Insulin Resistance, Brain Atrophy, and Cognitive Performance in Late Middle–Aged Adults

OBJECTIVEdInsulin resistance dysregulates glucose uptake and other functions in brain areas affected by Alzheimer disease. Insulin resistance may play a role in Alzheimer disease etio-pathogenesis. This longitudinal study examinedwhether insulin resistance among latemiddle–aged, cognitively healthy individualswas associatedwith 1) less graymatter in Alzheimer disease–sensitive brain regions and 2) worse cognitive performance. RESEARCH DESIGN ANDMETHODSdHomeostasis model assessment of insulin re-sistance, gray matter volume, and the Rey Auditory Verbal Learning Test (RAVLT) were acquired in 372 participants at baseline and a consecutive subset of 121 individuals ~4 years later. Voxel-based morphometry and tensor-based morphometry were used, respectively, to test the associ-ation of insulin resistance with baseline brain volume and progressive gray matter atrophy. RESULTSdHigher 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 of the voxel-wise analyses, confirmed that higher insulin resistance was related to medial temporal lobe atrophy. Atrophy itself corresponded to cognitive deficits in the RAVLT. Temporal lobe atrophy that was predicted by higher insulin resistance significantl