Demonstrated Brain Insulin Resistance in Alzheimer's Disease Patients Is Associated With IGF-1 Resistance, IRS-1 Dysregulation, and Cognitive Decline

J Clin Invest. 2012 Apr;122(4):1316-38. doi: 10.1172/JCI59903.

Abstract

While a potential causal factor in Alzheimer's disease (AD), brain insulin resistance has not been demonstrated directly in that disorder. We provide such a demonstration here by showing that the hippocampal formation (HF) and, to a lesser degree, the cerebellar cortex in AD cases without diabetes exhibit markedly reduced responses to insulin signaling in the IR→IRS-1→PI3K signaling pathway with greatly reduced responses to IGF-1 in the IGF-1R→IRS-2→PI3K signaling pathway. Reduced insulin responses were maximal at the level of IRS-1 and were consistently associated with basal elevations in IRS-1 phosphorylated at serine 616 (IRS-1 pS⁶¹⁶) and IRS-1 pS⁶³⁶/⁶³⁹. In the HF, these candidate biomarkers of brain insulin resistance increased commonly and progressively from normal cases to mild cognitively impaired cases to AD cases regardless of diabetes or APOE ε4 status. Levels of IRS-1 pS⁶¹⁶ and IRS-1 pS⁶³⁶/⁶³⁹ and their activated kinases correlated positively with those of oligomeric Aβ plaques and were negatively associated with episodic and working memory, even after adjusting for Aβ plaques, neurofibrillary tangles, and APOE ε4. Brain insulin resistance thus appears to be an early and common feature of AD, a phenomenon accompanied by IGF-1 resistance and closely associated with IRS-1 dysfunction potentially triggered by Aβ oligomers and yet promoting cognitive decline independent of classic AD pathology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Alzheimer Disease / psychology
  • Apolipoprotein E4 / genetics
  • Brain / drug effects
  • Brain / metabolism*
  • Brain / pathology
  • Cerebellar Cortex / metabolism
  • Cerebellar Cortex / pathology
  • Cognition Disorders / etiology*
  • Cognition Disorders / metabolism
  • Diabetes Complications / complications
  • Drug Resistance
  • Female
  • Glucose / metabolism
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Insulin / metabolism
  • Insulin / pharmacology
  • Insulin Receptor Substrate Proteins / chemistry
  • Insulin Receptor Substrate Proteins / genetics
  • Insulin Receptor Substrate Proteins / physiology*
  • Insulin Resistance*
  • Insulin-Like Growth Factor I / pharmacology*
  • Insulin-Like Growth Factor I / physiology
  • Male
  • Middle Aged
  • Phosphorylation
  • Phosphoserine / metabolism
  • Protein Processing, Post-Translational
  • Recombinant Proteins / pharmacology
  • Signal Transduction

Substances

  • Apolipoprotein E4
  • IRS1 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Recombinant Proteins
  • Phosphoserine
  • Insulin-Like Growth Factor I
  • Glucose