A recent pilot study by VA researchers found that a nasal insulin treatment improved memory, thinking skills, and functional ability in people with Alzheimer's disease or its precursor, mild cognitive impairment. Currently, there are no effective treatments to delay or prevent Alzheimer's.
Suzanne Craft, PhD, and colleagues with the Geriatric Research, Education and Clinical Center at the VA Puget Sound Health Care System led the trial, which was sponsored by the National Institute on Aging. The findings appeared in the Sept. 12 Archives of Neurology.
The study built on previous research—by Craft's group and others—that linked low brain levels of insulin to Alzheimer's. Insulin helps turns sugar in the bloodstream into energy for cells. In type 1 diabetes, the pancreas doesn't make enough insulin, and in type 2 diabetes, which affects nearly one in five VA patients, the body is resistant to the hormone's effects.
But insulin's role goes beyond blood-sugar metabolism and diabetes: It plays a key role in brain aging in general, and in several chronic diseases. So its connection to Alzheimer's is not surprising, says Craft, who is also a professor of psychiatry and behavioral sciences at the University of Washington.
Her group's latest clinical trial tested insulin given through a nebulizer-like device that fits around the nostrils and generates droplets that spread into the upper sinuses. The droplets reach the brain within minutes. There is no risk of increasing insulin levels throughout the whole body, which could drop blood sugar levels dangerously low.
The 104 adults in the study received 20 international units (IU) of insulin, 40 IU of insulin, or a saline placebo daily for four months, given through the nasal device. Treatment with 20 IU of insulin improved memory—specifically, the ability to recall a story after a delay. Both doses of insulin preserved general thinking skills and functional ability.
"The families and caregivers of the patients receiving the insulin scored them higher on their daily function than did the families of the patients not receiving insulin. So that was a very exciting finding," says Craft. She notes that for those patients who got a memory boost from the insulin, it was a 20 percent improvement, which she says could be considered "clinically significant."
VA Research Currents spoke with Craft to learn more about the intriguing link among diabetes, insulin, and Alzheimer's disease.
Research Currents: When did researchers first start to see a connection between diabetes and Alzheimer's disease?
Craft: It's been observed for quite some time, through imaging techniques such as positron emission tomography, that patients with Alzheimer's have reduced glucose metabolism in certain areas of their brain. In the early 1990s, there were studies by several groups looking at whether supplementing glucose might overcome that deficiency, at least temporarily.
We conducted a study in which we gave patients with Alzheimer's a glucose-rich drink to see how it affected their memory. We were able to improve their memory somewhat, but the improvement was associated most closely with the rise in insulin levels that occurred. Generally, whenever glucose is raised, insulin is raised as well, as the body produces insulin to help metabolize glucose. In a later study, in which were able to raise glucose but block the release of insulin, we found there was no longer any memory improvement. That showed us it was actually insulin, not glucose, that was critical.
A Japanese epidemiologic study came out in Neurology on Sept. 20 showing a strong link between diabetes and Alzheimer's. It seems this study complements yours.
I don't think it's entirely a coincidence, although there's no link between the two studies other than the topic they both deal with. When you look at how scientific knowledge accumulates, some describe it as a wave—you have this slow build-up, and then the studies begin to converge and "feed" on one another, if you will, and you get this crashing wave. I'd like to think we're at that point where we're going to get a lot of acceleration in this area.
Over the past five years, the converging evidence has come not just from epidemiologic studies and our clinical work, but from the basic science work as well, showing a very close relationship between insulin and beta amyloid, the protein that collects in the brain of patients with Alzheimer's disease. The two substances regulate each other in the brain. Another set of data both from animal studies and our human studies show that insulin plays an important role in synaptic health. The formation of links between synapses—the structures that allow for the passage of signals from one brain cell to another—is thought to be the physiological underpinning of memory. So the evidence is coming now from a number of different directions, and that's what we need to begin to address a very complex multifactorial disease like Alzheimer's.
Once you identified the effects of insulin on the brain, what was the next phase of your research?
We gave insulin intravenously. We were able to do this without lowering blood sugar by co-administering a small dose of dextrose. We found that this procedure improved memory. But this was only a proof of concept: If you administer insulin systemically, you have to be very careful to keep people's blood sugar stable, because the insulin could make it drop too low. Also, having very high levels of insulin chronically in the periphery is not good, the same way having high levels of glucose is not good. So you really need a way to get insulin into the brain.
That's where the nasal applicator comes in. How does it work?
It's an investigational device that is similar to a nebulizer, in that it has a droplet generator. It takes the liquid drug and projects it in a vortex that reaches the uppermost part of the sinuses. With a typical nose spray, most of it ends up in the bottom of your throat. With this new device, very little gets deposited there and almost all of the drug reaches the upper nasal cavities. That is where the pathways begin that traverse to the brain.
Does this help in crossing the blood-brain barrier?
The intranasal route actually bypasses the blood brain barrier, and that's an important point. Alzheimer's disease patients have a problem getting insulin across their blood-brain barrier. That's a feature of insulin resistance. In a normal person, insulin travels from the bloodstream into the brain within 15 to 30 minutes, and animal studies suggest that this is what we're able to achieve with intranasal delivery, even when insulin resistance is present.
Is insulin resistance the underlying reason why people with Alzheimer's have lower levels of this hormone in the brain?
Insulin resistance causes a reduction in the amount of insulin that crosses the blood brain barrier. It is the primary pathology that underlies diabetes, certainly, but also hypertension, high cholesterol, coronary artery disease. Half of all people with hypertension are also insulin-resistant, even if they're not diabetic. We think that is really the converging pathology among those diseases and Alzheimer's.
The other diseases you mentioned are tied together as part of the "metabolic syndrome." Are you suggesting Alzheimer's is also part of this syndrome?
That's correct. Insulin resistance appears to be an important driving force behind all these conditions. But remember, this doesn't apply to all Alzheimer's patients, because we know there are a few pathways that result in Alzheimer's pathology. But insulin resistance is one important pathway that affects quite a few patients with Alzheimer's, probably around half.
In your recent study, did you distinguish between patients with and without the Apoe4 genetic risk factor for Alzheimer's?
No, because it was a relatively small trial. But in the past, we've observed that patients who have the Apoe4 risk factor are not the ones who seem to have this insulin-resistance pathway. There are probably two major pathways to Alzheimer's, and one is the Apoe4 risk allele. That accounts for about half of those with Alzheimer's. We think that for the other half, this insulin-resistance pathway is the driving force behind the pathology.
Is it reasonable to suggest at this point that the same lifestyle steps that might help prevent diabetes—such as reduced sugar
intake, and more exercise—might also help ward off Alzheimer's?
Recently, there have been several studies that indicate a stronger link between diet and exercise and a reduction in the risk of Alzheimer's. This past June in the Archives of Neurology, for example, we reported on a clinical trial which suggested that diet could be a powerful factor to lower Alzheimer's risk. We compared a high-fat, high-glycemic-index diet with a low-fat, low-glycemic-index diet in 49 adults and found significant advantages to the "low" diet in terms of amyloid build-up, insulin levels, and other factors.
Where do you go from here with the research?
We have a study funded by the Alzheimer's Association to look at different formulations of insulin. We are going to compare long-acting insulin with regular insulin for a four-month period. We'll also look at the effects through brain imaging. Another study, funded by the National Institute on Aging, will look at different doses. Both are small to medium-size single-site studies. We also have an application in for a larger, multisite study, and we'll know in a few months if that will get funded.
All things considered, do you think insulin will pan out as a major treatment for Alzheimer's disease?
For patients for whom insulin resistance is the pathway that's promoting the disease, I think an insulin-related therapy may well provide lasting benefit. Whether it's this specific therapy is hard to say, because we're only at the beginning of this journey. But I think a therapy related to insulin and insulin function will be the most effective therapy for patients with Alzheimer's or certain other forms of dementia who have insulin resistance as the underlying pathology. There are still a lot of questions to answer, but we're very hopeful.