Intranasal Insulin Promising for MCI, Alzheimer's Disease

Megan Brooks

September 13, 2011

September 13, 2011 — In a pilot study, a nasal spray form of insulin, used daily for 4 months, stabilized or improved cognition, function, and cerebral glucose metabolism in adults with amnestic mild cognitive impairment (aMCI) and mild to moderate Alzheimer's disease (AD).

"Taken together, these results provide an impetus for future clinical trials of intranasal insulin therapy and for further mechanistic studies of insulin's role in the pathogenesis of AD," conclude Suzanne Craft, PhD, and colleagues from the University of Washington and Veterans Affairs Puget Sound Health Care System, in Seattle.

Dr. Suzanne Craft

Their study was published online September 12 in the Archives of Neurology. Some of the results were presented at the Alzheimer's Association International Conference on Alzheimer's Disease 2010 and reported by Medscape Medical News at that time.

"Exciting" Early-Stage Study

Laurie Ryan, PhD, program director, Alzheimer's Disease Clinical Trials, Division of Neuroscience, National Institute on Aging, Bethesda, Maryland, who was not involved in the study, called the results "exciting."

She cautioned, however, in an interview with Medscape Medical News, that this is "an early-stage study, and we have to follow up with a more definitive study that has more subjects and a longer duration of exposure to the intranasal insulin."

Insulin abnormalities contribute to the pathophysiology of AD. Insulin levels and insulin activity in the central nervous system (CNS) are reduced in AD; therefore, restoring insulin to normal levels in the brain may provide therapeutic benefit in adults with AD.

Intranasal insulin provides rapid delivery of insulin to the CNS without adversely affecting blood insulin or glucose levels. It has been shown to increase insulin levels in the CNS and to acutely enhance memory and functional ability in cognitively impaired adults.

In the current study, Dr. Craft's team randomly assigned 64 adults with aMCI and 40 with mild to moderate AD to receive 20 IU insulin, 40 IU insulin, or a saline placebo, all of which were administered through a nasal drug delivery device for 4 months.

Primary outcome measures consisted of changes from baseline to 4 months on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) and delayed story recall scores. Secondary measures included the Dementia Severity Rating Scale and the Alzheimer's Disease Cooperative Study-activities of daily living (ADCS-ADL) scale.

A subset of 23 participants also underwent lumbar puncture to test CSF for AD biomarkers, and 40 had fludeoxyglucose positron emission tomography scans both before and after treatment.

Benefits for Memory and Functional Ability

Compared with the placebo group, the group that received 20 IU insulin daily showed improved delayed memory (P < .05), whereas no improvement was observed for the group that received 40 IU insulin.

Patients treated with either dose of insulin experienced less decline in cognition, as assessed by the ADAS-cog score. Dr. Craft and colleagues say the effect of intranasal insulin therapy on the ADAS-cog score was mediated by age, "with younger participants showing greater decline in the placebo group and greater benefit in the 40-IU dose insulin group."

Compared with the placebo group, baseline scores on the Dementia Severity Rating Scale were preserved in both insulin groups (P = .01).

The benefit of intranasal insulin on functional ability was apparent only in participants with AD. Participants with AD who received either insulin dose had preserved function on the ADCS-ADL scale compared with placebo-treated participants with AD, who showed a slight decline. There was no change in the ADCS-ADL in participants with aMCI, regardless of treatment assignment.

Effect of APOE Status Unclear

Adjustment for APOE ε4 status, baseline modified Mini-Mental State Examination score, cholinesterase inhibitor therapy, sex, and education did not alter the pattern of any result, the researchers say.

They point out, however, that previous studies have documented a relationship between APOE genotype and response to acute intranasal insulin administration, with APOE ε4 carriers showing no memory boost, and adults without the ε4 allele showing memory enhancement.

"Our study was not powered to examine APOE genotype as an independent predictor of treatment response, but ε4 carriage status was considered as a covariate in all analyses and was not related to any treatment effect," the investigators note. They say a larger trial will be necessary to definitively determine the relationship of APOE ε4 carriage and insulin treatment response.

Overall, there were no changes in CSF concentrations of amyloid beta 42, amyloid beta 40, and tau protein, regardless of treatment assignment. However, in exploratory analyses, changes in memory and function correlated with changes both in the amyloid beta42 level and in the ratio of tau protein to amyloid beta42.

Progressive hypometabolism over time has been well documented in aMCI and AD in a number of brain regions, including the precuneus and cuneus regions and the parietal, temporal, frontal, and occipital cortices. Participants in both insulin groups experienced reduced progression of hypometabolism in some of these regions.

No serious adverse events related to intranasal insulin were seen, and compliance with treatment was excellent, the researchers say.

Summing up, they say these results support longer trials of intranasal insulin as a potential treatment for cognitive impairment.

Dr. Ryan said that "several groups of researchers are currently looking at this metabolic angle as a potential avenue of therapeutics for [AD]."

For example, one research group is studying the use of metformin in MCI in a pilot study, and another is looking at the effects of a combination of pioglitazone and exercise on cognitive impairment, she noted.

The study was supported by grants from the National Institute of Aging, the Nancy and Buster Alvord Endowment, and the Department of Veterans Affairs. The authors and Dr. Ryan have disclosed no relevant financial relationships.

Arch Neurol. Published online September 12, 2011. Abstract


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: