Is C1q elevation in human AD causally pathogenic or an epiphenomenon of neuroinflammation?

The domain expert noted lack of human genetic validation for C1q variants in AD GWAS, questioning whether C1q is a disease driver or consequence. This fundamental gap affects the entire therapeutic rationale for targeting C1q.

Source: Debate session sess_SDA-2026-04-12-gap-debate-20260410-112848-7ba6c2e1 (Analysis: SDA-2026-04-12-gap-debate-20260410-112848-7ba6c2e1)

Resolved when an evidence artifact establishes whether C1q elevation in human AD is causally pathogenic or an epiphenomenon of neuroinflammation, with one of: (1) human genetic evidence — AD GWAS analysis of C1q genes (C1QA, C1QB, C1QC, C1D) and complement pathway genes, testing whether coding or regulatory variants that increase C1q expression are associated with increased or decreased AD risk (n >= 10,000 cases, >=30,000 controls, OR >= 1.2 or <= 0.8 with 95% CI excluding 1); (2) causal inference studies — CRISPR-mediated C1Q knockout or overexpression in iPSC-derived microglia or neurons from AD patients, measuring synaptic engulfment (synaptic marker qPCR or ImageStream), inflammatory cytokine profiles (MSD or Luminex), and neuronal viability, establishing whether C1q changes drive pathology or result from it; (3) longitudinal biomarker studies — measuring C1q levels (CSF, plasma) and AD biomarkers (Aβ42, p-tau) in the same cohort over >=3 timepoints spanning >=5 years, demonstrating whether C1q changes precede or follow Aβ/tau pathology.