Could Diabetes Medications Reduce Alzheimer Disease Severity?

Vahram Haroutunian, PhD, a professor of psychiatry and neuroscience at the Icahn School of Medicine at Mount Sinai

Vahram Haroutunian, PhD

Recent study results have suggested that those who had been treated with anti-diabetic agents had significantly reduced numbers of abnormally expressed microvasculature and insulin receptor signaling pathway associated genes observed in Alzheimer disease.

Vahram Haroutunian, PhD, a professor of psychiatry and neuroscience at the Icahn School of Medicine at Mount Sinai, and colleagues noted that data propose that vigilance and diligence in the treatment of diabetes can potentially have beneficial effects on Alzheimer disease for those patients. The findings build on previous research on the link between Alzheimer and diabetes.

To provide further insight into the study’s findings and their context, Haroutunian spoke with NeurologyLive in an interview.

NeurologyLive: What prompted the research from this study?

Vahram Haroutunian, PhD: There’s always been a linkage identified between diabetes and Alzheimer in that some people with diabetes develop some cognitive deficits. Also, a lot of times when there is diabetes in the context of Alzheimer, the degree of dementia seems to be more severe. So, some years ago, we decided to look at that from a neuropathology point of view and kind of hypothesized that, if there was, in fact, an association between diabetes and Alzheimer disease, then the brains of people who had diabetes and Alzheimer disease would have more Alzheimer-related lesions, so more plaques and tangles than you would expect if it was just Alzheimer disease without diabetes. What we found, in fact, in that study was the reverse—that the brains of Alzheimer patients that we looked at who had diabetes seemed to have fewer Alzheimer-related lesions, statistically significantly fewer plaques and, at least nominally, fewer neurofibrillary tangles. That was puzzling. It didn’t meet our expectations. I generally believe data that doesn’t meet my expectations because I’m usually wrong in my hypothesis, and when you find something unexpected, to me, that’s more real than things that you would expect to see.

What was done in this specific assessment?

We decided to follow up on the previous work and ask what else is different about these people with diabetes and Alzheimer, and it was the fact that elderly people with diabetes are treated for their diabetes. In fact, when we looked at that in a second study, we found that all of the reductions in neuropathology that we were seeing were coming from people who were treated with insulin and oral antidiabetic agents. That intrigued us and we thought, “Well, why is that?” and, “Is there some way that we can capitalize on that from a treatment of Alzheimer disease and dementia perspective?” and, “Are there things that we could do that would reduce the likelihood of dementia or, at least cognitive impairment, in those that people with diabetes who do develop cognitive impairment?”

One of the primary things that have been known about diabetes forever, is that there are vascular abnormalities that are associated with diabetes. That’s why you get some of the diabetic neuropathies, you get the vision impairments in diabetes, and a lot of the impairments that go along with diabetes seem to be traceable to changes in the vascular system. We thought maybe there are changes in the vascular system in the brain and that’s why we’re seeing that with diabetes, and that maybe the treatment of diabetes is preventing these lesions that occur in the brain in the presence of diabetes.

So, we essentially developed methods for isolating brain capillaries from post-mortem tissue and looked at those capillaries from a molecular biological perspective in terms of what RNAs are expressed in those capillaries, and to what extent are those RNAs, are the capillaries, different in Alzheimer disease, in diabetes, and in Alzheimer disease and people with diabetes who are being treated with antidiabetic agents. That’s what this paper is all about.

What were the findings of the study?

What we found was that the treatment in those people who were being treated with anti-diabetic agents, the molecular biological changes in the capillaries that we saw in Alzheimer disease were reduced to a very large extent.

Obviously, it doesn’t mean that we can take people with Alzheimer disease and start giving them insulin and anti-diabetic agents when they don’t have diabetes, but it does point us to what pathways may be involved and opens the possibility that maybe we can find other mechanisms which we can prevent the changes that are occurring in the capillaries. Essentially, we’ve identified some target RNAs and some target proteins through this paper that one can go after to find medications, find treatments, that affect those particular targets and hopefully then reduce the Alzheimer associated lesions.

What is the main takeaway you want the clinician community to know?

That if there is diabetes in the presence of Alzheimer disease, is absolutely critical to treat the diabetes as aggressively as possible. In doing so, you will essentially be doing 2 things that are good: One is treating the diabetes itself, but then the secondary effect of that treatment would be to possibly reduce the impact of the Alzheimer disease. Very often, once you’ve identified Alzheimer changes, there’s a tendency to be less aggressive with other treatments and people then concentrate on treating the Alzheimer disease—which absolutely you should do—but what our data indicates is that being very vigilant and diligent in treating the diabetes itself can potentially have beneficial effects.

We were looking to identify targets that haven’t been addressed in the past, and generally, when people think about treatment of Alzheimer disease, they don’t think about treatments that are directed towards the capillaries and the microvascular system of the brain. Our data suggest that is an area that’s worth further study and further focus. There are clinical trials for Alzheimer disease that are consistent with this. There are clinical trials where there are people with Alzheimer disease are being administered with insulin through the nasal passage where the insulin is going to affect the brain, but it’s not necessarily going to affect the rest of the body because it’s a more direct route to the brain when you administer it through the nasal cavity. Our data would suggest that, potentially, those kinds of treatments are worth pursuing. Potentially, those treatments with insulin would be even more effective if they were combined with oral agents, or at least, agents that have similar effects on the brain as the oral agents, like metformin, for example, has in diabetes.

Transcript edited for clarity.