Diabetes Meds May Reduce Alzheimer's Pathology

Pauline Anderson

November 08, 2018

Diabetes drugs, including insulin and oral agents, appear to reduce Alzheimer's disease (AD) pathology, new research suggests.

Dr Vahram Haroutunian

Investigators at the Icahn School of Medicine at Mount Sinai, New York City, found changes in gene expression in the parahippocampal gyri in patients who had had type 2 diabetes (T2D) and AD relative to patients with T2D who had not had AD.

In addition, the number of abnormally expressed genes in AD patients who had been treated with antidiabetic agents was significantly reduced.

"This study suggests there are significant microvascular changes in the brains of people with Alzheimer's disease and diabetes, and that antidiabetes drugs seem to help normalize those abnormalities," principal investigator Vahram Haroutunian, PhD, professor of psychiatry and neuroscience at Icahn, told Medscape Medical News.

"We can take advantage of this new knowledge and begin to look at drugs that could reverse those abnormalities without affecting blood glucose. So it has given us a new target," he added.

The study was published online November 1 in PLOS One.

Close Relationship

A large body of evidence points to a close relationship between diabetes and AD.

"People with diabetes appear, from an epidemiological population point of view, to be more susceptible to Alzheimer's disease and to be more susceptible to dementia as a whole," said Haroutunian, who is also associate director for research at the Veterans Administration Mental Illness Research and Education Clinical Center, New York City.

Researchers assumed this meant individuals with dementia and diabetes would have more hallmark AD lesions, such as amyloid plaques and tau tangles, than those with dementia but not diabetes.

However, previous research showed that this was not the case, a situation Haroutunian found "puzzling" at the time.

A follow-up study by his team suggested the reason AD pathology is not more prominent in these patients may be that the patients had undergone treatment with antidiabetic medications.

"We wanted to know what it is that these antidiabetic drugs are doing," said Haroutunian.

Additional research identified the brain's insulin receptor signaling pathway (IRSP) as an underlying mechanism by which diabetes medications may modulate AD neuropathology.

Postmortem Study

To better understand the neurobiologic substrates of T2D and T2D medications in AD, the investigators developed a method of separating brain capillaries from brain tissue.

"We focused on capillaries and the microvasculature because we know that diabetes affects capillaries and microvasculature. That's why these patients have diabetic retinopathies and are prone to peripheral vascular diseases," said Haroutunian.

Using postmortem human tissue samples, the researchers examined gene expression in the parahippocampal gyri, with the goal of determining the extent to which IRSP and endothelial cell–related transcripts were altered in patients with AD in comparison with individuals who did not have AD.

They also examined whether AD-associated changes were normalized in the brains of patients with AD who had received antidiabetic medications of any kind and in any combination, including those who had received only insulin, those who had received only oral agents, and those who had received insulin plus oral agents.

The analysis included samples from 34 patients with AD and T2D, 19 from patients with AD but without T2D, and 30 people without AD or T2D, who served as control persons.

All donors had been older than 65 years (mean age, 85.3 years). Overall, the distribution of age, sex, and race was similar between groups.

The analyses revealed considerable abnormalities and reductions in gene expression in patients with AD that map directly to genes associated with the microvasculature and the IRSP.

The findings also indicated that the number of abnormally expressed genes associated with microvasculature IRSP in diabetic AD donors who had been treated with antidiabetic agents was significantly reduced.

Haroutunian noted that at least five markers were statistically significantly affected in patients who had had AD, and that in individuals who had been treated for diabetes, those microvascular abnormalities were "normalized" in the great majority of targets.

Even in areas where there was statistically significant reduction, "it was a nominal reduction," said Haroutunian, "so it was moving toward normality."

One of the examples the investigators used was expression levels of GLUT4 (SLC2A4), which encodes for an insulin-regulated glucose transporter. Levels of expression of this transcript were significantly reduced in the endothelial cell–enriched isolates from AD patients.

On the other hand, the levels of expression of this transcript in patients who had had both AD and T2D and who had undergone treatment with antidiabetic medications were similar to the levels detected in control persons.

"This suggests that anti-diabetic medications restored homeostasis to this critical glucose transporter and that dis-homeostasis of glucose transport in brain endothelial and non-endothelial cells may be a critical abnormality in AD that is restored by anti-diabetes medications," the authors write.

Normalization of abnormally expressed genes in AD by antidiabetes treatments went beyond transcripts associated with the IRSP and endothelial cells, carrying over to genes associated with immune-inflammation, microglia, cell adhesion, and synaptic function, investigators report.

New Targets for Drug Development?

These new results reinforce the idea that antidiabetes drugs "have the potential to reduce AD lesions," said Haroutunian.

Although it may seem reasonable to use diabetes medications to prevent dementia, "it would be unwise to give antidiabetes drugs directly to people who don't have diabetes.

"Obviously, you don't want to drive down blood glucose levels in people who don't have high blood glucose," said Haroutunian

He added that the mechanism by which antidiabetes drugs exert a positive effect on the brain may not be through blood glucose control.

"We don't know whether these medications are affecting those molecular pathways independent of blood glucose," said Haroutunian. He added that this will be the next line of inquiry in this research.

He added that he hoped the study has helped define targets for drug development.

"One of the advantages of this study is that at least we know that we should be looking at the microvasculature," said Haroutunian.

Significant Limitation

The study did not include individuals with type 1 diabetes, a disease that is much rarer in older adults and that, from a biological point of view, is very different from T2D, said Haroutunian.

Importantly, the study did not include patients who had had both AD and T2D and whose T2D had gone untreated.

"That's a significant inadequacy of the study," said Haroutunian, inasmuch as the normalization of microvasculature and IRSP gene expression could be due to diabetes and not its treatment.

However, he noted that it would be difficult to find patients with untreated T2D. "There aren't that many people who have type 2 diabetes who are not being medicated in 2018," he said.

The investigators are starting to explore ways of reversing abnormalities without affecting blood glucose. For instance, they are investigating nasal delivery of insulin, which is believed to affect the brain but has a lesser impact on blood glucose.

So far, these efforts have had mixed results with regard to effects on dementia, said Haroutunian.

He emphasized that the new results underscore the importance of treating diabetes in older patients.

Another Piece of the Puzzle

Commenting on the study for Medscape Medical News, Keith Fargo, PhD, director of scientific programs and outreach at the Alzheimer's Association, said it "provides another piece of the story" of how diabetes mayaffect AD.

"What this study shows is that in people with Alzheimer's, a number of genes associated with insulin signaling are more or less active than in people without Alzheimer's," said Fargo.

"What it can't show is whether Alzheimer's is causing these changes in gene signaling, whether it's the other way around, or whether there is some other factor entirely affecting both," he added.

That certain genes were normalized in people with AD in the study who had been treated for diabetes is "interesting," said Fargo.

However, he noted that "this is not an open and shut case," since there were no people in the study who had had AD and untreated T2D.

"It's impossible to know whether the effects on genes in the diabetes group were caused by the diabetes treatment or the diabetes itself," he said.

Fargo believes it's too early to say that this new research suggests new targets for drug development.

The study was funded by the Department of Veterans Affairs and the Veterans Health Administration. Dr Haroutunian has disclosed no reelvant financial relationships.

PLoS One. Published online November 1, 2018. Full text

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