Major Finding: Intranasally delivered insulin boosted cognition and brain activity in patients with mild cognitive impairment and early Alzheimer's disease.
Data Source: A placebo-controlled trial that randomized 104 patients to placebo or to 20 IU or 40 IU of intranasal insulin every day for 4 months.
Disclosures: The study was sponsored by the National Institute on Aging and the Department of Veterans Affairs. Dr. Craft said she had no financial disclosures.
Intranasal insulin boosted cognitive function and even brain activity in patients with mild cognitive impairment and early Alzheimer's disease in a 4-month, randomized, placebo-controlled trial.
The study, presented at the meeting, holds tantalizing hints of an Alzheimer's therapy that could be relatively inexpensive and easy to administer, but more research on a much larger scale is necessary before this science could move into the clinic.
Dr. Suzanne Craft of the University of Washington, Seattle, said growing evidence suggests that insulin may play a key role in cognition and that patients with 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 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,” she 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,” she said. “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 to 20 or 40 IU daily of intranasal insulin. The compound is sprayed into the nose, where 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 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 was ceased.
On the ADCS-ADL, placebo patients declined significantly more than 20-IU patients; 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 the 40-IU group scored significantly better than did the 20-IU group.
Dr. Craft said 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.
In a subgroup of 40 patients who underwent fluorodeoxyglucose PET scanning at baseline and during follow-up, those 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 subjects—a finding that Dr. Craft suggested may show slowing of disease progression.
“This is a new and very encouraging finding,” she said.