LAUSR

ABSTRACT Introduction Alzheimer’s disease (AD) is the main cause of dementia and represents a huge burden for patients, carers, and healthcare systems. Extensive efforts for over 20 years have failed to find effective disease-modifying drugs. Although amyloid-β (Aβ) accumulation in the brain predicts cognitive decline, effective reduction of plaque load by numerous drug candidates has not yielded significant clinical benefits. A similar pattern is now emerging for drugs which target hyperphosphorylated tau, and trials with anti-inflammatory drugs have been negative despite neuroinflammation appearing to have a crucial role in AD pathogenesis. Areas covered This article reviews key drugs that have been discontinued while in development for AD and delineates the future landscape for present and alternative approaches. Expert opinion Anti-Aβ drugs have failed to validate the Aβ cascade hypothesis of AD. Early findings suggest that the same is happening with therapeutics targeting tau and focussing future research solely on anti-tau drugs is inappropriate. Alternative targets should be pursued, including apolipoprotein E, immunomodulation, plasma exchange, protein autophagy and clearance, mitochondrial dysfunction, abnormal glucose metabolism, neurovascular unit support, epigenetic dysregulation, synaptic loss and dysfunction, microbiota dysbiosis, and combination therapies. Meanwhile, repurposing of drugs approved for other indications is justified where scientific rationale and robust preclinical evidence exist.