Diabetes Care, in press
Objective: Insulin resistance dysregulates glucose uptake and other functions in brain areas affected by Alzheimer’s disease. Insulin resistance may play a role in Alzheimer’s disease etiopathogenesis. This longitudinal study examined whether or not insulin resistance among late middle-aged, cognitively healthy individuals was associated with: 1) less gray matter in Alzheimer’s disease sensitive brain regions, and 2) worse cognitive performance. Research Design and Methods: The homeostatic assessment of insulin resistance, gray matter volume, and the Rey Auditory Verbal Learning Test were acquired in 372 participants at baseline and a consecutive subset of 121 individuals approximately 4 years later. Voxel-based morphometry and tensor-based morphometry were respectively used to test the association of insulin resistance with baseline brain volume and progressive gray matter atrophy. Results: Higher insulin resistance predicted less gray matter at baseline and 4 years later in medial temporal lobe, prefrontal cortices, precuneus, and other parietal gyri. A region of interest analysis, independent from the voxel-wise analyses, confirmed that more insulin resistance was related to medial temporal lobe atrophy. Atrophy itself corresponded to cognitive deficits in the Rey Auditory Verbal Learning Test. Temporal lobe atrophy that was predicted by higher insulin resistance significantly mediated worse Rey Auditory Verbal Learning Test encoding performance. Conclusions: These results suggest that insulin resistance in an asymptomatic, late middle-aged cohort is associated with progressive atrophy in regions impacted by early Alzheimer’s disease. Insulin resistance may also affect the ability to encode episodic information by negatively influencing gray matter volume in medial temporal lobe.