A manifesto for Alzheimer's disease drug discovery in the era of disease-modifying therapies.

After decades of disappointment, three disease-modifying therapies for Alzheimer's disease (AD) have been approved since 2021. Burgeoning clinical data on these amyloid β-protein (Aβ) targeting drugs validate the amyloid cascade hypothesis as a molecular roadmap for the development of yet more effective therapeutics and offer a template for drugging other AD-associated aggregation-prone proteins. While there remains much to be learned about the molecular pathology of AD, the current state of knowledge is sufficient to expedite the delivery of new drugs. Mindful of the urgent need of patients, we recommend prioritizing efforts in four directions: finishing the job on Aβ, accelerating and diversifying efforts on tau, and expanding discovery on apolipoprotein E and ⍺-synuclein. For each target, we explain the scientific premise, current efforts, and possible new approaches. In the short- and medium-term, we advocate focusing on the technical innovations required to better drug these already well validated targets. While the focus of this review is on expediating development of monotherapies, the subsequent approval of such agents will enable add-on or combination approaches best suited to individual patients.