Project: Finding Alzheimer’s disease progression markers by CSF proteomics
| Acronym | Figaro (Reference Number: JPND2024-239) |
| Project Topic | Alzheimer’s disease has a long predementia phase that starts with the aggregation of amyloid beta into plaques when cognition is still intact. It can then take up to 15 years for dementia to start. This provides a window of opportunity to slow down or even prevent dementia. However, individuals vary greatly in terms of cognitive decline and the underlying mechanisms related to disease progression remain largely unknown. We recently discovered five AD subtypes based on cerebrospinal fluid (CSF) proteomics that were characterized by distinct molecular processes: one with hyperplasticity, one with innate immune dysfunction, one with dysregulated RNA metabolism, one with choroid plexus dysfunction and one with blood-brain barrier impairment. These subtypes were already apparent in the predementia stage of AD, and subtypes differed in rates of cognitive decline and survival times. This leads us to hypothesize that different molecular mechanisms may explain differences in disease progression in AD. Testing this hypothesis requires a large sample of individuals with long-term clinical follow up, repeated CSF sampling, cognitive testing, and genetics, which does not exist yet and we will create in this consortium. The aim of this project is to improve the understanding of molecular pathways underlying disease progression in the predementia and early dementia stages of AD by CSF proteomics. Our four key objectives are to: 1. Find for each of the five AD subtypes which CSF proteomic markers are associated with disease progression. We will perform CSF proteomics in 700 individuals with existing repeated CSF samples over a 4–6-year time window (200 controls and 400 with predementia AD and 100 with early dementia). 2. Systematically study potential genetic drivers of AD molecular subtypes in n=1620 individuals with single time point CSF proteomics; and develop for each AD subtype polygenic risk scores to study how such genetic factors are related to disease progression in an extended sample of n=2000 individuals. 3. Develop new technologies based on mass spec and/or ELISAs that are easy to use in practice to stratify individuals according to their AD subtypes, and to monitor disease progression. 4. Co-create materials together with patients and carers to support effective communication of disease progression in predementia AD. This project will provide new insights into the mechanisms underlying disease progression in the earliest stages of AD. The results of our project will generate much needed molecular markers that can be used to select those individuals who mostly likely respond to treatment, as well as much needed markers to monitor disease progression. Thus, this research will enable more precise and personalised treatments with greater benefits for patients with AD. |
| Network | JPND |
| Call | Mechanisms and measurement of disease progression in the early phase of neurodegenerative diseases |