title: Demonstrated brain insulin resistance in Alzheimer's disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline.
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.
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-3403, USA. talbotk2@mail.med.upenn.edu
authors.forename: Konrad
authors.initials: K
authors.lastname: Talbot
authors.forename: Hoau-Yan
authors.initials: HY
authors.lastname: Wang
authors.forename: Hala
authors.initials: H
authors.lastname: Kazi
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Han
authors.forename: Kalindi P
authors.initials: KP
authors.lastname: Bakshi
authors.forename: Andres
authors.initials: A
authors.lastname: Stucky
authors.forename: Robert L
authors.initials: RL
authors.lastname: Fuino
authors.forename: Krista R
authors.initials: KR
authors.lastname: Kawaguchi
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Samoyedny
authors.forename: Robert S
authors.initials: RS
authors.lastname: Wilson
authors.forename: Zoe
authors.initials: Z
authors.lastname: Arvanitakis
authors.forename: Julie A
authors.initials: JA
authors.lastname: Schneider
authors.forename: Bryan A
authors.initials: BA
authors.lastname: Wolf
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.forename: Steven E
authors.initials: SE
authors.lastname: Arnold
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000523:psychology; D053327:Apolipoprotein E4 / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002525:Cerebellar Cortex / Q000378:metabolism / Q000473:pathology; D003072:Cognition Disorders / Q000209:etiology* / Q000378:metabolism; D048909:Diabetes Complications / Q000150:complications; D004351:Drug Resistance; D005260:Female; D005947:Glucose / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D007333:Insulin Resistance; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology* / Q000502:physiology; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction
chemical_list: D053327:Apolipoprotein E4; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D011994:Recombinant Proteins; D010768:Phosphoserine; D007334:Insulin-Like Growth Factor I; D005947:Glucose