Amyloid-β immunotherapy for alzheimer disease: Is it now a long shot?

The amyloid-beta (A beta) cascade hypothesis of Alzheimer disease (AD) holds that brain accumulation of A beta initiates the disease process. Accordingly, drug research has targeted A beta production, clearance, and deposition as therapeutic strategies. Unfortunately, candidate drugs have failed to show clinical benefit in established, early, or prodromal disease, or in those with high AD risk. Currently, monoclonal antibodies specifically directed against the most neurotoxic A beta forms are undergoing large-scale trials to confirm initially encouraging results. However, recent findings on the normal physiology of A beta suggest that accumulation may be compensatory rather than the pathological initiator. If this is true, alternative strategies will be needed to defeat this devastating disease. ANN NEUROL 2019;85:303-315.