Why do Alzheimer's disease genes confer risk across α-synucleinopathies despite different protein aggregates?

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The finding that AD risk genes (CD33, CR1, PSEN2) are shared risk factors across synucleinopathies challenges the protein-specific disease model, but the mechanistic basis for this cross-disease genetic overlap remains unexplained. This could fundamentally change how we classify neurodegenerative diseases. Gap type: contradiction Source paper: Deep sequencing of proteotoxicity modifier genes uncovers a Presenilin-2/beta-amyloid-actin genetic risk module shared among alpha-synucleinopathies. (2026, bioRxiv : the preprint server for biology, PMID:38496508)

Priority: 0.83 Domain: neurodegeneration Hypotheses: 0
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Landscape Summary: Why do Alzheimer's disease genes confer risk across α-synucleinopathies despite different protein aggregates? is a 0.83 priority gap in neurodegeneration. It has 0 linked hypotheses with average composite score 0.000. Status: open.

Key Unanswered Questions

Key Researchers

Colonna, Sevlever, et al. (TREM2 biology)

Clinical Trials

Why do Alzheimer's disease genes confer risk across α-synucleinopathies despite different protein aggregates? — INVOKE-2 (completed)

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activates (17)

AlzheimerOxidative StressAlzheimerApoptosisAlzheimerMtorAlzheimerMitophagyGENESAlzheimer
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associated with (8)

TauopathyAlzheimerAlzheimerAutophagyDiabetesAlzheimerDNAAlzheimerAlzheimerSenescence
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biomarker for (2)

GFAPAlzheimerNFLAlzheimer

expressed in (3)

APOEAlzheimerAPOE4AlzheimerTREM2Alzheimer

regulates (8)

APPAlzheimerAlzheimerOxidative StressDNAAlzheimerAKTAlzheimerAlzheimerLipid Metabolism
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therapeutic target (12)

AlzheimerApoptosisAlzheimerLipid MetabolismDNAAlzheimerAlzheimerImmune ResponseAlzheimerBlood-Brain Barrier
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