TRanslating Individual Alzheimer GEnetic risk into disease phenotypes

Socio-economic needs for advances in the treatment of Alzheimer’s Disease (AD) are more pressing than ever. Lessons learned from clinical trial failures have led to important conceptual advances. The field notably shifted away from a purely neurocentric view, largely since Genome-Wide Association Studies identified several risk genes that are primarily expressed in microglia and not in neurons. The challenge is now to leverage this massive amount of genetic data to decipher disease mechanisms and design effective therapeutic interventions for AD. The fact that personalised genetic profiles (polygenic risk scores) can be generated opens unique possibilities for stratification of patients and personal medicine. We here propose to develop a method to link the individual genetic risk of developing AD to functional information about the underlying disease process and manifestations with focus on the microglia. We will genotype 200 participants from a memory-clinic based cohort of individuals with biomarker-proven AD at different clinical stages (prodromal, early, mid and late dementia stage). We will also include 180 participants from a longitudinal observation cohort of older adults at high genetic risk of developing AD. We will calculate Polygenic Risk Scores and profile the immune system of alL individuals, and integrate those data with clinical data to obtain a complete map linking genetic profiles and disease manifestations across the entire spectrum of AD.