Pillar 4: sCOMICs

There are currently no curative treatments for Alzheimer’s disease (AD) or frontotemporal dementia (FTD). Developing effective therapies requires a deeper understanding of patient heterogeneity and the distinct molecular mechanisms underlying these conditions. Recent cerebrospinal fluid (CSF) proteomics research uncovered five distinct biological subtypes of AD—each characterized by unique proteomic signatures involving aberrant neuronal plasticity, immune activation, RNA misfolding, choroid plexus dysfunction, or blood-brain barrier dysfunction. Developing successful disease-modifying therapies requires tailored models that accurately reflect these patient-specific disease subtypes.

The goal of Pillar 4 (sCOMICS) is to refine and tailor experimental disease models to match specific patient subtypes across AD and FTD. The project is guided by five primary objectives:

Study AD subtype-specific mechanisms using data modalities generated across the MODEM consortium.
Investigate differences in CSF immune cell transcriptomes between distinct AD subtypes.
Prospectively analyze subtype-related mechanisms within cell line and animal models across pillars.
Conduct spatial omics analyses on postmortem brain tissue from sporadic FTD patients.
Map molecular brain signatures directly to CSF proteomic profiles across the five established AD subtypes.

Pillar 4 takes an integrative bioinformatics approach, unifying large-scale multi-omics datasets across the consortium. Specifically, sCOMICS integrates experimental results from cell, animal, and tissue models with CSF proteomic profiles from over 800 patients. The pillar collaborates directly across the consortium by:

Examining glia-neuron interactions specific to individual subtypes (in collaboration with Pillar 1: gliADiversity).
Generating subtype-specific iPSC lines for the neuronal hyperplasticity subtype (in collaboration with Pillar 2: SynSAD).
Leveraging PET imaging and blood-brain barrier models to analyze subtype differences in tau accumulation, synaptic density, and vascular health (in collaboration with Pillar 3: BrainBarriers).
Utilizing spatial multi-omics in tissue to investigate the mechanisms driving disease heterogeneity in sporadic FTD.

By bridging micro-level experimental models, spatial tissue omics, and large-scale patient fluid profiles, Pillar 4 will decipher the underlying heterogeneity of AD and FTD. This comprehensive framework will validate patient-tailored experimental models and identify new subtype-specific molecular targets for precision therapeutics.

Who are involved?

This project is led by prof. Pieter Jelle Visser (AUMC) and dr. Betty Tijms (AUMC), as they work together with prof. Guus Smit (VU), prof. dr. Bart Eggen (UMCG), dr. Lynn van Olst (UMCG), prof. dr. Ronald van Kesteren (VU), and dr. Elsmarieke van Giessen. Together, they supervise PhD students, postdocs, and other (non-)scientific staff.