Abstract
Introduction
Intranasal (IN) insulin acutely improves verbal memory in mild cognitive impairment (MCI)/Alzheimer’s disease (AD), but its therapeutic effects may be attenuated in apolipoprotein E4 (ApoE4) carriers. Furthermore, rapid-acting (RA) insulins may have superior therapeutic effects compared with regular insulin types.
Objectives
To measure the safety and efficacy of intranasally delivered RA glulisine in ApoE4 carriers with mild–moderate AD.
Methods
We performed a double-blinded, randomized, cross-over study of RA insulin glulisine in nine mild–moderate AD subjects to better understand the relationship between RA insulin, ApoE4 carrier status and memory performance.
Results
IN glulisine was well tolerated but failed to have an acute impact on cognition in ApoE4 carriers with AD. Serum insulin levels acutely dropped following treatment, but peripheral glucose levels remained unchanged.
Conclusion
Larger clinical trials of longer duration are necessary to better understand the relationships between RA insulin, ApoE4 carrier status and cognitive performance in AD.
References
Benedict C, Hallschmid M, Hatke A, et al. Intranasal insulin improves memory in humans. Psychoneuroendocrinology. 2004;29(10):1326–34.
Freiherr J, Hallschmid M, Frey WH 2nd, et al. Intranasal insulin as a treatment for Alzheimer’s disease: a review of basic research and clinical evidence. CNS Drugs. 2013;27(7):505–14.
Steen E, Terry BM, Rivera EJ, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease—is this type 3 diabetes? J Alzheimers Dis. 2005;7(1):63–80.
Reger MA, Watson GS, Frey WH 2nd, et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging. 2006;27(3):451–8.
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):29–38.
Schioth HB, Frey WH, Brooks SJ, Benedict C. Insulin to treat Alzheimer’s disease: just follow your nose? Expert Rev Clin Pharmacol. 2012;5(1):17–20.
Benedict C, Hallschmid M, Schultes B, Born J, Kern W. Intranasal insulin to improve memory function in humans. Neuroendocrinology. 2007;86(2):136–42.
Benedict C, Hallschmid M, Schmitz K, et al. Intranasal insulin improves memory in humans: superiority of insulin aspart. Neuropsychopharmacology. 2007;32(1):239–43.
Jafek BW, Linschoten MR, Murrow BW. Anosmia after intranasal zinc gluconate use. Am J Rhinol. 2004;18(3):137–41.
Davidson TM, Smith WM. The Bradford Hill criteria and zinc-induced anosmia: a causality analysis. Arch Otolaryngol Head Neck Surg. 2010;136(7):673–6.
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging–Alzheimer’s Association Workgroups on Diagnostic Guidelines for Alzheimer’s Disease. Alzheimers Dement. 2011;7(3):263–9.
Dulay MF, Gesteland RC, Shear PK, Ritchey PN, Frank RA. Assessment of the influence of cognition and cognitive processing speed on three tests of olfaction. J Clin Exp Neuropsychol. 2008;30(3):327–37.
Frank RA, Gesteland RC, Bailie J, Rybalsky K, Seiden A, Dulay MF. Characterization of the Sniff Magnitude Test. Arch Otolaryngol Head Neck Surg. 2006;132(5):532–6.
Reger MA, Watson GS, Green PS, et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-beta in memory-impaired older adults. J Alzheimers Dis. 2008;13(3):323–31.
Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997;278(16):1349–56.
Valla J, Yaari R, Wolf AB, et al. Reduced posterior cingulate mitochondrial activity in expired young adult carriers of the APOE epsilon4 allele, the major late-onset Alzheimer’s susceptibility gene. J Alzheimers Dis. 2010;22(1):307–13.
Acknowledgments and Conflict of Interest Disclosure
This work was supported by donations made to the HealthPartners Center for Memory and Aging and by department funds from the HealthPartners Center for Memory and Aging. The authors (M. H. Rosenbloom, T. R. Barclay, M. Pyle, B. L. Owens, A. B. Cagan, C. P. Anderson, W. H. Frey II and L. R. Hanson) have no conflicts of interest or disclosures.
Author information
Authors and Affiliations
Corresponding author
Electronic Supplementary Material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Rosenbloom, M.H., Barclay, T.R., Pyle, M. et al. A Single-Dose Pilot Trial of Intranasal Rapid-Acting Insulin in Apolipoprotein E4 Carriers with Mild–Moderate Alzheimer’s Disease. CNS Drugs 28, 1185–1189 (2014). https://doi.org/10.1007/s40263-014-0214-y
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40263-014-0214-y