Intranasal insulin boosted cognitive function and even brain activity in patients who had mild cognitive impairment and early Alzheimer's disease in a 4-month, randomized, placebo-controlled trial.
The study holds tantalizing hints of an Alzheimer's therapy that could be relatively inexpensive and easy to administer, although more research on a much larger scale is necessary before this science could move into the clinic.
Dr. Suzanne Craft of the Veterans Affairs Puget Sound Medical Center and the University of Washington, both in Seattle, said that growing evidence suggests that insulin might play a key role in cognition and that patients who have Alzheimer's disease have significantly disrupted brain-insulin interactions.
“Insulin plays a number of important roles in the brain, and many are functions of great relevance to Alzheimer's disease,” she said in an interview.
Insulin normally crosses the blood-brain barrier to bind with receptors in the hippocampus, frontal cortex, and other regions that are involved in cognition. “It also enhances memory, we believe through mediating glucose metabolism in the hippocampus, as well as by mediating levels of neurotransmitters, including acetylcholine,” Dr. Craft said.
Insulin also improves blood flow to the brain and works to prevent beta-amyloid from aggregating on neurons. “It appears to help the beta-amyloid move from inside the brain cells to the interstitial space, where it can be cleared,” Dr. Craft explained. “It also increases the availability of a specific enzyme that breaks down amyloid.”
In an extension of her previous work, Dr. Craft randomized 104 patients with mild cognitive impairment (MCI) or early Alzheimer's disease to placebo or 20 IU daily or 40 IU daily of intranasal insulin. The compound is sprayed into the nose, where the insulin bypasses the blood-brain barrier and travels directly into the brain along the perivascular channels around the olfactory and trigeminal nerves, allowing the drug to bind to brain receptors within 15-30 minutes of administration.
The patients' average age was 73 years. Their mean combined score on three baseline Mini-Mental State Examination tests was about 82. All of the patients took the Alzheimer's Disease Assessment Scale cognitive test for MCI (ADAS-cog/MCI), the Dementia Severity Rating Scale (DSRS), and the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) measures.
The 20-IU group experienced a significantly improved delayed story recall compared with the placebo group. The 20-IU group also showed significantly improved functional status on the DSRS. These improvements persisted for 2 months after insulin treatment was ceased.
On the ADCS-ADL, placebo patients declined significantly more than did the 20-IU patients, whereas the 40-IU patients had no change in their score. On the ADAS-cog/MCI test, placebo patients scored significantly worse than both intervention groups, and patients in the 40-IU group scored significantly better than did those in the 20-IU group.
Dr. Craft remarked that “it's hard to say for certain in a 4-month study that this would translate into clinical improvement, but on the ADAS-cog, we saw a 25% difference between the highest-dose insulin group and the placebo group. And we also saw improvements in a caregiver-rated functional scale. So I would say that these findings do suggest clinical improvement.”
The fact that the improvements were maintained throughout the study and even after treatment stopped suggests that insulin has a cumulative effect in improving brain function, she added. “It doesn't appear to be just a temporary boost.”
In a subgroup of 26 patients who had a lumbar puncture at baseline and again at 4 months, insulin-treated patients showed an alteration in their tau/beta-amyloid-42 level, indicating increased clearance of beta-amyloid.
Another subgroup of 40 patients underwent fluorodeoxyglucose PET scanning at baseline and during follow-up. Those patients who were taking placebo showed a slowing of the cerebral metabolic rate for glucose utilization. This slowing was not seen in either the 20-IU or 40-IU patients—a finding that Dr. Craft suggested may show slowing of disease progression.
“This is a new and very encouraging finding,” she said.
The National Institute on Aging and the Department of Veterans Affairs sponsored the study. Dr. Craft had no relevant disclosures.
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