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Target protein in diabetes drug linked to lower risk of Alzheimer’s

Mechanisms associated with a particular diabetes drug can also help to protect against Alzheimer’s disease, a study has reported.
The results of the Karolinska Institutet study published in Neurology on June 2 indicate that the drug’s target protein can be an interesting candidate for the treatment of Alzheimer’s disease.
Alzheimer’s disease is becoming increasingly common, but there are no drugs to affect the course of the disease and the development of new drugs is a slow, costly and complex process.
An alternative strategy is therefore to find already approved drugs that can prove efficacious against the disease and give them a new area of application.
Diabetes drugs have been put forward as possible candidates, but so far the studies that have tested diabetes drugs for Alzheimer’s disease have not produced convincing results.
In the present study, researchers from Karolinska Institutet used genetic methods to study this more closely.
Similar effects
“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,” said the study’s first author Bowen Tang, doctoral student at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet.
“We utilise 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 drug called sulphonylureas.
The researchers validated these variants by showing their association with, amongst other phenomena, higher insulin release, lower type two 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 analysing 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.
In the brain
“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,” said the study’s last author Sara Hägg, 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 randomisation which uses knowledge of genetic variants in individuals as a kind of natural randomisation, not unlike a randomised clinical study.
Individuals born with certain protective variants that mimic the effect of a certain drug can therefore be studied for their association to a disease.
The study was financed 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.
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Blood sugar spike after meals may increase Alzheimer’s risk

Sharp rises in blood sugar after meals may raise Alzheimer’s risk, according to genetic analysis of more than 350,000 adults.
The findings point to after-meal glucose, rather than overall blood sugar, as a possible factor in long-term brain health.
Researchers examined genetic and health data from over 350,000 UK Biobank participants aged 40 to 69, focusing on fasting glucose, insulin, and blood sugar measured two hours after eating.
The team used Mendelian randomisation, a genetic method that helps test whether biological traits may play a direct role in disease risk.
People with higher after-meal glucose had a 69 per cent higher risk of Alzheimer’s disease.
This pattern, known as postprandial hyperglycaemia (elevated blood sugar after eating), stood out as a key factor.
The increased risk was not explained by overall brain shrinkage (atrophy) or white matter damage, suggesting after-meal glucose may affect the brain through other pathways not yet fully understood.
Dr Andrew Mason, lead author, said: “This finding could help shape future prevention strategies, highlighting the importance of managing blood sugar not just overall, but specifically after meals.”
Dr Vicky Garfield, senior author, added: “We first need to replicate these results in other populations and ancestries to confirm the link and better understand the underlying biology.
“If validated, the study could pave the way for new approaches to reduce dementia risk in people with diabetes.”
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