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