Brain Mechanisms Linking Type 2 Diabetes to Alzheimer Disease: A Multimodal Imaging Framework

Type 2 diabetes mellitus is associated with an increased risk of Alzheimer disease and cognitive impairment; however, the mechanisms underlying these associations remain incompletely understood. Here, we propose and justify a mechanistic, multimodal imaging framework to examine how type 2 diabetes-associated hyperglycemia and neurovascular dysfunction may contribute to cognitive vulnerability and accelerated brain aging. Dynamic metabolic stress testing using multimodal glucose-challenge imaging methods is proposed as the central component of this framework to investigate cerebral blood flow, blood-brain barrier integrity, metabolic demand, functional connectivity, and structural brain alterations under conditions of acute hyperglycemia. By examining these complementary neurovascular and metabolic responses together, rather than as individual imaging measures, this proposed approach is intended as a mechanistic discovery platform to identify neurovascular pathways linking type 2 diabetes mellitus-related dysglycemia with cognitive vulnerability in a population with a high burden of metabolic risk. By integrating current mechanistic evidence with a proposed multimodal imaging approach, this work aims to generate testable mechanistic hypotheses and inform future biomarker-driven and longitudinal studies of diabetes-related dementia risk.