A new study has identified 75 genes associated with an increased risk of developing Alzheimer’s disease, with 42 of these not previously linked to the condition.
The findings of the international research, and largest study of its kind, could now be set to open new avenues for treatment and diagnosis.
Alzheimer’s disease is the most common form of dementia, a chronic neurodegenerative disorder that affects more than 26million people worldwide, with no treatment available to improve the course of the disease.
To better understand the origins of the disease, one of the major challenges of research is to better characterise its genetic risk factors by identifying the biochemical and cellular processes affected, and thereby propose novel therapeutic targets.
As part of an international collaboration, researchers from Inserm, Institut Pasteur de Lille, Lille University Hospital and Université de Lille, alongside Bristol Medical School at the University of Bristol, conducted a genome-wide association study (GWAS) on the largest Alzheimer’s patient group ever created, under the co-ordination of Inserm Research Director Professor Jean-Charles Lambert.
Encouraged by advances in genome analysis, these studies consist of analysing the entire genome of tens of thousands or hundreds of thousands of individuals, whether healthy or sick, with the aim of identifying genetic risk factors associated with specific aspects of the disease.
Using this method, the scientists were able to identify 75 regions of the genome associated with Alzheimer’s, 42 of which had never previously been implicated in the disease.
“Following this major discovery, we characterised these regions in order to give them meaning in relation to our clinical and biological knowledge, and thereby gain a better understanding of the cellular mechanisms and pathological processes at play,” explained Prof Lambert.
In Alzheimer’s disease, two damaging processes are already well documented – the accumulation of amyloid-beta peptides and the modification of the protein Tau, aggregates of which are found in brain cells.
Here, the scientists confirmed the importance of these pathological processes. Their analyses of the various genome regions confirm that some are implicated in amyloid peptide production and Tau protein function.
Furthermore, these analyses also reveal that a disturbance of innate immunity and of the action of the microglia is at play in Alzheimer’s disease.
Dr Susan Kohlhaas, director of research at Alzheimer’s Research UK, said: “Previous genetic discoveries underpin much of our current understanding of Alzheimer’s disease and the direction of research into new treatments.
“Creating an extensive list of Alzheimer’s disease risk genes is like having the edge pieces of a puzzle put together, and while this work doesn’t give us the full picture, it provides a valuable framework for future developments.
Professor Pat Kehoe, Gestetner Professor of Translational Dementia Research at Bristol Medical School, added: “Despite the knowledge we are amassing as to the biological mechanisms of Alzheimer’s disease we are still faced by gaps in our understanding.
“This means the devil is still in the detail and where studies like this will help to us to begin to fill those gaps and indeed something that future tissue studies from our own South West Dementia Brain Bank may continue to help in furthering our understanding of the proteins that these genes make in the disease process.”
Based on their findings, the researchers also devised a genetic risk score to try to better evaluate which patients with cognitive impairment will, within three years of the initial emergence of memory problems, go on to develop Alzheimer’s disease.
“While this tool is not at all intended for use in clinical practice at present, it could be very useful when setting up therapeutic trials in order to categorise participants according to their risk and improve the evaluation of the medications being tested,” added Prof Lambert.
