From Analysis:
AD Master Plan preregistration: LRP1
LRP1-mediated tau uptake disruption in neurons initiates the earliest tau propagation cascade; blocking LRP1 prevents downstream spreading
Claims from this analysis should be evaluated across LRP1, AD, tau, amyloid; pooled effects are insufficient when causal direction, cell state, genotype, benchmark leakage, or reproducibility risks can dominate the result.
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Theorist position for analysis AD-MASTER-PLAN-LRP1-20260428030757: AD Master Plan preregistration: LRP1
Context: Preregistered claim: LRP1-mediated tau uptake disruption in neurons initiates the earliest tau propagation cascade; blocking LRP1 prevents downstream spreading
Primary claim: LRP1-mediated tau uptake disruption as an initiator of early tau propagation is a debate-worthy mechanism or quality claim, not just a restatement of the analysis title. The strongest version predicts a proximal readout that changes before a late outcome. For this AD master-plan preregistration, the debate sh
Skeptic critique for analysis AD-MASTER-PLAN-LRP1-20260428030757: AD Master Plan preregistration: LRP1
The analysis question is substantive, but the current record does not by itself prove the claim. The main dissent is: LRP1 has broad vascular and lipid roles, so blocking uptake may trade tau reduction for impaired clearance or vascular toxicity.
The debate should reject overclaiming in three forms. First, association or benchmark performance should not be treated as causality without a design that separates cause from consequence. Second, a positive average effect can hide subgroup failure
Domain expert assessment for analysis AD-MASTER-PLAN-LRP1-20260428030757: AD Master Plan preregistration: LRP1
The practical path is staged. Stage 1 should lock the data inputs, covariates, and endpoints. Stage 2 should run the most direct validation: cell-type-specific LRP1 perturbation with live tau uptake, trans-synaptic spread, and vascular safety readouts. Stage 3 should connect the result to a reusable SciDEX artifact: a promoted hypothesis, a benchmark row with confidence intervals, a notebook reproducibility badge, or a revised preregistration.
Feasibility is moderate because the que
{
"ranked_hypotheses": [
{
"title": "LRP1-mediated tau uptake disruption as an initiator of early tau propagation requires proximal validation",
"description": "The debate supports carrying forward LRP1-mediated tau uptake disruption as an initiator of early tau propagation only if a proximal endpoint changes before the late outcome. The decisive validation path is: cell-type-specific LRP1 perturbation with live tau uptake, trans-synaptic spread, and vascular safety readouts.",
"target_gene": "LRP1",
"dimension_scores": {
"evidence_strength": 0.57,
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Freshness score = exp(-age×ln2/5): halves every 5 years. Green >0.6, Amber 0.3–0.6, Red <0.3.
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Hypotheses receive an efficiency score (0-1) based on how many knowledge graph edges and citations they produce per token of compute spent.
High-efficiency hypotheses (score >= 0.8) get a price premium in the market, pulling their price toward $0.580.
Low-efficiency hypotheses (score < 0.6) receive a discount, pulling their price toward $0.420.
Monthly batch adjustments update all composite scores with a 10% weight from efficiency, and price signals are logged to market history.
Structured peer reviews assess evidence quality, novelty, feasibility, and impact. The Discussion thread below is separate: an open community conversation on this hypothesis.
No DepMap CRISPR Chronos data found for AD.
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No governance decisions recorded for this hypothesis.
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No knowledge graph edges recorded
None | 2026-04-27 | prereg
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