Mechanistic description
Cancer-induced cystatin C prevents complement-mediated synaptic loss through TREM2-mediated microglial phenotype regulation, reducing C1q/C3 deposition and excessive pruning. This is clinically important but probably secondary to plaque remodeling plus microglial state change rather than a distinct mechanism. Synaptic biomarkers are noisy and slower-moving than amyloid PD markers, making mechanism proof difficult in humans.
Evidence for (3)
TREM2 deficiency causes abnormal synaptic pruning and memory deficits
Cystatin C prevents excitotoxic synapse loss in vitro
Complement inhibition reduces synaptic loss in AD mouse models
Evidence against (2)
TREM2 loss-of-function shows baseline requirement, not that activation improves pruning
Cachexia confounding in cancer-bearing mice may affect synaptic plasticity independently
Bayesian persona consensus
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