Anti-tau vaccine in Alzheimer's disease: a tentative step

No disease-modifying treatment is available for Alzheimer's disease, which is the most common form of dementia. In the past 20 years, most therapeutic approaches for Alzheimer's disease were directed against the production and accumulation of amyloid β but, up to now, these approaches have not shown clinical efficacy. 1 Panza F Seripa D Solfrizzi V et al. Emerging drugs to reduce abnormal β-amyloid protein in Alzheimer's disease patients. Expert Opin Emerg Drugs. 2016; (published online Oct 6.)https://doi.org/10.1080/14728214.2016.1241232 Crossref PubMed Scopus (54) Google Scholar Amyloid pathology is not always present in the brain of people with clinically diagnosed Alzheimer's disease, suggesting that dementia can arise as a consequence of tau pathology in the absence of amyloid β. 2 Ahmed RM Paterson RW Warren JD et al. Biomarkers in dementia: clinical utility and new directions. J Neurol Neurosurg Psychiatry. 2014; 85: 1426-1434 Crossref PubMed Scopus (94) Google Scholar Tau pathology in Alzheimer's disease is principally characterised by abnormal phosphorylation of tau proteins, 3 Grundke-Iqbal I Iqbal K Tung YC et al. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA. 1986; 83: 4913-4917 Crossref PubMed Scopus (2873) Google Scholar but also proteolytic cleavage (truncation), glycation, nitration, acetylation, O-GlcNAcylation, ubiquitination, and other abnormal post-translational modifications. 4 Panza F Solfrizzi V Seripa D et al. Tau-based therapeutics for Alzheimer's disease: active and passive immunotherapy. Immunotherapy. 2016; 8: 1119-1134 Crossref PubMed Scopus (51) Google Scholar Both hyperphosphorylated tau by itself and oligomeric tau are involved in synaptic loss. Proteolytically stable tau oligomers are able to propagate between neurons and initiate the cascade of self-propagating misfolded proteins from neuron to neuron. 5 Clavaguera F Bolmont T Crowther RA et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009; 11: 909-913 Crossref PubMed Scopus (1266) Google Scholar The pharmacological targeting of tau in Alzheimer's disease includes several approaches: microtubule-stabilising drugs, tau protein kinase inhibitors, tau aggregation inhibitors, active and passive immunotherapies, and inhibitors of tau acetylation. 4 Panza F Solfrizzi V Seripa D et al. Tau-based therapeutics for Alzheimer's disease: active and passive immunotherapy. Immunotherapy. 2016; 8: 1119-1134 Crossref PubMed Scopus (51) Google Scholar Animal studies have shown that both active and passive approaches can remove tau pathology and, in some cases, improve cognitive function. 4 Panza F Solfrizzi V Seripa D et al. Tau-based therapeutics for Alzheimer's disease: active and passive immunotherapy. Immunotherapy. 2016; 8: 1119-1134 Crossref PubMed Scopus (51) Google Scholar Two active vaccines targeting either non-phosphorylated (AADVac1) or phosphorylated (ACI-35) tau are being assessed in phase 1 studies. 4 Panza F Solfrizzi V Seripa D et al. Tau-based therapeutics for Alzheimer's disease: active and passive immunotherapy. Immunotherapy. 2016; 8: 1119-1134 Crossref PubMed Scopus (51) Google Scholar Safety and immunogenicity of the tau vaccine AADvac1 in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase 1 trialAADvac1 had a favourable safety profile and excellent immunogenicity in this first-in-man study. Further trials are needed to corroborate the safety assessment and to establish proof of clinical efficacy of AADvac1. Full-Text PDF