Temporal dysregulation of PPARG-PRKAG2 co-localization in gray matter: Implications for cognitive decline and intervention targets in type 2 diabetes

Background Type 2 diabetes (T2DM) is associated with increased risk for neurodegeneration, including Alzheimer's disease. Objective To determine the differences in gray matter PPARG and PRKAG2 co-localization in T2DM compared to non-diabetic controls. Methods Neuroimaging was obtained for 1802 adults (66 ± 9 years, 47% male) of whom N = 271 had T2DM. We applied imaging transcriptomics to examine trajectories of PPARG and PRKAG2 co-localization with gray matter volume. Results Gene co-localization with gray matter was higher in early stages but weakened in later stages among T2DM compared to controls (χ 2 = 13.82, p = 0.001). Co-localization was significantly associated with cognitive function in controls (F = 3.17, p < 0.001) but not T2DM. Metformin use was associated with greater gene co-localization stability over time (χ 2 = 12.42, p = 0.006). Conclusions PPARG -mediated metabolic remodeling and PRKAG2 /AMPK-driven energy sensing may act as neuroprotective mechanisms in response to both pathological (T2DM) and normative (aging) contexts. These processes appear to become dysregulated in T2DM, potentially resulting in cognitive decline and increased risk for dementia.