What determines the temporal sequence of cholinergic dysfunction versus amyloid/tau pathology in human AD?

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Composite

69%

Novelty

60%

Mechanistic

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Druggability

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Priority

88%

Importance

95%

Tractability

45%

Market price

44%

Description

Despite being the core debate question, causality remains unresolved due to reliance on cross-sectional human data and artificial animal models. The expert noted this chicken-and-egg problem prevents optimal therapeutic targeting strategies.

Source: Debate session sess_SDA-2026-04-16-gap-pubmed-20260411-082446-2c1c9e2d (Analysis: SDA-2026-04-16-gap-pubmed-20260411-082446-2c1c9e2d)

Resolution criteria

Resolution requires: (1) longitudinal cohort study (n≥200, follow-up ≥5 years) measuring cholinergic markers (ChAT activity, ACh release) vs amyloid/tau PET burden at matched timepoints; (2) causal modeling (e.g., Granger causality, structural equation modeling) establishing directionality; (3) intervention study where cholinergic enhancement slows amyloid/tau progression, not just symptoms. Correlation at single timepoint is insufficient.

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