3 hypotheses
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8 open gaps
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0 live debates
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0 tokens funded
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3/7 hub

What we know

  • 3 active hypothesises in scope
  • 8 open frontiers with evidence gaps
  • 10 indexed papers in corpus
3 hypotheses in scope top ranked
18 open frontiers
0 in-flight debates
0 tokens funded

Top hypotheses

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  1. #1 CX3CR1-Targeted HDAC3 Knockdown in Microglia via AAV9 Delivery 62% proposed HDAC3 (class I histone deacetylase) PMID:29198936PMID:27959704 +1 refs
  2. #2 Brain-Ester Prodrug Strategy for CNS-Selective HDAC6 Inhibition 57% proposed HDAC6 (class IIb histone deacetylase) PMID:25983193PMID:23576762 +1 refs
  3. #3 CX3CR1-Targeted AntimiR-155 Oligonucleotides for Microglial Priming Reversal 53% proposed MIR155 (microRNA-155) PMID:29967349 +5 refs

Open frontiers

All gaps →
What safety margins exist for membrane-disrupting nanobodies between therapeutic efficacy and cellular toxicity?

The debate raised major safety concerns about widespread membrane disruption but provided no data on therapeutic windows. Understanding the selectivity ratio between pathological and normal vesicles is crucial for clinical viability. Source: Debate session sess_SDA-2026-04-10-SDA-2026-04-09-gap-debate-20260409-201742-ca7016f1 (Analysis: SDA-2026-04-09-gap-debate-20260409-201742-ca7016f1)

priority 75%
What is the therapeutic window between selective tau vesicle penetration and non-specific membrane toxicity?

Safety concerns about membrane disruption were raised but not quantified. Determining the selectivity ratio between pathological and normal vesicles is essential for assessing therapeutic viability and establishing dosing parameters. Source: Debate session sess_SDA-2026-04-10-SDA-2026-04-09-gap-debate-20260409-201742-ca7016f1 (Analysis: SDA-2026-04-09-gap-debate-20260409-201742-ca7016f1)

priority 75%
How can circadian autophagy rhythms be selectively restored without disrupting other essential circadian processes?

The debate identified intervention complexity as a major challenge but provided no clear mechanism for selective targeting. Understanding how to decouple autophagy timing from other circadian functions is crucial for therapeutic safety and efficacy. Source: Debate session sess_sda-2026-04-01-gap-011 (Analysis: sda-2026-04-01-gap-011)

priority 80%
Which metabolic pathways are modulated by current AD therapeutics to enable biomarker-drug matching?

The debate assumed metabolic biomarkers could distinguish therapeutic response but didn't establish which approved or pipeline therapeutics actually modulate measurable metabolic pathways. This mechanistic gap limits biomarker clinical application. Source: Debate session sess_SDA-2026-04-04-SDA-2026-04-04-gap-debate-20260403-222618-c698b06a (Analysis: SDA-2026-04-04-gap-debate-20260403-222618-c698b06a)

priority 71%
How can CNS-selective HDAC/DNMT inhibitors be developed to avoid systemic toxicity?

Both theorist and domain expert acknowledged that existing epigenetic modulators cause significant off-target effects when used systemically. The debate did not resolve how to achieve brain-specific targeting or identify which specific isoforms are critical in microglia. Source: Debate session sess_SDA-2026-04-04-gap-20260404-microglial-priming-early-ad (Analysis: SDA-2026-04-04-gap-20260404-microglial-priming-early-ad)

priority 78%
What are the long-term safety implications of chronic PARP1 modulation in the aging brain?

The Domain Expert raised concerns about cancer risk and cognitive impairment from PARP inhibitors, but no long-term CNS safety data exists. This knowledge gap is critical given AD requires chronic treatment in elderly populations. Source: Debate session sess_SDA-2026-04-02-gap-seaad-v2-20260402032945 (Analysis: SDA-2026-04-02-gap-seaad-v2-20260402032945)

priority 75%
How do proposed therapeutic mechanisms avoid off-target effects across multiple brain cell types?

The theorist presented cell-type-specific therapies but the skeptic raised concerns about reference validity. The selectivity and safety profiles of targeting these pathways across different brain cell populations remains unexplored. Source: Debate session sess_SDA-2026-04-02-gap-seaad-v3-20260402063622 (Analysis: SDA-2026-04-02-gap-seaad-v3-20260402063622)

priority 71%
What is the therapeutic window for P2Y12 modulation between efficacy and immunocompromise?

While P2Y12 inverse agonists scored highest for feasibility, the debate noted safety concerns about infection susceptibility. The balance between suppressing pathological pruning while preserving antimicrobial responses needs empirical definition. Source: Debate session sess_SDA-2026-04-01-gap-v2-691b42f1 (Analysis: SDA-2026-04-01-gap-v2-691b42f1)

priority 80%

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