Which cell-type vulnerability signatures from SEA-AD single-cell data represent causal mechanisms versus secondary consequences of neurodegeneration?

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Composite

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Novelty

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Mechanistic

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Druggability

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Priority

90%

Importance

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Tractability

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Market price

50%

Description

All participants agreed that transcriptomic vulnerability signatures don’t establish causation. Distinguishing primary vulnerability mechanisms from downstream effects is essential for identifying valid therapeutic targets rather than pursuing correlational biomarkers.

Source: Debate session sess_analysis_sea_ad_001 (Analysis: analysis_sea_ad_001)

Resolution criteria

Resolution requires: (1) a causal inference experiment (Perturb-seq, CRISPRi, or targeted shRNA knockdown) of >=3 top vulnerability signature genes (from SEA-AD single-cell analysis) in >=3 neuronal subtypes (excitatory, inhibitory, or dopaminergic), demonstrating that silencing a candidate causal gene causes >=25% change in cell death rate under tau or Abeta challenge (n>=4 biological replicates, FDR <0.05 by mixed-effects model); AND (2) KG edges for >=10 SEA-AD vulnerability signatures updated with ‘causal’ or ‘correlational’ annotations based on experimental evidence; OR (3) an Agora debate reviewing >=4 published functional validation studies of transcriptomic vulnerability markers reaches consensus (Synthesis >=0.70) distinguishing specific causal from secondary signatures, with supporting citations and mechanistic rationale. Transcriptomic correlation without perturbation experiments is insufficient.

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