1119 Immunotherapy (2016) 8(9), 1119–1134 ISSN 1750-743X 10.2217/imt-2016-0019 © 2016 Future Medicine Ltd Pharmacological manipulation of tau protein in Alzheimer’s disease included microtubule-stabilizing agents, tau protein kinase inhibitors, tau aggregation inhibitors, active and passive immunotherapies and, more recently, inhibitors of tau acetylation. Animal studies have shown that both active and passive approaches can remove tau pathology and, in some cases, improve cognitive function. Two active vaccines targeting either nonphosphorylated (AAD-vac1) and phosphorylated tau (ACI-35) have entered Phase I testing. Notwithstanding, the recent discontinuation of the monoclonal antibody RG7345 for Alzheimer’s disease, two other antitau antibodies, BMS-986168 and C2N-8E12, are also currently in Phase I testing for progressive supranuclear palsy. After the recent impressive results in animal studies obtained by salsalate, the dimer of salicylic acid, inhibitors of tau acetylation are being actively pursued. First draft submitted: 25 Jan 2016; Accepted for publication: 16 May 2016; Published online: 3 August 2016 Keywords:฀ active฀immunotherapy฀•฀Alzheimer’s฀disease฀•฀passive฀immunotherapy Introduction The 2015 figures suggested that Alzheimer’s disease (AD) may affect over 5.3 million people in the USA [1] . Notwithstanding the epidemiological impact of this devastat- ing disease on public health and consider- able advances in the AD neurobiology and medicinal chemistry, no disease-modifying treatments have been introduced for this dev- astating and progressive neurodegenerative disease [2] . The neuropathological hallmarks of AD are intracellular neurofibrillary tangles (NFTs) composed of paired helical filaments (PHFs) and straight filaments mainly con- stituted of hyperphosphorylated tau protein, a microtubule-associated protein, neuropil threads, dystrophic neuritis and extracellular deposits of β-amyloid (Aβ) as the major com- ponent of senile plaques in the brain. Many therapeutic approaches in clinical develop- ment for AD treatment have been directed against the production and accumulation of Aβ [3] . Unfortunately, several drugs targeting Aβ with different mechanisms of action have failed to demonstrate efficacy in randomized clinical trials or their development has been halted [2,4,5] . Passive anti-Aβ immunization is at a more advanced stage of clinical development for treating AD, and solanezumab, a monoclonal antibody directed at the mid-region of Aβ, also failed but suggested some beneficial cog- nitive effects in mildly affected patients [4] . A Phase III study with a planned size of 2100 mild AD patients is ongoing to confirm these potential benefits. Solanezumab is also being tested in a prevention study in asymptomatic older subjects, who have positive positron emission tomography (PET) scans for brain amyloid deposits [4] . Two other monoclonal antibodies, gantenerumab, which preferen- tially binds to fibrillar Aβ, and crenezumab, which preferentially binds to soluble, oligo- meric and fibrillar Aβ deposits, are being Tau-based therapeutics for Alzheimer’s disease: active and passive immunotherapy Francesco Panza *,1,2,3 , Vincenzo Solfrizzi 4 , Davide Seripa 3 , Bruno P Imbimbo 5 , Madia Lozupone 1 , Andrea Santamato 6 , Rosanna Tortelli 1,2 , Ilaria Galizia 7 , Camilla Prete 8 , Antonio Daniele 9 , Alberto Pilotto 8 , Antonio Greco 3 & Giancarlo Logroscino 1,2,9 1 Neurodegenerative฀Disease฀Unit,฀ Department฀of฀Basic฀Medicine,฀ Neuroscience,฀&฀Sense฀Organs,฀University฀ of฀Bari฀Aldo฀Moro,฀Bari,฀Italy 2 Department฀of฀Clinical฀Research฀in฀ Neurology,฀University฀of฀Bari฀Aldo฀Moro,฀ ‘Pia฀Fondazione฀Cardinale฀G.฀Panico,’฀ Tricase,฀Lecce,฀Italy 3 Geriatric฀Unit฀&฀Laboratory฀of฀ Gerontology฀&฀Geriatrics,฀Department฀of฀ Medical฀Sciences,฀IRCCS฀‘Casa฀Sollievo฀ della฀Sofferenza,’฀San฀Giovanni฀Rotondo,฀ Foggia,฀Italy 4 Geriatric฀Medicine-Memory฀Unit฀&฀Rare฀ Disease฀Centre,฀University฀of฀Bari฀Aldo฀ Moro,฀Bari,฀Italy 5 Research฀&฀Development฀Department,฀ Chiesi฀Farmaceutici,฀Parma,฀Italy 6 Physical฀Medicine฀&฀Rehabilitation฀ Section,฀‘OORR’฀Hospital,฀University฀of฀ Foggia,฀Foggia,฀Italy 7 Psychiatric฀Unit,฀Department฀of฀Basic฀ Medicine,฀Neuroscience,฀&฀Sense฀Organs,฀ University฀of฀Bari฀Aldo฀Moro,฀Bari,฀Italy 8 Department฀of฀OrthoGeriatrics,฀ Rehabilitation฀&฀Stabilization,฀Frailty฀ Area,฀E.O.฀Galliera฀NR-HS฀Hospital,฀ Genova,฀Italy 9 Institute฀of฀Neurology,฀Catholic฀ University฀of฀Sacred฀Heart,฀Rome,฀Italy *Author฀for฀correspondence:฀ geriat.dot@geriatria.uniba.it ‡ Authors฀contributed฀equally part of Review For reprint orders, please contact: reprints@futuremedicine.com