In a recent study, scientists at the Karolinska Institute in Stockholm, Sweden, and the National Institute of Aging, investigate the association between the risk for Alzheimer’s disease (AD) and genetic variation in the targets of four classes of anti-diabetic drugs.

Sara Hägg, PhD, research group leader in molecular epidemiology at the Karolinska Institute, is the senior author of the study. [Andreas Andersson]

Senior author of the study, Sara Hägg, PhD, research group leader in molecular epidemiology at the Karolinska Institute said, “We need to find new strategies to prevent AD. If there are drugs that can be repurposed for the primary prevention of AD, this could speed up the drug discovery process. There is some prior observational evidence for an association between diabetes and AD, which inspired our investigation to dig deeper.”

In addition to neuronal loss, amyloid deposits, and cognitive decline, AD is accompanied by insulin resistance and impaired glucose control in the brain, which has led scientists to designate it “type 3 diabetes.”

Developing new drugs for AD is critical. But with nearly 400 candidates failing Phase III trials in recent years, scientists are considering alternative possibilities of repurposing and repositioning drugs approved for other diseases, reasoning that these drugs that already have well-documented mechanistic and safety profiles offer a quicker and more cost-effective route to AD therapeutics.

Anti-diabetic drugs that aim to increase insulin signaling and regulate glucose metabolism, have been highlighted as candidates that could be repurposed for AD, in earlier studies.

In a new research article published in the journal Neurology titled, “Genetic Variation in Targets of Anti-diabetic Drugs and Alzheimer Disease Risk: A Mendelian Randomization Study,” researchers identified a genetic link between targets of anti-diabetic drugs and risk for AD, where individuals harboring protective genetic variants that mimic the modulation of sulphonylureas, a class of anti-diabetic drugs, have a lower risk of AD.

In this study, the researchers analyzed genetic summary statistics for blood glucose from 326,885 participants from the UK Biobank data and summary statistics for AD from genome-wide association studies (GWAS) of 24,087 patients clinically diagnosed with AD as well as 55,058 normal individuals.

“We have identified genetic variants that mimic this drug target modulation for diabetes drugs by searching through different databases and performing validation analyses using genotype data,” explained Hägg.

Bowen Tang, a PhD student at the department of medical epidemiology and biostatistics at the Karolinska Institute, is the lead author of the study. [Yali Wang]

First author Bowen Tang, a PhD student at the department of medical epidemiology and biostatistics at the Karolinska Institute said, “Genetic variants within or nearby the genes that encode a drug’s target proteins can cause physiological changes similar to the effects of the drug. We utilize such variants to test the repurposing potential of already approved drugs.”

Based on the large dataset, the authors conducted a two-sample Mendelian randomization study, which is a statistical tool that uses genetic variants as “instrumental variables” that make it possible to draw causal inferences from observational data, such as causal inferences between exposures and outcomes. In this study design, genetic variants are assigned randomly, before the onset of disease, and is therefore considered a “natural” randomized controlled trial as it minimizes confounding and reverse causation. In addition, the researchers conducted positive control analysis on type 2 diabetes (T2DM), insulin secretion, insulin resistance, and obesity-related traits to validate the selection of instrumental variables.

Susanna Larsson, PhD, an associate professor of surgical sciences at Uppsala University, and who was not involved in the current study, said, “This is an interesting and very well-conducted study based on the Mendelian randomization design, which reduces biases, such as confounding and reverse causality, that are common in traditional observational studies. The study provides evidence that anti-diabetic drugs, specifically sulfonylureas, may reduce the risk of AD. Considering the paucity of modifiable risk factors for AD and the increasing prevalence of this disease, the findings of this study can be of great clinical and public health importance. However, further research is necessary to confirm these findings.”

“This work investigates genetic variants that mimic interventions for T2DM, in particular sulfonylureas. Individuals carrying such variants have a low level of natural protection against T2DM, equivalent to taking a lifelong low dose of this drug. In addition to their associations with risk of T2DM and other diabetes-related traits, such as insulin secretion, body mass index, and waist circumferences, these variants were also shown to be associated with lower risk of AD,” said Stephen Burgess, PhD, a statistician and research group leader at the MRC Biostatistics Unit at the University of Cambridge.

Burgess added, “This provides intriguing evidence from human genetics that interventions on pathways targeted by T2DM medications may also reduce the risk of AD. These results must be validated in randomized trials before affecting clinical practice but provide an early indication of a potential route to reduce AD risk. Similar associations with AD were observed for genetic variants that mimic GLP-1 [glucagon-like peptide-1] agonists, although the evidence is less convincing due to less certainty in how well the genetic variants mimic this class of antidiabetic drugs.”

The findings open doors for future investigations into the biological mechanisms in the brain that link the genetic variants that protect against diabetes and the mechanism of action of sulfonylureas with the risk for AD.