JPND TRanslating Individual Alzheimer GEnetic risk into disease phenotypes

By sequencing the genome of an individual, we can calculate a measure called a polygenic risk score (PRS). This is a single number that represents the risk that that individual has for developing a particular disease, such as Alzheimer's disease. We will be creating PRSs for two groups of individuals - one group from a memory clinic, and one group who have a high genetic risk for developing Alzheimer's disease. We will then take some cell samples from a subset of those individuals and turn them into pluripotent cells - cells which have the potential to become any other type of cell. We will differentiate these cells into microglia, which are a type of cell found between neurons in the brain. Microglia have recently been linked to the development of Alzheimer's disease. We can take these microglia and look at how they behave when transplanted into mice, and when interacting with simple brain models called organoids. From this we can learn how the PRSs we have calculated are linked to the way that microglia behave in the brain. This will teach us about how risk for developing Alzheimer's disease translates into the behavior of cells in the brain. This has the potential to point us towards new interventions and medicines for Alzheimer's patients, and will provide new information for researchers developing clinical trials.

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.
From a selected subset of individuals across this map, we will generate induced pluripotent stem cells and differentiate them into microglia. We will then investigate microglia responses unbiasedly by single-cell RNA sequencing and functionally on synapse, amyloid and Tau effects, both in vivo in the context of a mature brain, after transplantation into mouse models for Abeta and/or Tau pathology, and in vitro in brain organoids. Both datasets will be benchmarked against ex-vivo human brain tissue. We will investigate how different PRS 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.
By maximally exploiting clinical and research data and linking them to an individual risk score, this project will establish a roadmap towards precision medicine for AD. Our results will reveal novel therapeutic targets in AD and lay the foundations of a pre-clinical drug testing platform for AD.

The most immediate impact of TRIAGE will be the ability to use PRS to refine inclusion criteria for clinical trials. Genetic stratification is already used today, for example in the Generation Program (a collaboration between Novartis, Amgen and the Banner Alzheimer's Institute), but it relies only on one gene polymorphism (APOE). The whole-genome and pathway-specific PRS defined in the present study will allow a much more precise stratification, supported by extensive knowledge of the associated microglia biology and clinical manifestations. Similarly, pathway-specific PRS will enable to determine the predisposition to disease and deliver timely and targeted prevention, for example by implementing specific diets (e.g. LipidiDiet study, http://www.lipididiet.eu/) for individuals having a high lipid-associated pathway PRS.
In the mid-term, we expect that our study will impact all aspects of personalised medicine and will impact the entire healthcare system by:
- exploiting innovative and human relevant pre-clinical models to gain a deeper understanding of the biological mechanisms that trigger and drive AD;
- developing effective therapeutic interventions based on these biological insights by using translatable models and performing clinical trials on carefully stratified populations;
- using whole-genome and pathway-specific PRS for early screening and to tailor the right therapeutic strategy for each individual at any given time, thus effectively improving care.