The Impact of Insulin Resistance on Grey Matter Changes Along the Alzheimer's Disease Continuum

Background and ObjectivesInsulin resistance is emerging as a modifiable risk factor for Alzheimers, though its impact on grey matter volume across clinical stages remains poorly understood. The objective of the research is to investigate how insulin resistance affects grey matter integrity across the Alzheimers disease continuum using structural MRI. MethodsImaging, clinical, and metabolic data were extracted from 374 non-diabetic participants within the Alzheimers Disease Neuroimaging Initiative (ADNI) dataset. Participants were classified as cognitively impaired (CI: n=186; 137 mild cognitive impairment, 49 early-to-moderate dementia; all AD biomarker positive) or cognitively unimpaired (CU: n=188; 122 amyloid-negative, 66 amyloid-positive). Insulin resistance was assessed at the time of MRI and clinical evaluation using the dichotomized triglyceride-glucose index (TyG). The Interactions between TyG and diagnostic group on grey matter volume were investigated using both voxel-wise and region-of-interest (ROI) based analyses, adjusted for age, sex, education, vascular risk factors, and global cognitive performance across the AD continuum. ResultsInsulin resistance significantly impacted gray matter volume across the AD continuum, demonstrating stage-dependent effects. In early AD disease stages, insulin resistance was associated with lower grey matter volume in fronto-parietal regions, a finding that extended to several cortical areas in CI individuals. Temporal and fronto-limbic regions were particularly highlighted by the IR-diagnosis interaction. In amyloid-positive CU individuals, IR was linked to bilateral temporal atrophy, in contrast to amyloid-negative CU participants. DiscussionThis study underscores the impact of insulin resistance on brain structure across the AD continuum, particularly within key vulnerability areas characteristic of AD pathology. These findings highlight the need for future research into potential therapeutic strategies targeting insulin signaling to mitigate neurodegeneration in AD.