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The compromised microvascular and insulin receptor signaling pathways seen in Alzheimer disease have been shown to be reduced or normalized by exposure to antidiabetic therapies.
Vahram Haroutunian, PhD
Exposure to antidiabetic treatments may help reduce or normalize the compromised microvascular and insulin receptor signaling pathways (IRSP) observed in Alzheimer disease, according to data from the first study of its kind.
The results showed that those who had been treated with anti-diabetic agents had significantly reduced numbers of abnormally expressed microvasculature and IRSP associated genes. The data suggest that vigilance and diligence in the treatment of diabetes can potentially have beneficial effects on Alzheimer disease for those patients.
“If there is diabetes in the presence of Alzheimer disease, is absolutely critical to treat the diabetes as aggressively as possible,” Vahram Haroutunian, PhD, a professor of psychiatry and neuroscience at the Icahn School of Medicine at Mount Sinai, told NeurologyLive. “In doing so you will essentially be doing 2 things that are good. One is treating diabetes itself, but then the secondary effect of that treatment would be to possibly reduce the impact of the Alzheimer’s disease.”
Led by Haroutunian, this new study sought to follow-up on the link between diabetes and Alzheimer by exploring vessels and brain tissue of donors with Alzheimer without type 2 diabetes (n = 19) and those with both Alzheimer and type 2 diabetes (n = 34), as well as a group of controls (n = 30).
“Some years ago, we decided to look at [the link between diabetes and Alzheimer] 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 than you would expect than if it was just Alzheimer disease without diabetes,” Haroutunian said. “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. That was puzzling.”
“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,” he added.
Findings showed that, compared to controls’ micro RNA expression in whole tissue, 12 of the 18-endothelial cell and IRSP associated genes assayed were significantly (unadjusted P <.05; 6 of 12 after false discovery rate [FDR] correction) altered in Alzheimer patients. In donors with Alzheimer who had a history of receiving antidiabetic treatment, only 4 of these 12 genes remained significant before FDR correction and only 1, ANGPT1, after FDR correction.
The micro RNA expression in endothelial cells of the parahippocampal gyrus showed that compared to the controls, when unadjusted for FDR, 5 endothelial and IRSP-related genes were abnormally expressed in untreated donors with Alzheimer. None of the associated genes met the FDR-corrected threshold. Of note, the IRS1 expression level was unchanged in donors with Alzheimer but was significantly increased in those with Alzheimer who had been treated with antidiabetic medications (P = .05)
As well, 23 micro RNAs were examined in parahippocampal gyrus samples for non-IRSPs and non-endothelial cells. Unsurprisingly to Haroutunian and colleagues, the expression of 8 of these was affected in the whole tissue homogenates of untreated donors with Alzheimer. Antidiabetic medication exposure reduced the number of adversely affected mRNAs to 3. Significantly fewer of these markers were affected in the endothelial cell-enriched fraction, where 2 of the 23 markers were affected in untreated Alzheimer samples and altered expression remained significant, though nominally moderated in the treatment group.
Noted by Haroutunian and colleagues, the lack of brains from donors with both Alzheimer and diabetes which were untreated with antidiabetic agents was a considerable weakness, though as the vast majority of patients with type 2 diabetes are treated with these agents, the untreated donor would be difficult to include.
“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,” Haroutunian explained. “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.”
Although this study could not determine whether or not these abnormalities contribute to the genesis of Alzheimer neuropathology, or whether they result from other neuropathological changes, given the dual epidemics of type 2 diabetes and dementia in the most rapidly growing group of the population, Haroutunian and colleagues stated that there is enormous importance in elucidating the basis for cognitive impairment in type 2 diabetes so that potentially meaningful interventions can be evaluated.
“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, and our data suggests that is an area that’s worth further study and further focus,” Haroutunian said.
Katsel P, Roussos P, Beeri MS, et al. Parahippocampal gyrus expression of endothelial and insulin receptor signaling pathway genes is modulated by Alzheimer’s disease and normalized by treatment with anti-diabetic agents. Plos One. Epub November 1, 2018.