AbstractBackgroundThere is significant heterogeneity in cognitive function in patients with bipolar I disorder (BDI); however, there is a dearth of research into biological mechanisms that might underlie cognitive heterogeneity, especially at disease onset. To this end, this study investigated the association between accelerated or delayed age-related brain structural changes and cognition in early-stage BDI.MethodsFirst episode patients with BDI (n = 80) underwent cognitive assessment to yield demographically normed composite global and domain-specific scores in verbal memory, non-verbal memory, working memory, processing speed, attention, and executive functioning. Structural magnetic resonance imaging data were also collected from all participants and subjected to machine learning to compute the brain-predicted age difference (brainPAD), calculated by subtracting chronological age from age predicted by neuroimaging data (positive brainPAD values indicating age-related acceleration in brain structural changes and negative values indicating delay). Patients were divided into tertiles based on brainPAD values, and cognitive performance compared amongst tertiles with ANCOVA.ResultsPatients in the lowest (delayed) tertile of brainPAD values (brainPAD range −17.9 to −6.5 years) had significantly lower global cognitive scores (p = 0.025) compared to patients in the age-congruent tertile (brainPAD range −5.3 to 2.4 yrs), and significantly lower verbal memory scores (p = 0.001) compared to the age-congruent and accelerated (brainPAD range 2.8 to 16.1 yrs) tertiles.ConclusionThese results provide evidence linking cognitive dysfunction in the early stage of BDI to apparent delay in typical age-related brain changes. Further studies are required to assess how age-related brain changes and cognitive functioning evolve over time.