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Peripheral insulin and brain structure in early Alzheimer disease

From the Departments of Neurology (J.M.B., H.S.A., L.S.-G., G.T., B.B.C., Z.H., D.K., D.H., W.M.B.) and Biostatistics (M.S.M.), University of Kansas School of Medicine, Kansas City, KS; and Energy Balance Laboratory and Center for Physical Activity, Nutrition, and Weight Management (J.E.D.), University of Kansas, Schiefelbusch Institute for Lifespan Studies, Lawrence, KS.

Address correspondence and reprint requests to Dr. Jeffrey M. Burns, University of Kansas School of Medicine, 3599 Rainbow Blvd., MSN 2012, Kansas City, KS 66160 jburns2{at}kumc.edu

Objective: Accumulating evidence suggests insulin and insulin signaling may be involved in the pathophysiology of Alzheimer disease (AD). The relationship between insulin-mediated glucoregulation and brain structure has not been assessed in individuals with AD.

Methods: Nondemented (Clinical Dementia Rating [CDR] 0, n = 31) and early stage AD (CDR 0.5 and 1, n = 31) participants aged 65 years and older had brain MRI to determine whole brain and hippocampal volume and 3-hour IV glucose tolerance tests to determine glucose and insulin area under the curve (AUC). Linear regression models were used to assess the relationship of insulin and glucose with brain volume, cognition, and dementia severity.

Results: In early AD, insulin and glucose AUCs were related to whole brain (insulin ß = 0.66, p < 0.001; glucose ß = 0.45, p < 0.01) and hippocampal volume (insulin ß = 0.42, p < 0.05; glucose ß = 0.46, p < 0.05). These relationships were independent of age, sex, body mass index, body fat, cardiorespiratory fitness, physical activity, cholesterol, and triglycerides. Insulin AUC, but not glucose, was associated with cognitive performance in early AD (ß = 0.40, p = 0.04). Insulin AUC was associated with dementia severity (Pearson r = –0.40, p = 0.03). Glucose and insulin were not related to brain volume or cognitive performance in nondemented individuals.

Conclusions: Increased peripheral insulin is associated with reduced Alzheimer disease (AD)–related brain atrophy, cognitive dysfunction, and dementia severity, suggesting that insulin signaling may play a role in the pathophysiology of AD.

Abbreviations: Aß = amyloid-beta peptides; AD = Alzheimer disease; AUC = area under the curve; CDR = Clinical Dementia Rating; IDE = insulin-degrading enzyme; GSK = glycogen synthase kinase; HV = hippocampal volumes; IVGTT = IV glucose tolerance test; MMSE = Mini-Mental State Examination; NS = not significant; PASE = Physical Activity Scale in the Elderly; VO₂^peak = peak oxygen consumption; WBV = whole brain volume.

This study was supported by grant R03AG026374-01 from the National Institutes of Aging, grant K23NS058252 from the National Institute on Neurological Disorders and Stroke, and generous support from the University of Kansas Endowment Association, William and Carolie Hougland, and the Fraternal Order of Eagles. The University of Kansas General Clinical Research Center (M01RR023940) provided essential space, expertise, and nursing support. The Hoglund Brain Imaging Center is supported by grant C76 HF00201, and Dr. Brooks is supported by NS039123 and AG026482.

Disclosure: The authors report no conflicts of interest.

Received November 30, 2006. Accepted in final form April 9, 2007.

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