A cost-effective tool to obtain individual risk profiles
Alzheimer’s is a very complex disease with many different underlying causes. This leads to differences in clinical symptoms and implies that some treatments may only be effective for specific groups of patients. So far, experimental drugs have been typically tested on mixed patient groups, which could partially explain their high failure rate.
While non-familial forms of neurodegenerative diseases are the most common, specific gene variants can be strong risk factors. Today we lack the knowledge and tools to screen people at risk based on genetic information, and to link this to individual disease mechanisms.
So far, about 30 Alzheimer’s risk genes have been identified. Many risk genes are highly active in a specific type of cells in the brain, called microglia, which are involved in immune responses. In the brains of patients, microglia don’t function well, causing abnormal, harmful immune reactions.
By identifying which risk genes a person has, geneticists can calculate a personalized ‘polygenic risk score’. These scores are becoming increasingly powerful in predicting the chance that someone will develop Alzheimer’s disease, but their ability to predict the underlying disease mechanisms remains to be validated.
In addition, we can use blood samples to detect and measure specific changes in immune responses caused by the abnormal activity of microglia. The latest laboratory methods are so advanced that over 1,500 parameters can be studied – known as ‘deep-immunophenotyping’.
We will link the polygenic risk scores of Alzheimer’s patients with changes in immune responses, to obtain more informative individual risk profiles. In the long term, this approach will be valuable not only to fight Alzheimer’s disease, but also many other diseases that have a strong genetic component.
Sierksma et al. 2020 (Science) Translating genetic risk of Alzheimer’s disease into mechanistic insight and drug targets
This article reviews the genes associated with a higher risk for Alzheimer’s disease, and highlights the need for a mechanistic understanding of the different forms of genetic risk. (Read the VIB news article)
Sierksma et al. 2020 (EMBO Mol Med) Novel Alzheimer risk genes determine the microglia response to amyloid‐β but not to TAU pathology
This study coordinated by Prof. Bart De Strooper and Dr. Mark Fiers investigated the link between Alzheimer’s risk genes and the two major disease hallmarks, amyloid-beta and tau pathology, in mouse models. The results show that the genetic risk for Alzheimer’s is reflected in the responses of microglia (the brain’s immune cells) to amyloid, rather than to tau.
Sala Frigerio et al. 2019 (Cell Reports) The Major Risk Factors for Alzheimer’s Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques
The research group of Prof. Bart De Strooper investigated the microglia response to amyloid in a mouse model for Alzheimer’s disease. The response seemed to be influenced by the three main risk factors for the disease (aging, gender and genetics), suggesting that microglia are a potential therapeutic target. (more information)