Alzheimer’s Disease

Neurodegenerative disease. Major topic across Nobel panels — Session IV and Session XII.

The Amyloid Paradox

• Antibodies (lecanemab) can make brains essentially plaque-free — yet cognitive decline only slows by 27% (Südhof, Session XII)
• Most Alzheimer’s patients carry APOE4/APOE3 defects, not APP mutations (Schekman, Session IV)
• The field spent decades and billions on the wrong frontier

Südhof’s iPSC Data

• APP Swedish mutation in iPSC neurons: increased synapse density and synaptic events — not loss
• A-beta 40: consistently increased synapse formation; A-beta 42 toxic only at aggregation concentrations
• Pre-synaptic compartment selectively shrinks before neuron death
• “We don’t actually know whether the little beneficial effect was due to decrease in plaques — or increase in free A-beta — or both”

Alternative Approaches

• Baker: designed tau binders that suppress/disassemble fibrils; bioPROTAC for complete tau clearance; designed TDP-43 protease
• Südhof: drugs that promote synaptic connectivity rather than modulating receptors
• Südhof: would invest in integrative cell biology bridging atomic and whole-organism scales — reconcile the inflammation and amyloid camps

Cross-References

• Translation cliff — animal models for neurodegeneration are a persistent failure point
• LRRK2 — related neurodegenerative target in Parkinson’s
• Bertozzi’s glycoscience BBB shuttle may be relevant

Related sdd-wiki Content

• Amyloid-Beta (Aβ) — existing sdd-wiki concept hub on Aβ biology
• Neurometabolic Dysfunction in Alzheimer’s — PHGDH-linked metabolic perspective