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Insulin Resistance and Neurodegeneration: Progress Towards the Development of New Therapeutics for Alzheimer’s Disease

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Abstract

Alzheimer’s disease (AD) should be regarded as a degenerative metabolic disease caused by brain insulin resistance and deficiency, and overlapping with the molecular, biochemical, pathophysiological, and metabolic dysfunctions in diabetes mellitus, non-alcoholic fatty liver disease, and metabolic syndrome. Although most of the diagnostic and therapeutic approaches over the past several decades have focused on amyloid-beta (Aβ42) and aberrantly phosphorylated tau, which could be caused by consequences of brain insulin resistance, the broader array of pathologies including white matter atrophy with loss of myelinated fibrils and leukoaraiosis, non-Aβ42 microvascular disease, dysregulated lipid metabolism, mitochondrial dysfunction, astrocytic gliosis, neuro-inflammation, and loss of synapses vis-à-vis growth of dystrophic neurites, is not readily accounted for by Aβ42 accumulations, but could be explained by dysregulated insulin/IGF-1 signaling with attendant impairments in signal transduction and gene expression. This review covers the diverse range of brain abnormalities in AD and discusses how insulins, incretins, and insulin sensitizers could be utilized to treat at different stages of neurodegeneration.

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Acknowledgements

Supported by AA-11431 from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Neurology, Rhode Island Hospital, and the Alpert Medical School of Brown University, Pierre Galletti Research Building, 55 Claverick Street, Room 419, Providence, RI, 02903, USA

    Suzanne M. de la Monte

  2. Department of Neurosurgery, Rhode Island Hospital, and the Alpert Medical School of Brown University, Providence, RI, USA

    Suzanne M. de la Monte

  3. Department of Neuropathology, Rhode Island Hospital, and the Alpert Medical School of Brown University, Providence, RI, USA

    Suzanne M. de la Monte

  4. Department of Pathology, Rhode Island Hospital, and the Alpert Medical School of Brown University, Providence, RI, USA

    Suzanne M. de la Monte

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The author has consulted and delivered a paid lecture for Novo Nordisk in 2016, and is on the Scientific Advisory Board for T3D Pharmaceuticals, Inc.

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de la Monte, S.M. Insulin Resistance and Neurodegeneration: Progress Towards the Development of New Therapeutics for Alzheimer’s Disease. Drugs 77, 47–65 (2017). https://doi.org/10.1007/s40265-016-0674-0

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