Microglial TREM2 Activation to Enhance Synaptic Pruning Regulation

Microglial TREM2 connectomics market 56% proposed
Composite
53%
Novelty
75%
Feasibility
50%
Impact
65%
Mechanistic
70%
Druggability
55%
Safety
40%
Confidence
65%

Mechanistic description

Microglial TREM2 Activation to Enhance Synaptic Pruning Regulation

Evidence for (5)

  • TREM2 loss-of-function variants increase AD risk 2-4 fold

    PMID:26928458

  • TREM2 is required for microglial response to amyloid plaques

    PMID:26551527

  • TREM2 agonist promotes microglial clustering around plaques and reduces neurite dystrophy

    PMID:31171641

  • Hub regions show heightened connectivity burden correlating with pathology

    PMID:19219025

  • Synaptic loss in AD correlates with dysregulated microglial surveillance

    PMID:29186337

Evidence against (4)

  • AL002c (TREM2 agonist) failed to meet primary endpoint in INVOKE-2 Phase 2 trial (2024)

    PMID:38427984

  • TREM2 deficiency reduces amyloid pathology in some contexts (reduced microglial clustering)

    PMID:29307019

  • Microglial states in AD are heterogeneous - single pathway modulation insufficient

    PMID:31249461

  • Mouse-to-human microglial translation limitations affect validity

    PMID:29422609