Target protein for diabetes drug linked to a lower risk of Alzheimer’s disease
According to a study from the Karolinska Institutet in Sweden that was published in the journal Neurology, mechanisms connected to a specific diabetic medication may also help protect against Alzheimer’s disease. The findings suggest that the target protein of the drug may be a promising candidate for the treatment of Alzheimer’s disease.
The prevalence of Alzheimer’s disease is rising, yet there are currently no treatments that may alter the course of the disease, and creating new medications is a lengthy, expensive, and challenging process.
Therefore, an alternative approach is to identify previously approved medications that may demonstrate effectiveness against the condition and provide them with a new area of use. Diabetic medications have been proposed as potential possibilities, however, up to this point, no conclusive evidence has been obtained from studies testing diabetes medications for Alzheimer’s disease.
In the current study, scientists from Karolinska Institutet employed genetic techniques to investigate this in further detail.
“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,” says the study’s first author Bowen Tang, a doctoral student at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet. “We utilize such variants to test the repurposing potential of already approved drugs.”
The researchers began by identifying genetic variants that mimic the pharmacological effect of diabetes drugs, namely lowering blood glucose. This was done through an analysis of data from over 300,000 participants in the UK Biobank register.
The analysis identified variants in two genes that together code for the target protein of a class of diabetes drugs called sulphonylureas. The researchers validated these variants by showing their association with, amongst other phenomena, higher insulin release, lower type 2 diabetes risk, and higher BMI, which is consistent with the drug’s effects.
The researchers then examined the link between the identified genetic variants and the risk for Alzheimer’s disease. They did this by analyzing data collected previously from over 24,000 people with Alzheimer’s disease and 55,000 controls. They found that the genetic variants in the sulphonylurea genes were linked to a lower risk of Alzheimer’s disease.
“Our results suggest that the target protein of sulphonylureas, the KATP channel, may be a therapeutic target for the treatment and prevention of Alzheimer’s disease,” says the study’s last author Sara Hägg, a docent at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet. “This protein is expressed in the pancreas, but also in the brain, and further studies are needed to fully understand the underlying biology.”
The method of analysis applied in the study is called Mendelian randomization which uses knowledge of genetic variants in individuals as a kind of natural randomization, not unlike a randomized clinical study. Individuals born with certain protective variants that mimic the effect of a certain drug can therefore be studied for their association with a disease.
Reference: “Genetic Variation in Targets of Anti-diabetic Drugs and Alzheimer Disease Risk: A Mendelian Randomization Study” by Bowen Tang, Yunzhang Wang, Xia Jiang, Madhav Thambisetty, Luigi Ferrucci, Kristina Johnell and Sara Hägg, 2 June 2022, Neurology.
The study was funded by the Swedish Research Council, a KI-NIH doctoral grant, Karolinska Institutet Foundation, Karolinska Institutet’s grant for the Strategic Research Area in Epidemiology (SFOepi), King Gustaf V and Queen Victoria’s Foundation of Freemasons and the National Institutes of Health. The researchers report no potential conflicts of interest.