Why do >95% of AD cases fail to clear Aβ peptides while <5% develop disease from overproduction?

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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

85%

Importance

92%

Tractability

75%

Market price

50%

Description

The abstract identifies fundamentally different mechanisms between sporadic (clearance failure) and familial (overproduction) AD, but doesn’t explain why clearance systems fail in the vast majority of cases. Understanding this mechanism could reveal therapeutic targets for the predominant disease form.

Gap type: unexplained_observation Source paper: Alzheimer’s disease. (2015, Nature reviews. Disease primers, PMID:27188934)

Resolution criteria

Resolved when an evidence artifact identifies the mechanistic basis for clearance system failure in sporadic AD versus overproduction in familial AD, with one of: (1) proteomic comparison of Aβ degradation machinery (IDE, neprilysin, ECE1, MMP-9) activity and expression in post-mortem brain tissue from sporadic AD (Braak III-VI) versus age-matched controls and familial AD mutation carriers, showing >=40% reduction in >=2 degradation enzymes in sporadic but not familial AD; (2) functional studies in patient-derived iPSC neurons (sporadic AD versus familial AD APOE4/4 or APP/PSEN1) measuring Aβ42 clearance rates (ELISA of conditioned media at 24h, 48h, 72h), with n >= 5 lines per group, showing >=50% reduced clearance in sporadic but not familial AD; (3) systems-level modeling (flux balance analysis or mechanistic ODE model) of Aβ production versus clearance pathways constrained by human brain metabolomics data, identifying the minimal set of parameter changes that replicate the sporadic AD clearance-failure phenotype.

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