Mechanistic description
TREM2 agonistic antibodies restore microglial phagocytosis and plaque compaction in Alzheimer’s disease, particularly for R47H variant carriers with ~3-fold increased AD risk. Multiple agonistic antibodies (AL002c, 4D9) are in development targeting the SYK/PLCγ2/CARD9 cascade. Critical uncertainties include biphasic dose-response pharmacology, appropriate mouse model design (conditional knockout rather than constitutive knockout), and the temporal window for therapeutic intervention given biphasic CSF sTREM2 patterns in AD patients.
Evidence for (3)
TREM2 R47H variant increases AD risk ~3-fold
TREM2-deficient mice show altered microglial transcriptomics around plaques
Trem2 haploinsufficiency accelerates plaque pathology in 5xFAD mice
Evidence against (3)
TREM2 loss paradoxically reduces plaque burden in some 5xFAD crosses
CSF sTREM2 shows biphasic temporal pattern in AD—elevated early, suppressed late
High TREM2 agonist concentrations cause receptor internalization and desensitization
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