Trajectory-Oriented Brain Vulnerability Framework for Cognitive Decline in Type 2 Diabetes

Type 2 diabetes mellitus (T2DM) is associated with heterogeneous cognitive and functional trajectories rather than a single diabetes-specific encephalopathy. This structured narrative review proposes a conceptual, hypothesis-generating exposure-injury-structure-function framework linking metabolic, vascular, and frailty-related exposures with molecular and neurovascular injury, structural change, cognitive decline, and loss of independence. Its contribution is the temporal assignment of measurements, lagged testing between adjacent levels, and comparison with clinical-risk and unordered biomarker models. For example, a study-specific threshold of at least 10% improvement in held-out root-mean-square error for 24-36-month executive/processing-speed decline could indicate incremental value. Repeated failure of a specified temporal link challenges that link; failure to improve prediction rejects incremental predictive value, not biological plausibility. Molecular hypotheses focus on AGE-RAGE signalling, NLRP3-IL-1β activation, mitochondrial quality control, endothelial dysfunction, and neuroglial injury, although human timing is uncertain. Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are considered complementary therapeutic probes. Both offer systemic benefits, but neither has proven efficacy in preventing cognitive decline or direct target engagement in the human brain. Visceral adiposity, skeletal-muscle health, sarcopenia, sex/gender, kidney function, co-pathology, and reserve are treated as exposures or modifiers. This framework is intended for longitudinal research, not clinical staging or treatment selection.