Scientists have discovered 75 genetic risk factors for Alzheimer’s disease in research which could help with the development of new therapies.
An international group of scientists from Inserm, Institut Pasteur de Lille, Lille University Hospital, and Université de Lille and the University of Bristol set out to understand the link between certain genetic factors and Alzheimer’s disease.
The scientists undertook the largest ever genome-wide associated study (GWAS) on a group of 111,326 people with Alzheimer’s or who had close relatives with the condition, as well as 677,663 healthy participants who acted as the control group1. To identify genetic risk factors associated with the disease, the scientists analysed the entire genome of everyone in the research.
This resulted in the scientists identifying 75 areas of the genome which are associated with the disease, 42 of those having never been implicated with Alzheimer’s disease before now. The team now hopes that this new biological understanding will open up new avenues for treatment and diagnosis.
Alzheimer’s disease is the most common form of dementia and usually develops after the age of 65. Scientists know that the disease has a strong genetic component, and most cases are thought to be caused by the interaction of different genetic predisposition factors with environmental (e.g. diet, lifestyle) factors. Currently, the only medications available to treat Alzheimer’s disease are mostly aimed at slowing cognitive decline and reducing certain behavioural disorders.
In Alzheimer’s disease, two damaging processes are already well understood: the accumulation of amyloid-beta peptides and the modification of the protein Tau, aggregates of which are found in brain cells.
In this recent study, the scientists confirmed the importance of these pathological processes. The team’s analyses of the various genome regions confirmed 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 (immune cells present in the central nervous system act like a “trash collector” to eliminate damaging substances) is at play in Alzheimer’s disease.
Finally, this study shows for the first time that the tumour necrosis factor alpha (TNF-alpha)-dependent signalling pathway, important in inflammation, is involved in disease.
Professor Pat Kehoe, Gestetner Professor of Translational Dementia Research at Bristol Medical School, said: “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.”
“These findings confirm and add to our knowledge of the pathological processes involved in the disease and opens up new avenues for therapeutic research. For example, they confirm the utility of the following: the conduct of clinical trials of therapies targeting the amyloid precursor protein, the continuation of microglial cell research that was initiated a few years ago, and the targeting of the TNF-alpha signalling pathway.”
In order to validate and expand their findings, the team would now like to continue its research in an even broader group. Beyond this exhaustive characterisation of the genetic factors of Alzheimer’s disease, the team is also developing numerous cellular and molecular biology approaches to determine their roles in its development.
Furthermore, with the genetic research having been conducted primarily on Caucasian populations, one of the considerations for the future will be to carry out the same type of studies in other groups to determine whether the risk factors are the same from one population to the next, which would reinforce their importance in the pathophysiological process.
The team also developed 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. The tool isn’t intended for clinical use yet, but it could be used for setting up clinical trails to help categorise a patient’s risk factor.