Alzheimer’s Disease: The Identification of 75 Genetic Risk Factors Brings New Insights

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.​​


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. 

The findings, published in Nature Genetics, bring new knowledge of the biological mechanisms at play and open up new avenues for treatment and diagnosis. 

Alzheimer's disease is the most common form of dementia. 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 behavioral 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. 

As part of an international collaboration, Ruth Frikke-Schmidt from Department of Clinical Biochemistry, Copenhagen University Hospital – Rigshospitalet and her Danish colleagues have contributed with more than 10.000 genetic analyses to the study. The international collaboration is the largest genetic Alzheimer’s study set up until now and is under the coordination of Inserm Research Director Jean-Charles Lambert. 

Encouraged by advances in genome analysis, these studies consist of analyzing 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 (loci) of the genome associated with Alzheimer's, 42 of which had never previously been implicated in the disease. 

- Following this major discovery, we characterized 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, explains Lambert. 

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 tumor necrosis factor alpha (TNF-alpha)-dependent signaling 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 signaling 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. 

- This genetic risk score work paves the way for the development of a personalized risk estimation taking into account both genetic factors and other environmental risk factors,” explains Ruth Frikke-Schmidt, who is the Danish collaborator in the study.

-​ Our previous work in this field showed that prevention of cardiovascular risk factors is important. We discovered that a healthy cardiovascular lifestyle halves the risk of developing dementia even among the individuals with highest genetic risk. With the novel genetic findings from the European collaboration, we now have the possibility to develop a European dementia risk score, that precisely can identify the persons with highest risk that will benefit the most from early preventive interventions, says Ruth Frikke-Schmidt.

Sources

New insights into the genetic etiology of Alzheimer’s disease and related Dementias

Bellenguez et al

Researcher contact

Ruth Frikke-Schmidt, MD, PhD, DMSci
Chief Physician at Copenhagen University Hospital - Rigshospitalet
& Professor at Department of Clinical Medicine, University of Copenhagen
Ph: +45 3545 4348; mobile: +45 2281 2081 




Responsible editor