Tau-targeting therapies for Alzheimer disease: current status and future directions

Alzheimer disease (AD) is the most common cause of dementia in older individuals. AD is characterized pathologically by amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the brain, with associated loss of synapses and neurons, which eventually results in dementia. Many of the early attempts to develop treatments for AD focused on Aβ, but a lack of efficacy of these treatments in terms of slowing disease progression led to a change of strategy towards targeting of tau pathology. Given that tau shows a stronger correlation with symptom severity than does Aβ, targeting of tau is more likely to be efficacious once cognitive decline begins. Anti-tau therapies initially focused on post-translational modifications, inhibition of tau aggregation and stabilization of microtubules. However, trials of many potential drugs were discontinued because of toxicity and/or lack of efficacy. Currently, the majority of tau-targeting agents in clinical trials are immunotherapies. In this Review, we provide an update on the results from the initial immunotherapy trials and an overview of new therapeutic candidates that are in clinical development, as well as considering future directions for tau-targeting therapies. The limited success of amyloid-β-targeting therapies for Alzheimer disease has led to a shift in focus towards the tau protein. This Review provides an update on the initial trials of tau-targeting therapies, focusing particularly on immunotherapies, and considers future directions for these therapies. Key points The limited success of amyloid-β-targeting therapies for Alzheimer disease (AD) has led to a shift in focus towards the tau protein — the main component of the neurofibrillary tangles that comprise the other major pathological hallmark of AD. Therapies targeting the expression, post-translational modifications, aggregation and clearance of tau have advanced to testing in humans. These therapies have been largely safe and well tolerated. The clinical efficacy of tau-targeting therapies has yet to be established and some trials have failed; however, multiple trials are ongoing and new candidates continue to enter trials. Antisense oligonucleotides have shown promising results in testing in humans for reducing tau expression, and larger studies will determine whether these findings translate into clinical benefits. Most of the tau-targeting therapies in ongoing trials are immunotherapies, which can target tau intracellularly and/or extracellularly, alt