Alzheimer’s disease (AD) is characterized by the accumulation of amyloid neurodegeneration and progressive cognitive decline. While recently approved anti-amyloid therapies have demonstrated that reducing amyloid can slow disease progression, their benefits remain modest and can be accompanied by significant side effects. Increasing evidence suggests that enhancing the brain’s own protective immune responses, particularly those mediated by microglia, may provide a complementary therapeutic strategy. Although much effort has focused on activating beneficial microglial pathways, far less is known about inhibitory immune checkpoints that limit these protective responses.
Dr. Colonna has identified leukocyte immunoglobulin-like receptor B4 (LILRB4) as a previously unrecognized inhibitory immune checkpoint that is highly expressed in plaque-associated microglia in AD and increases with disease severity. LILRB4 directly binds APOE, the strongest genetic risk factor for late-onset AD, linking APOE biology to suppression of protective microglial function. In preliminary studies using a humanized mouse model, Dr. Colonna’s team demonstrated that blocking LILRB4 with a monoclonal antibody enhances microglial activation, increases expression of phagocytic programs, and significantly reduces amyloid burden without depleting microglia. Additional findings suggest that LILRB4 is also expressed by border-associated macrophages that regulate vascular amyloid clearance, expanding its potential therapeutic relevance. They hypothesize that LILRB4 functions as a critical inhibitory checkpoint that restrains protective microglial and border-associated macrophage responses, and that antibody-mediated blockade of LILRB4 will enhance endogenous amyloid clearance, reduce tau pathology, improve vascular amyloid removal, and increase the effectiveness of anti-amyloid immunotherapies.
They will investigate this hypothesis using 3 aims. First, they will determine whether blocking LILRB4 reduces tau pathology, neuronal injury, and neurodegeneration in both amyloid mouse models (5XFAD) seeded with pathological tau and primary tauopathy mice (PS19). Second, they will examine whether LILRB4 blockade improves clearance of vascular amyloid and reduces cerebral amyloid angiopathy using a vascular amyloid mouse model (Tg-SwDI) by enhancing the activity of border-associated macrophages. Third, they will evaluate whether combining LILRB4 blockade with anti-amyloid antibodies, including lecanemab, produces greater therapeutic benefit than either treatment alone in amyloid mice (5XFAD) while also assessing potential treatment-related vascular side effects.
If successful, this work will establish LILRB4 as a novel therapeutic target for AD and provide preclinical validation of immune checkpoint modulation as a new disease-modifying strategy. By enhancing the brain’s endogenous protective immune responses, this approach has the potential to complement existing anti-amyloid therapies and inform the development of next-generation immunotherapies for AD.
