Genetic Knowledge of Alzheimer’s Expanded in Large International Study

Alzheimer: Phosphorylation of Tau proteins leads to disintegration of microtubuli in a neuron axon
Credit: selvanegra/Getty Images

A large international group of researchers in Europe, Australia and the U.S., led by scientists at the Institut Pasteur in Lille, have identified 42 new genetic regions linked to the pathology of Alzheimer’s disease.

As described in the journal Nature Genetics, the researchers also confirmed 33 previously discovered genetic regions linked to the condition.

Over 6 million people are estimated to have Alzheimer’s disease in the U.S., most of whom are over the age of 65 years. Despite this high number and many years of research, there is no cure for this neurodegenerative condition, only moderately effective treatments to manage the symptoms.

“Alzheimer’s disease is the most common form of dementia. The heritability is high, estimated to be between 60% and 80%,” write the authors.

“This strong genetic component provides an opportunity to determine the pathophysiological processes… and to identify new biological features, new prognostic or diagnostic markers and new therapeutic targets through translational genomics.”

Genetic studies can help enhance knowledge of Alzheimer’s and the neurological processes behind it, as well as help researchers and companies develop new and more effective treatments.

With this in mind, lead author Jean-Charles Lambert, Inserm Research Director, and colleagues carried out two large genome-wide association studies (GWAS) including 111,326 cases of Alzheimer’s disease (either clinically diagnosed or a diagnosis stated by relatives – ‘proxy’ cases) and 677,663 controls.

They discovered 75 risk areas in total, with functional analyses confirming action of the amyloid/tau pathway and also of dysfunctional microglia in the disease process. Microglia are specialized immune cells in the central nervous system that act to eliminate toxic or harmful substances from around nerve cells.

In the group of 42 new associations, the team identified 31 genes that added to knowledge of disease physiology. For example, implicating the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex.

The researchers used the genetic variants they discovered to build a polygenic risk score for the condition to assess risk of future disease in those carrying some or all of the variants. They found the relative risk of developing future Alzheimer’s or dementia, or progressing from a mild case to a serious case, increased by 60-90% comparing those in the lowest score group with the highest (top 10% with bottom 10%). Age and carriage of the APOE ε4 allele, which carries significant increased risk of the condition, were additive to the score and not included in it.

“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,” explained Lambert in a press statement.

The team now hopes to continue their work and further validate their findings. Particularly in a more ethnically diverse cohort, as the participants of this study were mostly from white European backgrounds.

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