Implications of the Approval of Lecanemab for Alzheimer Disease Patient Care Incremental Step or Paradigm Shift?

The amyloid cascade model of the pathogenesis of Alzheimer disease (AD) is well supported in observational studies. Its therapeutic corollary asserts that removal of amyloid-beta peptide ("amyloid") would provide clinical benefits. After 2 decades of pursuing the strategy of amyloid removal without success, clinical trials of the antiamyloid monoclonal antibody (AAMA) donanemab and a phase 3 clinical trial of lecanemab have reported clinical benefits linked to amyloid removal. Lecanemab (trade name, Leqembi) is the first with published phase 3 trial results. When administered through IV every 2 weeks to patients with elevated brain amyloid and mild cognitive impairment or mild dementia, lecanemab delayed cognitive and functional worsening by approximately 5 months in an 18-month double-blind, placebo-controlled trial. The trial was well conducted, and the results favoring lecanemab were internally consistent. The demonstration that lecanemab treatment delayed clinical progression in persons with mild symptoms due to AD is a major conceptual achievement, but a better appreciation of the magnitude and durability of benefits for individual patients will require extended observations from clinical practice settings. Amyloid-related imaging abnormalities (ARIA) that were largely asymptomatic occurred in approximately 20%, slightly more than half of which were attributable to treatment and the rest to underlying AD-related amyloid angiopathy. Persons who were homozygous for the APOE epsilon 4 allele had greater ARIA risks. Hemorrhagic complications with longer-term lecanemab use need to be better understood. Administration of lecanemab will place unprecedented pressures on dementia care personnel and infrastructure, both of which need to grow exponentially to meet the challenge.