Effects of Regular and Long-Acting Insulin on Cognition and Alzheimer’s Disease Biomarkers: A Pilot Clinical Trial

Abstract

Background: Long acting insulin detemir administered intranasally for three weeks enhanced memory for adults with Alzheimer’s disease dementia (AD) or amnestic mild cognitive impairment (MCI). The investigation of longer-term administration is necessary to determine whether benefits persist, whether they are similar to benefits provided by regular insulin, and whether either form of insulin therapy affects AD biomarkers.Objective: The present study aimed to determine whether four months of treatment with intranasal insulin detemir or regular insulin improves cognition, daily functioning, and AD biomarkers for adults with MCI or AD.Methods: This randomized, double-blind, placebo-controlled trial included an intent-to-treat sample consisting of 36 adults diagnosed with MCI or mild to moderate AD. Participants received placebo (n = 12), 40 IU of insulin detemir (n = 12), or 40 IU of regular insulin (n = 12) daily for four months, administered with a nasal delivery device. A cognitive battery was administered at baseline and after two and four months of treatment. MRI was administered for all participants and lumbar puncture for a subset (n = 20) at baseline and four months. The primary outcome was change from baseline to four months on a memory composite (sum of Z scores for delayed list and story recall). Secondary outcomes included: global cognition (Alzheimer’s Disease Assessment Scale-Cognition), daily functioning (Dementia Severity Rating Scale), MRI volume changes in AD-related regions of interest, and cerebrospinal fluid AD markers.Results: The regular insulin treated group had better memory after two and four months compared with placebo (p < 0.03). No significant effects were observed for the detemir-assigned group compared with the placebo group, or for daily functioning for either group. Regular insulin treatment was associated with preserved volume on MRI. Regular insulin treatment was also associated with reduction in the tau-P181/Aβ42 ratio.Conclusion: Future research is warranted to examine the mechanistic basis of treatment differences, and to further assess the efficacy and safety of intranasal insulin.

Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums

“…As noted previously, intranasal insulin administration enhances memory functions in healthy individuals and in those with insulin resistance 114–123,273 . This finding was also observed in patients with AD or MCI, but only in those who did not carry an APOE ε4 allele 119,122 .…”

Novel calcium-related targets of insulin in hippocampal neurons

“…Intranasal insulin therapy has been shown to improve memory function in AD patients and in healthy individuals (Benedict et al , 2004; Reger et al , 2006; Hanson & Frey, 2008; Reger et al , 2008; Craft et al , 2012; Schioth et al , 2012b; Freiherr et al , 2013; Craft et al , 2017). Further, animal models of aging and AD also show the positive impact of intranasal insulin in combating cognitive decline (Francis et al , 2008; Marks et al , 2009; Apostolatos et al , 2012; de la Monte, 2013; Adzovic et al , 2015; Salameh et al , 2015; Anderson et al , 2016; Maimaiti et al , 2016).…”

Intranasal insulin in Alzheimer’s dementia or mild cognitive impairment: a systematic review

“…Seven articles were eventually deemed eligible, including a total of 293 patients (30–36); 172 were diagnosed with MCI and 121 with AD. The patients were assigned either to IN insulin or placebo group.…”