Intranasal insulin therapy may help preserve general cognitive abilities in patients with amnestic mild cognitive impairment (aMCI) or Alzheimer’s disease, according to a pilot study published in the September 12 online Archives of Neurology. Compared with placebo-treated participants, those who received insulin also showed lower Alzheimer’s-related biomarker levels and reduced cerebral glucose metabolism.
“Reduced levels of insulin activity may contribute to a number of pathological processes that characterize Alzheimer’s disease,” wrote lead author Suzanne Craft, PhD, from the Geriatric Research, Education, and Clinical Center at the Veterans Affairs Puget Sound Health Care System in Seattle. Citing previous studies that have suggested that insulin dysregulation may play a role in the pathophysiology of Alzheimer’s disease, Dr. Craft and her colleagues hypothesized that “restoring insulin to normal levels in the brain may therefore provide therapeutic benefit to adults with Alzheimer’s disease.”
Insulin-Treated Patients Had Stabilized or Improved Cognition and Function
A total of 104 older adults (64 with aMCI and 40 with probable Alzheimer’s disease) participated in the trial. Participants were randomly assigned to receive a daily dosage of 20 IU of insulin, 40 IU of insulin, or placebo for four months via a nasal drug delivery device.
The cognitive and functional examinations were administered at baseline, months two and four of treatment, and two months after treatment. “The coprimary outcome measures were the delayed story recall score and the Dementia Severity Rating Scale (DSRS) score, both of which had previously demonstrated the beneficial effects of insulin,” the authors wrote. A small subset of participants from each group also underwent PET with fludeoxyglucose F 18 (FDG) imaging and CSF biomarker testing.
“Compared with the participants in the placebo group, participants treated with the 20-IU dose of insulin showed improved delayed memory, and both insulin doses preserved the study partner–rated ability to perform daily functions,” the authors reported. “General cognitive abilities, as assessed with the Alzheimer Disease’s Assessment Scale–cognitive subscale, were also preserved by both doses of intranasal insulin.”
Changes in CSF Biomarker Levels and Cerebral Glucose Metabolism
“The CSF biomarkers of amyloid-beta 42 (Aβ42) level, tau protein level, and the tau protein–to–Aβ42 ratio are related to fundamental pathophysiologic characteristics of Alzheimer’s disease,” the researchers noted. When Dr. Craft and her team examined biomarker levels in a subset of study participants, they found that adults with aMCI or Alzheimer’s disease typically showed lowered CSF Aβ42 concentrations and elevated tau protein–to–Aβ42 ratios.
The investigators reported that they did not observe treatment-related changes in biomarker values for the insulin-treated groups as a whole. “In exploratory analyses, however, we observed that changes in the Aβ42 level and the tau protein–to–Aβ42 ratio were correlated with cognitive and functional changes for insulin-treated participants,” they added. “No similar associations were observed for the placebo group, suggesting that these correlations were not due to general factors such as disease progression.”
Dr. Craft and her colleagues also collected FDG-PET data to measure participants’ cerebral glucose metabolism. “Progressive hypometabolism over time has been well documented in Alzheimer’s disease and aMCI in a number of brain regions,” they explained. “In particular, reduced glucose metabolism in the precuneus and cuneus regions … can be observed at the earliest stages of Alzheimer’s disease.
“Participants in both insulin treatment groups showed reduced progression of hypometabolism in the precuneus region, as well as in the frontal and occipital cortices, compared with the placebo group,” they reported. The 20-IU dose group also showed less progression of temporal hypometabolism, while the 40-IU dose group showed less parietal hypometabolism.
Preliminary Results Support Need for Further Research
Although this trial produced promising results, larger trials and more research into the mechanisms of insulin’s effect on cognition and function are necessary, according to the researchers. They also noted that because the CSF and FDG-PET data were collected for only a subset of participants, the results might be subject to sampling biases. “Our trial was a small, single-site pilot study, which presents special challenges in the interpretation of results; clearly a longer, larger multisite trial is needed to confirm and extend our findings.
“Group performance on several measures was characterized by a pattern of decline in the placebo group and preservation or slight improvement in both insulin-treated groups,” the investigators concluded. “Safety profiles and compliance were excellent for this short-term intervention. 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 Alzheimer’s disease.”
—Ariel Jones