Is Insulin a Potential Therapy for Alzheimer's Disease?
April 1, 2012 3 minutes read
Is Insulin a Potential Therapy for Alzheimer's Disease?
Abstract & Commentary
By Michael Lin, MD, PhD, Associate Professor of Neurology and Neurosciences, Weill Cornell Medical College. Dr. Lin reports no financial relationships relevant to this field of study.
Synopsis: Preliminary trials of low-dose intranasal insulin suggest a possible benefit that warrants further investigation.
Source: Craft S, et al. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment. A pilot clinical trial. Arch Neurol 2012;69:29-38.
A potential role for insulin in Alzheimer's Disease (AD) pathogenesis has become a topic of recent interest and has spurred several small pilot trials of insulin as a treatment for AD or amnestic mild cognitive impairment (aMCI), which in a majority of cases likely represents very early-stage AD. Intranasal insulin delivery by nebulizer increased cerbrospinal fluid (CSF) insulin levels within 30 minutes and acutely improved memory in healthy young adults, without affecting systemic glucose or insulin levels. In a 3-week, double-blind, placebo-controlled trial of 24 aMCI or AD subjects, 20 IU intranasal insulin given daily improved verbal recall and caregiver-related functional status.1
The most recent of these pilot trials, the Study of Nasal Insulin to Fight Forgetfulness (SNIFF), was initially reported at the 2010 international conference on AD and and has attracted significant attention in the popular press. SNIFF-120 was a 4-month, Phase 2, double-blind, randomized, placebo-controlled trial conducted by Suzanne Craft and colleagues at the University of Washington, Seattle. Subjects with aMCI (n = 64) or mild/moderate AD (n = 40) were randomized to receive saline (n = 30), 20 IU insulin (n = 36), or 40 IU insulin (n = 38) by intranasal nebulizer divided into two doses daily for 4 months. Cognition (delayed story recall, AD Assessment Scale Cognitive subportion [ADAS-Cog]) and function (Dementia Severity Rating Scale, ADAS-ADL) were assessed in all subjects at baseline, 2 months, 4 months, and after 2 months washout. A subset of participants also underwent FDG-PET (n = 40) and CSF biomarker analysis (n = 23).
With respect to memory, 20 IU insulin improved delayed story recall compared to placebo, but the 40 IU dose did not. Both dose groups showed less deterioration in global cognition (ADAS-Cog) compared to placebo. Both doses also resulted in less functional decline (DSRS, ADAS-ADL) compared to placebo. There were no significant changes in CSF biomarker concentrations for the placebo or insulin-treated groups as a whole, but on FDG-PET, insulin treatment (n = 24) was associated with less reduction in cerebral glucose use compared to placebo (n = 16). No treatment-related severe adverse events occurred, although aggregate insulin treatment resulted in more minor adverse events (such as rhinitis) compared to placebo.
Commentary
These are encouraging results and are plausible based on our current understanding of the role of insulin in the brain. Brain insulin receptors are densely localized in areas particularly vulnerable in AD, including the hippocampus, entorhinal cortex, and frontal cortex. Insulin receptors are found primarily in synapses, and insulin signaling contributes to synaptogenesis, synaptic remodeling, regulation of neuronal glucose metabolism, and modulation of long-term potentiation. Of direct relevance to AD, brain insulin levels and activity are decreased in AD. Insulin stimulates trafficking of amyloid precursor protein and reduces intraneuronal Aβ levels, regulates levels of insulin-degrading enzyme (one of the major Aβ-degrading enzymes), and protects against the synaptotoxic effects of Aβ oligomers.
But these findings are clearly still preliminary. An application for a larger, multisite, 18-month trial to be run under the auspices of the AD Cooperative Study group has been submitted to the National Institute on Aging.
Reference
1. Reger MA, et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 2008;70:440-448.
Preliminary trials of low-dose intranasal insulin suggest a possible benefit that warrants further investigation.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content