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Landmark study reveals 42 new genes associated with increased risk of Alzheimer’s disease

4 April 2022

A major new international study involving researchers from Cardiff University has identified 75 genes associated with an increased risk of developing Alzheimer’s disease, including 42 new genes which had not previously been implicated in the condition.

As well as confirming previous findings implicating the proteins amyloid-beta and tau that build up in and around nerve cells as the disease progresses, the study provides compelling evidence to support a role for inflammation and the immune system in the disease.

Alzheimer’s disease is the most common cause of dementia, a condition that affects more than 850,000 people in the UK.

The largest study of its kind involved researchers analysing the genome of more than 100,000 people with Alzheimer’s disease and comparing them with more than 600,000 healthy individuals to look for differences in genetic makeup.

In the UK, the project was co-led by researchers Dr Rebecca Sims and Professor Julie Williams from the UK Dementia Research Institute (UK DRI) at Cardiff University, and funded by the Medical Research Council.

The findings are published today in the journal Nature Genetics.

Dr Rebecca Sims, Senior Research Fellow at Cardiff University and UK DRI Co-Investigator, and co-leader of the study, said: “This study more than doubles the number of identified genes influencing risk for the more common form of Alzheimer’s disease. It provides exciting new targets for therapeutic intervention and advances our ability to develop algorithms to predict who will develop Alzheimer’s in later life.”

Professor Julie Williams, Centre Director at the UK DRI at Cardiff University, co-author of the study and leader of the Genetic and Environmental Risk for Alzheimer’s disease consortium, said: “This is a landmark study in the field of Alzheimer’s research and is the culmination of 30 years’ work. Genetics has and will continue to help us identify specific disease mechanisms which we can target therapeutically. This piece of work is a major leap forward in our mission to understand Alzheimer’s, and ultimately produce several treatments needed to delay or prevent the disease.

“The results support our growing knowledge that Alzheimer’s disease is an extremely complex condition, with multiple triggers, biological pathways and cell types involved in its development. We are unmasking more of these causes year on year, and this also provides greater opportunities from which to develop therapeutics.”

The findings show for the first time that a specific biological signalling pathway involving TNF-alpha, a protein with an important role in inflammation and the immune system, is implicated in Alzheimer’s.

Additionally, there is more evidence that the dysfunction of microglia, immune cells in the brain that are responsible for eliminating toxic substances, contribute to disease pathology.

Based on these results, the researchers also devised a genetic risk score to determine how likely patients with cognitive impairment will, within three years of first showing symptoms, go on to develop Alzheimer's disease. The score is not intended for use in clinical practice at present, but researchers hope it will improve the evaluation of new drugs in clinical trials.

In future, the scientists hope the findings can be used to identify people within the population who are at greatest risk of developing Alzheimer’s disease before they start to develop the condition.

The project was carried out in research centres in eight partner countries, including the UK, US, Australia and across Europe and spearheaded by Professor Jean-Charles Lambert, Research Director of Inserm, the French National Institute of Health and Medical Research.

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