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-β
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 ε4 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.