Antibody-based immunotherapy targeting FAM19A5 reverses synaptic loss and improves cognitive function in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by the progressive loss of synapses, leading to cognitive decline. Immunotherapies targeting amyloidosis or tauopathy have shown promise in AD treatment, but additional therapies are needed to inhibit continuous and excessive synaptic loss, which could improve clinical outcomes by modifying the course of the disease. Understanding the mechanisms of synaptic loss is essential for the development of new therapies. Here, we propose an antibody-based immunotherapy targeting FAM19A5, a secretory protein in the brain. We found that FAM19A5 binds to LRRC4B, a post-synaptic adhesion molecule, which disassembles synaptic connections, leading to synapse elimination. FAM19A5 levels increased in association with aging and the progression of tau accumulation. We inhibited FAM19A5 using NS101, an anti-FAM19A5 monoclonal antibody, in mouse models of AD. NS101 preserved synaptic connections despite the presence of amyloid or tau aggregates. Consequently, the number of mature synapses and their function were restored, resulting in improved cognitive performance. In study participants, NS101 was delivered to the human brain across the blood-brain barrier, bound to FAM19A5, and cleared into the peripheral circulation without any toxicity. These findings demonstrate that restoring synapses by inhibiting synaptic elimination can be an effective therapeutic strategy and provide a fundamental basis for modifying AD. ### Competing Interest Statement HB.K, SJ.Y, HY.K, SX.M, RH.K, MH.L, N.H, EH.C, SM.L, JW.J, WK.K, YS.P, SI.P, SG.K and JY.S are employed by Neuracle Science, Co., Ltd. MH.L, SM.L, WK.K, SW.H, HC.P, and JY.S are shareholders of Neuracle Science, Co., Ltd. The remaining authors have no conflicts of interest to declare.