02/10/2020

In this week’s edition of Science, researchers at VIB and the UK DRI highlight the need for a better understanding of the environmental and genetic risks of Alzheimer’s disease. Gene variants should be studied in the right cell types and in the right context, they argue, if we want to make progress in our search for effective therapies.

The number of people suffering from dementia worldwide already slightly exceeds the number of people with cancer today, and is expected to increase even more over the next decades. But just like cancer, dementia may arise as a consequence of a variety of disease mechanisms.

Alzheimer’s disease is the most well-known and also the most common cause of dementia; but since clinical dementia often manifests only late in life, the conflation between the two complicates scientific and clinical studies, explains Annerieke Sierksma from the VIB-KU Leuven Center for Brain & Disease Research:

“People with mild Alzheimer’s symptoms may be excluded, and those who are, unknowingly, in the pre-symptomatic stages could be mixed in as healthy controls. This decreases our chances of fully mapping the genetic basis for Alzheimer’s and thus makes it more difficult for us to understand the molecular and cellular triggers that cause someone to develop the disease.”

The way forward would be to zoom in on genetic risk. A large proportion of the genetic risk of Alzheimer’s is explained by common variations in the genome. Each individual variation on its own does not predict a person’s risk of disease, but it can be combined in a so-called polygenic risk score. The authors state that the field is currently struggling to translate the concept of polygenic risk scores into meaningful functional hypotheses about what causes Alzheimer’s.

“Over the past decades, we have made tremendous progress to map the genetic landscape of Alzheimer’s disease,” says Bart De Strooper. “But interpretation of this genetic risk becomes critically dependent on a better definition of the disease and its underlying mechanisms.”

Sierksma believes we need a more refined definition of all aspects of Alzheimer’s disease to help clear up the existing confusion. To do so, we need to model better, not more.

“At the functional level, we need to get away from the classical molecular biology paradigms of one gene, one function, one drug target. Gene variants affect gene function in specific genetic backgrounds (mice are not humans), in specific cell types, in specific cell states, and in specific stages of the disease,” she writes in a new review published in this week in Science, together with De Strooper (VIB-KU Leuven) and Valeria Escott-Price (Cardiff University, UK DRI).

An improved definition should also take into account the preclinical phase of Alzheimer’s, when disease processes in the brain have been set in motion but clinical symptoms do not yet manifest.

According to De Strooper, this lack of mechanistic understanding of genetic variation has become the major bottle neck in the search for novel drug targets for Alzheimer’s. He is convinced that more sophisticated models that better represent specific disease mechanisms and better stratification of patients will accelerate the journey from therapeutic concept to clinic. 

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