Targeting tau in Alzheimer’s Disease: rationale, approach and challenges

Alzheimer’s Disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia characterised by the accumulation of beta amyloid (Aβ) plaques and neurofibrillary tangles (NFT). Several monoclonal antibodies against amyloid in early AD have shown the utility of reducing brain amyloid in large phase 3 studies, resulting in modest clinical benefit. To further slow, or even halt disease progression, targeting additional pathobiological pathways is likely to be necessary. In this review, we aim to appraise the scientific rationale for targeting tau in AD. The burden of tau pathology is correlated with disease severity and its role in AD progression is complex, involving synapse dysfunction, neuronal loss, neuroinflammation and autophagy impairment. Evidence suggests that hypersecretion, post-translational modifications and aggregation propensity, dependent and independent of amyloid, are also linked to neurodegeneration. We review the therapeutic agents in development including tau synthesis modifiers, active and passive immunotherapies, post-translational modifiers and aggregation inhibitors. Finally, we consider the available biomarker tools for patient selection and drug effectiveness evaluation, and we identify key knowledge gaps that future novel biomarkers might address to make clinical trials of tau therapies more likely to succeed.