal gyrus) for HC. However, this protective effect disappeared in patients with MDD. We did not find a clear effect of rs1994336 on the age-related CT reduction. The findings indicate that the widespread accelerated brain ageing occurs early in adult-onset depression and this ageing may be a pathological mechanisms of depression rather than an outcome of the disease. The ANK3 rs10994359 polymorphism may partially affect regional cortical ageing in MDD. © 2020 The Authors