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Impaired insulin signalling and allostatic load in Alzheimer disease

Nature Reviews Neuroscience volume 23, pages 215–230 (2022)Cite this article

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Abstract

The discovery of insulin in 1921 revolutionized the treatment of diabetes and paved the way for numerous studies on hormone signalling networks and actions in peripheral tissues and in the central nervous system. Impaired insulin signalling, a hallmark of diabetes, is now established as a key component of Alzheimer disease (AD) pathology. Here, we review evidence showing that brain inflammation and activation of cellular stress response mechanisms comprise molecular underpinnings of impaired brain insulin signalling in AD and integrate impaired insulin signalling with AD pathology. Further, we highlight that insulin resistance is an important component of allostatic load and that allostatic overload can trigger insulin resistance. This bidirectional association between impaired insulin signalling and allostatic overload favours medical conditions that increase the risk of AD, including diabetes, obesity, depression, and cardiovascular and cerebrovascular diseases. Finally, we discuss how the integration of biological, social and lifestyle factors throughout the lifespan can contribute to the development of AD, underscoring the potential of social and lifestyle interventions to preserve brain health and prevent or delay AD.

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Fig. 1: Mechanisms leading to impaired brain insulin signalling in AD.
Fig. 2: Intersections between AD pathology, inflammation and impaired insulin signalling in the brain.
Fig. 3: Impaired insulin signalling, allostatic load and their links to the development of dementia.

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Acknowledgements

F.G.D.-F. would like to dedicate this review to the memory of Bruce S. McEwen, an exceptionally beautiful and generous mind. The discussions we had over the past 5 years have inspired this review and my research. Research in F.G.D.-F. and S.T.F. labs is supported by grants from the Weston Brain Institute (to F.G.D.-F.), Alzheimer’s Society Canada (to F.G.D.-F.), and from the Brazilian funding agencies Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (467546/2014-2 to F.G.D.-F., 406436/2016-9 to S.T.F.), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) (202.944/2015 to F.G.D.-F., 201.432/2014 to S.T.F.), and the National Institute for Translational Neuroscience (INNT/Brazil) (465346/2014-6 to F.G.D.-F. and S.T.F.). PhD salary (to R.A.G.) was supported by grants from the Weston Brain Institute and Alzheimer’s Society Canada (to F.G.D.-F.).

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Authors and Affiliations

  1. Centre for Neuroscience Studies, Department of Biomedical and Molecular Sciences & Department of Psychiatry, Queen’s University, Kingston, Ontario, Canada

    Fernanda G. De Felice & Rafaella A. Gonçalves

  2. D’Or Institute for Research and Education (IDOR), Rio de Janeiro, RJ, Brazil

    Fernanda G. De Felice

  3. Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Fernanda G. De Felice & Sergio T. Ferreira

  4. Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Sergio T. Ferreira

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  1. Fernanda G. De Felice
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F.G.D.-F. and R.A.G. researched data for article, made substantial contribution to the discussion of content, and wrote, reviewed and edited the manuscript before submission. S.T.F. made substantial contribution to the discussion of content and wrote, reviewed and edited the manuscript before submission.

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Correspondence to Fernanda G. De Felice.

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Nature Reviews Neuroscience thanks L. Reagan, J. Fallon, and D. Kapogiannis for their contribution to the peer review of this work.

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De Felice, F.G., Gonçalves, R.A. & Ferreira, S.T. Impaired insulin signalling and allostatic load in Alzheimer disease. Nat Rev Neurosci 23, 215–230 (2022). https://doi.org/10.1038/s41583-022-00558-9

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