Type 2 diabetes mellitus accelerates brain aging and cognitive decline: complementary findings from UK Biobank and meta-analyses
Authors: Antal Botond , McMahon Liam P. , Sultan Syed Fahad , Lithen Andrew , Wexler Deborah J. , Dickerson Bradford , Ratai Eva-Maria , Mujica-Parodi Lilianne R. 
Published: May 2021

AbstractBackgroundType 2 diabetes mellitus is known to be associated with neurobiological and cognitive deficits; however, their extent, overlap with aging effects, and the effectiveness of existing treatments in the context of the brain are currently unknown.MethodsWe characterized neurocognitive effects independently associated with T2DM and age in a large cohort of human subjects from the UK Biobank with cross-sectional neuroimaging and cognitive data. We then proceeded to evaluate the extent of overlap between the effects related to T2DM and age by applying correlation measures to the separately characterized neurocognitive changes. Our findings were complemented by meta-analyses of published reports with cognitive or neuroimaging measures for T2DM and healthy controls (HC). We also evaluated in a cohort of T2DM diagnosed individuals using UK Biobank how disease chronicity and metformin treatment interact with the identified neurocognitive effects.ResultsThe UK Biobank dataset included cognitive and neuroimaging data (N=20,314) including 1,012 T2DM and 19,302 HC, aged between 50 and 80 years. Duration of T2DM ranged from 0–31 years (mean 8.5±6.1 years); 498 were treated with metformin alone, while 352 were unmedicated. Our meta-analysis evaluated 34 cognitive studies (N=22,231) and 60 neuroimaging studies: 30 of T2DM (N=866) and 30 of aging (N=1,088). As compared to age, sex, education, and hypertension-matched HC, T2DM was associated with marked cognitive deficits, particularly inexecutive functioningandprocessing speed. Likewise, we found that the diagnosis of T2DM was significantly associated with gray matter atrophy, primarily within theventral striatum,cerebellum, andputamen, with reorganization of brain activity (decreased in thecaudateandpremotor cortexand increased in thesubgenual area,orbitofrontal cortex, brainstemandposterior cingulate cortex). The structural and functional changes associated with T2DM show marked overlap with the effects correlating with age but appear earlier, with disease duration linked to more severe neurodegeneration. Metformin treatment status was not associated with improved neurocognitive outcomes.ConclusionsThe neurocognitive impact of T2DM suggests marked acceleration of normal brain aging. T2DM gray matter atrophy occurred approximately 26% ± 14% faster than seen with normal aging; disease chronicity was associated with faster atrophy. Mechanistically, our results suggest a neurometabolic component to brain aging. Clinically, neuroimaging-based biomarkers may provide a valuable adjunctive measure of T2DM progression and treatment efficacy based on neurological effects.FundingThe research described in this paper was funded by the W. M. Keck Foundation (to LRMP), the White House Brain Research Through Advancing Innovative Technologies (BRAIN) Initiative (NSFNCS-FR 1926781 to LRMP), and the Baszucki Brain Research Fund (to LRMP). None of the funding sources played any role in the design of the experiments, data collection, analysis, interpretation of the results, the decision to publish, or any aspect relevant to the study. DJW reports serving on data monitoring committees for Novo Nordisk. None of the authors received funding or in-kind support from pharmaceutical and/or other companies to write this manuscript.