The TREM2 agonistic antibody AL002 in early Alzheimer's disease: a phase 2 randomized trial

# The TREM2 agonistic antibody AL002 in early Alzheimer's disease: a phase 2 randomized trial *Published: 2026 May* Triggering receptor expressed on myeloid cells 2 (TREM2) regulates microglial function and is implicated in Alzheimer's disease (AD) pathogenesis. Here we conducted a phase 2, randomized, double-blind, placebo-controlled trial of a humanized TREM2 agonistic monoclonal antibody in 381 participants with early AD. Participants were randomized (1:1:1:1) to receive AL002 (15 mg kg-1, 40 mg kg-1 or 60 mg kg-1) or placebo intravenously every 4 weeks for 48-96 weeks. AL002 demonstrated sustained target engagement and pharmacodynamic responses in the central nervous system, as demonstrated by reductions in soluble TREM2 and increases in osteopontin in cerebrospinal fluid, respectively. The study did not meet the primary endpoint of change from baseline in the Clinical Dementia Rating-Sum of Boxes score (versus placebo) (least squares mean difference versus placebo (95% confidence interval) at week 96: 15 mg kg-1 -0.31 (-1.61 to 0.98), 40 mg kg-1 0.13 (-1.18 to 1.43) and 60 mg kg-1 -0.17 (-1.49 to 1.15); P > 0.05 from mixed-effects model for repeated measures). The most frequent treatment-emergent adverse events were magnetic resonance imaging changes resembling amyloid-related imaging abnormalities (ARIA). This first trial of a TREM2 agonistic antibody in early AD was negative but provides findings relevant to the study of TREM2 therapeutics and ARIA. ClinicalTrials.gov: NCT04592874 . DOI: 10.1038/s41591-026-04273-1