Identifying genetic risk factors for Alzheimer's disease is essential if we are to improve our understanding and treatment of it. Progress in human genome analysis along with genome-wide association studies are now leading to major advances in the field. Researchers in Europe, the US and Australia have identified 75 regions of the genome that are associated with Alzheimer's disease. Forty-two of these regions are novel, meaning that they have never before been implicated in the disease. The findings, published in Nature Genetics, bring new knowledge of the biological mechanisms at play and open up new avenues for treatment and diagnosis. The group at the University of Cologne, Professor Dr Alfredo Ramirez at University Hospital Cologne and the Faculty of Medicine, was responsible for establishing and testing risk scores reflecting the genetic predisposition for Alzheimer’s disease.
‘The article in “Nature Genetics” is the result of a joint effort of the largest European consortium for Alzheimer's disease, the European Alzheimer's DNA Biobank (EADB). In this study, we were able to double the number of genetic regions that modulate Alzheimer's disease risk. As a result, we now have 75 regions carrying variants that increase the risk of Alzheimer's dementia. We show in this paper that when these 75 genetic regions are combined into a score that reflects the genetic burden for Alzheimer's disease, individuals with a higher score have a higher likelihood of progressing to the end stage of Alzheimer's disease, that is, the dementia stage. Finally, we have identified several molecular signaling pathways associated with Alzheimer's risk that represent an interesting target for future intervention,’ explained Professor Ramirez, head of the Section of Neurogenetics and Molecular Psychiatry at the Department of Psychiatry and Psychotherapy at University Hospital Cologne and the Faculty of Medicine. Ramirez also conducts research at the UoC’s CECAD Cluster of Excellence for Aging Research.
The project ‘Identification of genetic risk factors influencing the progression rate of Alzheimer's disease’ within the EADB was funded by the German Federal Ministry of Education and Research. The EADB is funded as part of the ‘EU Joint Programme - Neurodegenerative Disease Research (JPND)’.
Alzheimer's disease is the most common form of dementia, affecting around 1.6 million people in Germany. This complex, multifactorial disease, which usually develops after the age of 65, has a strong genetic component. The majority of cases are thought to be caused by the interaction of different genetic predisposition factors with environmental factors.
Although our understanding of the disease continues to improve, there is no cure at this time. The medications available are mainly aimed at slowing cognitive decline and reducing certain behavioural disorders. In order to better understand the origins of the disease, one of the major challenges of research is to better characterize its genetic risk factors by identifying the pathophysiological processes at play, and thereby propose novel therapeutic targets.
Genome-wide association studies analyse the entire genome of tens of thousands of individuals, whether healthy or sick, with the aim of identifying genetic risk factors associated with specific aspects of the disease. In order to grasp the entire genome, several millions of specific genetic variations were compared, which are spread across the entire human genome. Using this method, the scientists were able to identify 75 regions (loci) of the genome associated with Alzheimer's, 42 of which had never previously been implicated in the disease.
Highlighting pathological phenomena
In Alzheimer's disease, two pathological brain phenomena are already well documented: namely, the accumulation of amyloid-beta peptides and the modification of the protein Tau, aggregates of which are found in the neurons. 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 dysfunction of innate immunity and of the action of the microglia (immune cells present in the central nervous system that play a ‘trash collector’ role by eliminating toxic 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 is involved in disease.
These findings confirm and add to our knowledge of the pathological processes involved in the disease and open 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.
Risk score
Based on their findings, the researchers also devised a genetic risk score in order to better evaluate which patients with cognitive impairment will, within three years of its clinical manifestation, 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 categorize participants according to their risk and improve the evaluation of the medications being tested,’ said Ramirez.
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 characterization 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 populations of European heritage, one of the considerations for the future will be to carry out the same type of studies in other groups in order to determine whether the risk factors are the same from one population to the next, which would reinforce their importance in the pathophysiological process.
Publication:
DOI: 10.1038/s41588-022-01024-z
https://www.nature.com/articles/s41588-022-01024-z
Media contact
Professor Dr. Dr. med Alfredo Ramirez
Head of Neurogenetics and Molecular Psychiatry
Clinic and Polyclinic of Psychiatry and Psychotherapy
University Hospital Cologne, Faculty of Medicine of the University of Cologne
+49 221 47898041
alfredo.ramirez[at]uk-koeln.de
Press contact
Mirko Ristau
Deputy press spokesperson
University Hospital Cologne
+49 221 478 5548 and +49 152 54695952
Publication:
DOI: 10.1038/s41588-022-01024-z