**6.1 Immunotherapy**

Although the mechanism is not fully elucidated, tau immunotherapy, either active or passive, shows protective effects on tau pathology and cognitive performance in AD model animals and is consequently becoming an essential strategy in the development of AD therapies [17]. Two vaccines for active immunotherapy of AD, AADvac-1 which is a synthetic peptide of tau (aa 294–305) and ACI-35 which is a phosphorylated tau peptide containing pS396/S404 are now in clinical trials (**Table 4**) [140]. Since active immunization may increase the risk of autoimmune reaction and other disadvantages [141], passive immunization currently accounts for the majority of the immunotherapy for tau (**Table 4**).

Passive immunotherapy is a short-term immunization administered by continuous injection of antibody that is designed specifically to pathological epitopes. Intravenously injection of tau antibody decreases both Aβ and tau pathologies in animal models, implying a therapeutic potential in the treatment of AD and related tauopathies [142]. There are 8 specific tau antibodies in clinical trials up to now. Their targets mainly focus on the N-terminus (ABBV-8E12 and Semorinemab), phosphorylation sites (Lu AF87908 and JNJ-63733657) or microtubule-binding region (Bepranemab and E2814) of tau protein (**Table 4**). Some antibodies (e.g. Bepranemab) also show potential in the treatment of other neurodegenerative diseases


*Data from: https://clinicaltrials.gov/, https://www.alzforum.org/therapeutics/*

### **Table 4.**

*Tau-based therapies for AD.*

like PSP (https://www.alzforum.org/therapeutics) [143]. Of course, tau-based passive immunization also faces some challenges, of which the key problem is how to deliver the antibodies more efficiently through the blood–brain-barrier (BBB) into specific brain region with tau pathology [144].
