Insulin is differentially related to cognitive decline and atrophy in Alzheimer's disease and aging.

We assessed the relationship of insulin resistance with cognitive decline and brain atrophy over two years in early Alzheimer's disease (AD, n=48) and nondemented controls (n=61). Intravenous glucose tolerance tests were conducted at baseline to determine insulin area-under-the-curve (AUC). A standard battery of cognitive tasks and MRI were conducted at baseline and 2-year follow-up. In nondemented controls, higher baseline insulin AUC was associated with 2-year decline in global cognitive performance (beta=-0.36, p=0.005). In early AD, however, higher insulin AUC was associated with less decline in global cognitive performance (beta=0.26, p=0.06), slower global brain atrophy (beta=0.40, p=0.01) and less regional atrophy in the bilateral hippocampi and cingulate cortices. While insulin resistance is associated with cognitive decline in nondemented aging, higher peripheral insulin may have AD-specific benefits or insulin signaling may be affected by systemic physiologic changes associated with AD. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.

[1]  S. Bandinelli,et al.  Insulin resistance in cognitive impairment: the InCHIANTI study. , 2005, Archives of Neurology.

[2]  S. Yoshida,et al.  Insulin prevents apoptosis of external granular layer neurons in rat cerebellar slice cultures , 1995, Neuroscience Letters.

[3]  Paul K Crane,et al.  Different patterns of cerebral injury in dementia with or without diabetes. , 2009, Archives of neurology.

[4]  D. Marcus,et al.  White matter lesions are prevalent but differentially related with cognition in aging and early Alzheimer disease. , 2005, Archives of neurology.

[5]  J. Morris,et al.  Accelerated weight loss may precede diagnosis in Alzheimer disease. , 2006, Archives of neurology.

[6]  J. Morris.  The Clinical Dementia Rating (CDR) , 1993, Neurology.

[7]  J. Wands,et al.  Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes? , 2005, Journal of Alzheimer's disease : JAD.

[8]  K. Davis,et al.  Type 2 diabetes is negatively associated with Alzheimer's disease neuropathology. , 2005, The journals of gerontology. Series A, Biological sciences and medical sciences.

[9]  R. Mayeux,et al.  Hyperinsulinemia and risk of Alzheimer disease , 2004, Neurology.

[10]  R. Martins,et al.  Insulin Effects on Glucose Metabolism, Memory, and Plasma Amyloid Precursor Protein in Alzheimer's Disease Differ According to Apolipoprotein‐E Genotype , 2000, Annals of the New York Academy of Sciences.

[11]  G. Schellenberg,et al.  Effects of intranasal insulin on cognition in memory-impaired older adults: Modulation by APOE genotype , 2006, Neurobiology of Aging.

[12]  A. Newman,et al.  The metabolic syndrome, inflammation, and risk of cognitive decline. , 2004, JAMA.

[13]  S. Craft.  Insulin Resistance Syndrome and Alzheimer Disease: Pathophysiologic Mechanisms and Therapeutic Implications , 2006, Alzheimer disease and associated disorders.

[14]  Stephen M. Smith,et al.  Accurate, Robust, and Automated Longitudinal and Cross-Sectional Brain Change Analysis , 2002, NeuroImage.

[15]  J. Kushner,et al.  Insulin Receptor Substrate-2 Deficiency Impairs Brain Growth and Promotes Tau Phosphorylation , 2003, The Journal of Neuroscience.

[16]  P. Greengard,et al.  Stimulation of β-Amyloid Precursor Protein Trafficking by Insulin Reduces Intraneuronal β-Amyloid and Requires Mitogen-Activated Protein Kinase Signaling , 2001, The Journal of Neuroscience.

[17]  J. Livingston,et al.  Insulin receptors in the central nervous system: Localization, signalling mechanisms and functional aspects , 1991, Progress in Neurobiology.

[18]  G. Schellenberg,et al.  Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease , 1998, Neurology.

[19]  C. Kahn,et al.  Role for neuronal insulin resistance in neurodegenerative diseases , 2004 .

[20]  M. Tohyama,et al.  Activation of Akt Kinase Inhibits Apoptosis and Changes in Bcl‐2 and Bax Expression Induced by Nitric Oxide in Primary Hippocampal Neurons , 1999, Journal of neurochemistry.

[21]  Ronald C Petersen,et al.  Increased risk of type 2 diabetes in Alzheimer disease. , 2004, Diabetes.

[22]  M. Vitek,et al.  Akt Activation Protects Hippocampal Neurons from Apoptosis by Inhibiting Transcriptional Activity of p53* , 2001, The Journal of Biological Chemistry.

[23]  A Hofman,et al.  Diabetes mellitus and the risk of dementia , 1999, Neurology.

[24]  S. Asthana,et al.  Insulin increases CSF Aβ42 levels in normal older adults , 2003, Neurology.

[25]  Hollis T. Cline,et al.  Insulin Receptor Signaling Regulates Synapse Number, Dendritic Plasticity, and Circuit Function In Vivo , 2008, Neuron.

[26]  W. Markesbery,et al.  Brain infarction and the clinical expression of Alzheimer disease. , 1997, JAMA.

[27]  John Ashburner,et al.  A fast diffeomorphic image registration algorithm , 2007, NeuroImage.

[28]  P. Mehta,et al.  Intranasal insulin improves cognition and modulates β-amyloid in early AD , 2008, Neurology.

[29]  P. J. Koudstaal,et al.  Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI , 2003, Diabetologia.

[30]  W. Markesbery,et al.  Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. , 1997, JAMA.

[31]  G. Landreth.  PPARγ agonists as new therapeutic agents for the treatment of Alzheimer's disease , 2006, Experimental Neurology.

[32]  M. Strachan.  Insulin and cognitive function in humans: experimental data and therapeutic considerations. , 2005, Biochemical Society transactions.

[33]  T. Gómez-Isla,et al.  Serum insulin-like growth factor I regulates brain amyloid-β levels , 2002, Nature Medicine.

[34]  L. Launer,et al.  Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. , 2002, Diabetes.

[35]  B. Winblad,et al.  The Effect of Borderline Diabetes on the Risk of Dementia and Alzheimer’s Disease , 2007, Diabetes.

[36]  D. Leroith,et al.  Insulin and insulin-like growth factor receptors in the nervous system , 2008, Molecular Neurobiology.

[37]  A. Sinclair,et al.  Diabetes is associated with a slower rate of cognitive decline in Alzheimer disease , 2009, Neurology.

[38]  E. Barrett-Connor,et al.  Diabetes, impaired fasting glucose, and development of cognitive impairment in older women , 2004, Neurology.

[39]  W. Brooks,et al.  Reduced limbic and hypothalamic volumes correlate with bone density in early Alzheimer's disease. , 2010, Journal of Alzheimer's disease : JAD.

[40]  J. Donnelly,et al.  Peripheral insulin and brain structure in early Alzheimer disease , 2007, Neurology.

[41]  M. Folstein,et al.  Clinical diagnosis of Alzheimer's disease , 1984, Neurology.

[42]  W. Klein,et al.  Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers , 2009, Proceedings of the National Academy of Sciences.

[43]  Wei⁃qin Zhao,et al.  Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer's disease. , 2009, Biochimica et biophysica acta.

[44]  B. Winblad,et al.  Diabetes, Alzheimer disease, and vascular dementia , 2010, Neurology.

[45]  L. Rubin,et al.  Activated Phosphatidylinositol 3-Kinase and Akt Kinase Promote Survival of Superior Cervical Neurons , 1997, The Journal of cell biology.

[46]  James A. Mortimer,et al.  Brain Infarction and the Clinical Expression of Alzheimer Disease-Reply , 1997 .

[47]  M. M. Mielke,et al.  High total cholesterol levels in late life associated with a reduced risk of dementia , 2005, Neurology.

[48]  M. Nomura,et al.  MRI of the brain in diabetes mellitus , 2004, Neuroradiology.

[49]  P. O'Brien,et al.  Risk of dementia among persons with diabetes mellitus: a population-based cohort study. , 1997, American journal of epidemiology.

[50]  L. Lannfelt,et al.  Impaired insulin secretion increases the risk of Alzheimer disease , 2008, Neurology.

[51]  J. Price,et al.  Mild cognitive impairment represents early-stage Alzheimer disease. , 2001, Archives of neurology.

[52]  Christina A. Wilson,et al.  GSK-3α regulates production of Alzheimer's disease amyloid-β peptides , 2003, Nature.

[53]  F. Pasquier,et al.  Alzheimer disease with cerebrovascular disease and vascular dementia: clinical features and course compared with Alzheimer disease , 2008, Journal of Neurology, Neurosurgery, and Psychiatry.

[54]  G. Ramakers,et al.  Insulin signaling in the central nervous system: Learning to survive , 2006, Progress in Neurobiology.

[55]  L. Launer,et al.  Fasting insulin and incident dementia in an elderly population of Japanese-American men , 2004, Neurology.