What determines cell-type-specific vulnerability patterns beyond transcriptomic signatures?

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Description

While transcriptomic data identifies vulnerable cell populations, the debate revealed that correlation doesn’t establish causation. The underlying mechanisms that make specific neuronal subtypes susceptible to AD pathology remain unclear.

Source: Debate session sess_SDA-2026-04-03-gap-seaad-v4-20260402065846 (Analysis: SDA-2026-04-03-gap-seaad-v4-20260402065846)

Resolution criteria

Resolution requires: (1) Perturb-seq or CRISPR screen targeting >=200 candidate vulnerability genes in iPSC-derived neurons from AD patients, measuring both transcriptomic change (cell death readout) and downstream signaling pathway activation; (2) spatial metabolomics (DESI or MALDI) of AD brain sections showing metabolic signatures unique to vulnerable cell types; (3) epigenetic landscape analysis (ATAC-seq) of isolated vulnerable neurons identifying chromatin accessibility patterns that predict susceptibility. Demonstrating correlation between transcriptomic signatures and vulnerability without perturbing the causal mechanism is insufficient.

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