Type 2 diabetes mellitus accelerates brain aging and cognitive decline: complementary findings from UK Biobank and meta-analyses

Abstract

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 independently 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 respect to the identified neurocognitive effects.FindingsThe UK Biobank dataset included cognitive and neuroimaging data (N=26,125) including 1,270 T2DM and 24,855 HC. Duration of T2DM ranged from 0–45 years (mean 9.7±7.9 years); 559 were treated with metformin alone, while 473 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=1088). As compared to age, sex, and education-matched HC, T2DM was associated with marked cognitive deficits, particularly in executive functioning and processing speed. Likewise, we found that the diagnosis of T2DM was significantly associated with gray matter atrophy, primarily within the ventral striatum, cerebellum, and putamen, with reorganization of brain activity (decreased in the caudate, frontal eye fields, and premotor cortex and increased in the subgenual area, thalamus, brainstem and posterior 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.InterpretationThe neurocognitive impact of T2DM suggests marked acceleration of normal brain aging, by approximately 24% ± 10%; T2DM chronicity was associated with increased atrophy. As such, neuroimaging-based biomarkers may provide a valuable adjunctive measure of T2DM progression and treatment efficacy based on neurological effects.