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

Background: Type 2 diabetes mellitus (T2DM) is associated with increased risk for cognitive decline and diagnosis of Alzheimer’s disease (AD). The mechanisms of T2DM related dementia remain unclear. Methods: Brain magnetic resonance imaging was retrospectively obtained for 1,802 adults (age 66 +/- 9 years, 47% male) of whom N = 271 had T2DM. We applied an accelerated longitudinal design and imaging transcriptomics to non-invasively examine the group-level trajectories of PPARG and PRKAG2 co-expression in gray matter. Results: Gene expression trajectories differed significantly between T2DM and controls (χ² = 13.82, p = 0.001). Co-expression was higher in early stages and then weakened in later stages among T2DM, while remaining stable over time in controls. PPARG and PRKAG2 co-expression was significantly associated with cognitive function in controls (F = 3.17, p < 0.001) but not T2DM (F = 7.72, p = 0.299) suggesting dysregulated or failed compensatory mechanisms. Individuals with T2DM not taking metformin demonstrated unstable gene co-expression over time compared to those taking metformin (χ² = 12.42, p = 0.006). Conclusions: The convergence of PPARG -mediated metabolic remodeling and PRKAG2 /AMPK-driven energy sensing may act as a coordinated neuroprotective mechanism, upregulated in response to cellular stress in both pathological (T2DM) and normative (aging) contexts. However, these processes appear to become dysregulated in T2DM, potentially resulting in cognitive decline and increased risk for dementia.