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Insulin and Alzheimer Disease—Reply

Insulin and Alzheimer Disease—Reply In reply In their interesting commentary, Dandona and colleagues highlight several of the potential mechanisms through which insulin may modulate Alzheimer disease (AD) pathologic processes. Indeed, one of the attractive features of insulin as a therapeutic agent for AD is that it affects multiple pathways of direct relevance to AD pathophysiology. Numerous points of interaction between insulin and amyloid processing have been identified including modulation of amyloid-related gene expression in peripheral mononuclear blood cells as observed by Dandona et al, regulation of proteases and lipoproteins related to amyloid clearance, and protection against amyloid toxicity.1,2 Insulin-related effects on inflammation, tau phosphorylation, and vascular function are other pathways that may influence the expression of AD pathology.3 These findings, combined with growing evidence of reduced insulin availability or action in the central nervous system of patients with AD, provide a rationale for therapeutic approaches that target insulin delivery to the brain. We have made initial forays in this direction using a straightforward method involving the most common form of insulin delivered with a device specialized for nose-to-brain transport, using doses with demonstrated efficacy in acute challenge paradigms.4 We are encouraged by our preliminary findings, especially the coordinated positive results of cognitive, functional, and positron emission tomography with fludeoxyglucose F 18 measures. However, we know full well that our study is a first step in a longer journey toward validating and optimizing this therapeutic approach. It is our hope that these initial results will be validated in longer, larger, multisite trials, providing a basis for rapid translation to therapy. A similarly important goal that we hope to achieve at this stage of inquiry is to inspire widespread focus on this promising area to promote mechanistic understanding of how brain insulin deficiencies contribute to the pathogenesis of AD. With such knowledge in hand, we can undertake the design of optimal treatment and prevention strategies aimed at correcting these deficiencies. Back to top Article Information Author Affiliation: Veterans Affairs Puget Sound Healthcare System, University of Washington School of Medicine, Seattle, Washington. Correspondence: Dr Craft, Veterans Affairs Puget Sound Healthcare System, University of Washington School of Medicine (S-182-GRECC), 1660 S Columbian Way, Seattle, WA 98108 (scraft@uw.edu).Box Reference Guidelines for Letters Letters discussing a recent Archives of Neurology article will have the best chance of acceptance if they are received within 4 weeks of the article's publication date. They should not exceed 400 words of text and 5 references. Letters reporting original research should not exceed 600 words and 6 references. All letters should include a word count. Letters must not duplicate other material published or submitted for publication. Letters will be published at the discretion of the editors and are subject to editing and abridgment. A signed statement for authorship criteria and responsibility, financial disclosure, copyright transfer, and acknowledgment is required for publication. Letters not meeting these specifications are generally not considered. Before submitting a Research Letter, please review the Instructions for Authors (September 2004 or http://archneur.ama-assn.org/misc/ifora.dtl). References 1. De Felice FG, Vieira MN, Bomfim TR, et al. Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A. 2009;106(6):1971-197619188609PubMedGoogle ScholarCrossref 2. Zhao WQ, Townsend M. Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer's disease. Biochim Biophys Acta. 2009;1792(5):482-49619026743PubMedGoogle ScholarCrossref 3. Craft S. The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. Arch Neurol. 2009;66(3):300-30519273747PubMedGoogle ScholarCrossref 4. Craft S, Baker LD, Montine TJ, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012;69(1):29-3821911655PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Neurology American Medical Association

Insulin and Alzheimer Disease—Reply

Craft, Suzanne
Archives of Neurology , Volume 69 (5) – May 1, 2012
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References (4)

Publisher
American Medical Association
Copyright
Copyright © 2012 American Medical Association. All Rights Reserved.
ISSN
0003-9942
eISSN
1538-3687
DOI
10.1001/archneurol.2012.45
Publisher site
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Abstract

In reply In their interesting commentary, Dandona and colleagues highlight several of the potential mechanisms through which insulin may modulate Alzheimer disease (AD) pathologic processes. Indeed, one of the attractive features of insulin as a therapeutic agent for AD is that it affects multiple pathways of direct relevance to AD pathophysiology. Numerous points of interaction between insulin and amyloid processing have been identified including modulation of amyloid-related gene expression in peripheral mononuclear blood cells as observed by Dandona et al, regulation of proteases and lipoproteins related to amyloid clearance, and protection against amyloid toxicity.1,2 Insulin-related effects on inflammation, tau phosphorylation, and vascular function are other pathways that may influence the expression of AD pathology.3 These findings, combined with growing evidence of reduced insulin availability or action in the central nervous system of patients with AD, provide a rationale for therapeutic approaches that target insulin delivery to the brain. We have made initial forays in this direction using a straightforward method involving the most common form of insulin delivered with a device specialized for nose-to-brain transport, using doses with demonstrated efficacy in acute challenge paradigms.4 We are encouraged by our preliminary findings, especially the coordinated positive results of cognitive, functional, and positron emission tomography with fludeoxyglucose F 18 measures. However, we know full well that our study is a first step in a longer journey toward validating and optimizing this therapeutic approach. It is our hope that these initial results will be validated in longer, larger, multisite trials, providing a basis for rapid translation to therapy. A similarly important goal that we hope to achieve at this stage of inquiry is to inspire widespread focus on this promising area to promote mechanistic understanding of how brain insulin deficiencies contribute to the pathogenesis of AD. With such knowledge in hand, we can undertake the design of optimal treatment and prevention strategies aimed at correcting these deficiencies. Back to top Article Information Author Affiliation: Veterans Affairs Puget Sound Healthcare System, University of Washington School of Medicine, Seattle, Washington. Correspondence: Dr Craft, Veterans Affairs Puget Sound Healthcare System, University of Washington School of Medicine (S-182-GRECC), 1660 S Columbian Way, Seattle, WA 98108 (scraft@uw.edu).Box Reference Guidelines for Letters Letters discussing a recent Archives of Neurology article will have the best chance of acceptance if they are received within 4 weeks of the article's publication date. They should not exceed 400 words of text and 5 references. Letters reporting original research should not exceed 600 words and 6 references. All letters should include a word count. Letters must not duplicate other material published or submitted for publication. Letters will be published at the discretion of the editors and are subject to editing and abridgment. A signed statement for authorship criteria and responsibility, financial disclosure, copyright transfer, and acknowledgment is required for publication. Letters not meeting these specifications are generally not considered. Before submitting a Research Letter, please review the Instructions for Authors (September 2004 or http://archneur.ama-assn.org/misc/ifora.dtl). References 1. De Felice FG, Vieira MN, Bomfim TR, et al. Protection of synapses against Alzheimer’s-linked toxins: insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci U S A. 2009;106(6):1971-197619188609PubMedGoogle ScholarCrossref 2. Zhao WQ, Townsend M. Insulin resistance and amyloidogenesis as common molecular foundation for type 2 diabetes and Alzheimer's disease. Biochim Biophys Acta. 2009;1792(5):482-49619026743PubMedGoogle ScholarCrossref 3. Craft S. The role of metabolic disorders in Alzheimer disease and vascular dementia: two roads converged. Arch Neurol. 2009;66(3):300-30519273747PubMedGoogle ScholarCrossref 4. Craft S, Baker LD, Montine TJ, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012;69(1):29-3821911655PubMedGoogle ScholarCrossref

Journal

Archives of Neurology – American Medical Association

Published: May 1, 2012

Keywords: alzheimer's disease,insulin

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