Critical to our understanding of Alzheimer’s disease (AD) and other neurodegenerative dementias (NDDs), as well as to finding disease-modifying therapies, is the development of biomarkers for the underlying disease processes. To facilitate improved diagnostics and drug discovery, we have developed methods to measure markers of amyloid and tau pathology, central and peripheral nervous system injury, astrocytic and microglial activation, as well as neuroinflammation. Our most exciting advancement in this field so far is the development of phosphorylated tau assays sensitive enough to measure this protein in plasma to detect AD pathology in the brain and to allow for disease stratification and monitoring based on AD pathology. I now propose to develop new high-throughput biomarker tools that will enable the analysis of large cohort studies combining clinical, imaging, genetic and biomarker data to provide truly comprehensive molecular disease phenotypes that will inform interventions, drug discovery and translational research, clinical trial stratification, detection of risk and resilience factors (lifestyle-related, as well as genetic), and ultimately drive the quest towards clinically accessible personalised medicine in the NDD field. A large part of the research efforts will be focused on discovering new biomarkers for TDP-43 and α-synuclein pathologies, non-AD tau pathology, and lysosomal and synaptic dysfunction, through general and targeted proteomics on CSF samples, and through employing a novel cell type-biased tandem mass tag proteomics workflow to discover biomarkers related to neuronal, astrocytic, and microglial cells, and their different activation states. Promising CSF biomarkers will be examined in blood; biomarker candidates that are measurable in this matrix and correlate with CSF will be developed into sensitive and specific blood tests using cutting-edge technology, as we have previously done for Aβ40, Aβ42, T-tau, P-tau, NfL, and GFAp.
