About TRIAGE
The many shapes and faces of Alzheimer's disease
The TRIAGE study has been designed to leverage the most recent advances in the field of genetics, immunology and stem cell biology to decipher the heterogeneity of Alzheimer's disease in terms of clinical presentations, genetic causes and underlying mechanisms. Our central hypothesis is that the individual genetic make-up largely accounts for the heterogeneity of Alzheimer's disease clinical presentation, and that a so-called polygenic risk score can be directly translated into specific cellular and molecular pathways that trigger and drive the disease.
We want to
- build a map of Alzheimer's clinical manifestations in relation to the polygenic risk score;
- identify the elements responsible for pathology in representative individuals across this map by using innovative disease models focusing on microglial responses;
- establish a preclinical therapeutic exploration platform that can be directly linked to the polygenic risk score;
- generate a roadmap towards personalized medicine for Alzheimer's disease.
Profiling (potential) patients
We are developing a method to link the individual genetic risk of developing Alzheimer's disease to functional information about the underlying disease process and manifestations. We focus on microglia, the immune cells of the brain.
We analyse DNA of 200 participants from a memory-clinic based cohort of individuals with biomarker-proven Alzheimer's disease at different clinical stages: prodromal (when dementia symptoms don't manifest yet), early, mid and late-stage dementia. We will also include 180 older adults at high genetic risk of developing Alzheimer's. For all participants, we calculate an individual Polygenic Risk Score and we profile the immune system. This data is integrated with clinical data to obtain a complete map linking genetic profiles and disease manifestations across the entire spectrum of Alzheimer's.
Tailored models of disease
We generate induced pluripotent stem cells from a selected subset of participants. These are differentiated into microglia, the primary immune cells of the brain, to see how they respond to Alzheimer's pathology. We will investigate how different polygenic risk scores affect the response of microglia to amyloid plaques, neuronal tangles and their interaction with synapses. This work will establish how AD genetic risk translates into microglia behavior, and point to molecular and cellular pathways contributing to pathogenesis.
Towards improved care
We want to use polygenic risk scores to refine inclusion criteria for clinical trials. Genetic stratification as applied today relies on only one gene polymorphism (APOE). The much more extensive and detailed polygenic risk score that we'll define through TRIAGE will allow a much more precise stratification. We hope to pave the way for more personalized medicine by:
- exploiting innovative and human-relevant pre-clinical disease models to gain a deeper understanding of the biological mechanisms that trigger and drive Alzheimer's disease;
- developing effective therapeutic interventions based on these biological insights by using translatable models and performing clinical trials on carefully stratified populations;
- using risk scores for early screening and to tailor the right therapeutic strategy for each individual at any given time, thereby drastically improving care.
