TREM2 loss-of-function variants increase AD risk (~3-4x), and agonistic antibodies can enhance beneficial microglial responses including amyloid phagocytosis and plaque-associated microglial coverage. AL002 (Alector) in Phase 2 provides immediate clinical validation. Critical uncertainty remains regarding stage-dependency: TREM2 activation may benefit early amyloid phases but could worsen tau pathology or neuritic dystrophy in later disease stages. BBB penetration requires transporter-mediated delivery strategies.