Patients with Alzheimer disease (AD) and amnestic mild cognitive impairment (aMCI), who were treated with intranasal insulin did better on cognitive and functional tests than their untreated counterparts, results of a pilot study published in the American Medical Association’s Archives of Neurology indicate.
Improvements in the primary endpoint of delayed story recall tests (P=0.02, Cohen f effect size=0.36) were observed among patients who received 20 IU of intranasal insulin daily for four months compared with patients who received placebo, according to Suzanne Craft, PhD, of Veterans Affairs Puget Sound Health Care System, and colleagues.
“These promising results provide an impetus for longer-term trials of intranasal insulin therapy in adults with aMCI or AD,” the researchers wrote.
The researchers conducted the pilot study to confirm results from a small three-week trial that showed insulin therapy improved delayed story recall and functional status in AD patients, who are known to have lower insulin levels in the central nervous system. They hypothesized that bringing insulin back up to normal levels might help these patients maintain cognitive ability.
To avoid hypoglycemia and other adverse events associated with parenteral insulin administration, Craft and colleagues randomly assigned 104 adults to receive either 20 IU or 40 IU insulin intranasally daily, or placebo for four months.
Patients had a mean age of 72 years, about one-third had AD (n=40) and the remainder had aMCI (n=64), a condition thought to precede AD.
The researchers found that patients in both active treatment groups showed less cognitive decline as indicated by the Alzheimer Disease’s Assessment Scale cognitive subscale (20 IU dose, P=0.04 level for treatment group × time interaction and Cohen f=0.27; 40 IU dose, P=0.002 and Cohen f=0.40).
However, these differences varied by age, with younger patients experiencing greater improvements with the 40 IU dose than older patients (r= −0.31, P=0.06).
When the researchers assessed function on a daily living scale, they found that insulin helped preserve function among the AD patients, but not those with aMCI.
Additionally, an exploratory analysis indicated that patients treated with insulin showed changes in AD biomarkers, including Aβ42 levels and tau protein that correlated with cognitive and functional improvements.
A subset of patients that underwent positron emission tomography had less evidence of dementia-related hypometabolism in multiple areas of the brain that receive insulin, including the right precuneus and bilateral frontal and occipital cortices.
In discussion of the discrepencies in outcomes on the story recall portion of the study between patients taking the 20 IU dose and those taking the 40 IU dose, the researchers noted that they had previously observed a “∩-shaped” response curve with insulin therapy, with negative effects when insulin doses where either too high or too low.
Study limitations included the short duration of treatment and limited data on the effect of insulin on AD biomarkers. The researchers warned that, “although we achieved statistical significance for our primary outcome measures, the observed effects were small in absolute terms, and thus their clinical significance is unclear,” and stressed the importance of “a longer, larger, multisite trial,” to confirm the findings.