Lecanemab in AD: not a paradigm shift, but a small step forward

Lecanemab, the first disease-modifying therapy for Alzheimer’s disease, may have finally been approved; however, this does not end discussions on its clinical utility. Its efficacy is statistically solid, but evidence of clinical benefit seems “whisper thin.”

In a session on breakthroughs in neurology, Dr Matilde Bruno (University of Rome Tor Vergata, Italy) reflected on lecanemab and the future of monoclonal antibodies (mAbs) targeting amyloid-beta in general [1]. She reminded her audience that the EMA initially rejected lecanemab because its modest cognitive benefits were deemed not to outweigh the risks, in particular, amyloid-related imaging abnormalities (ARIAs). Later, the EMA still granted approval, but the widespread adoption of mAbs targeting amyloid-beta is hindered by different factors, Dr Bruno argued. Variability in infrastructure, reimbursement policies, and regulatory approval decides who may be eligible for lecanemab and who may not be.

First, strict eligibility criteria limit patient access. Lecanemab, a humanised monoclonal antibody targeting amyloid protofibrils, is approved for the treatment of adults in the early stages of AD (MCI or AD with MMSE <22), who have one or no copies of the apolipoprotein E4 gene (ApoE4), and with biomarker positivity for amyloid (either at PET or in the CSF). Consequently, only a small proportion of patients qualify for treatment. Unequal access to diagnostics and disease-modifying therapies reflects significant inter- and intra-national healthcare disparities. MRI monitoring for ARIA is required 1 year before, at study baseline and prior to the 5^th,7^th and 14^th infusion. Treatment centre requirements include diagnostic expertise, such as access to biomarker testing; infusion facilities, including rooms equipped with emergency response equipment; specialised neuroimaging (notably MRI) and radiologists trained to detect ARIAs; and the necessary monitoring infrastructure for tracking patient outcomes and adverse events.

Dr Bruno also noted that marketing authorisation marks a pivotal shift: from rigorously selected trial populations to the very heterogeneous real-world patients. Post-marketing surveillance data are essential to bridge this translational gap and to capture the safety and efficacy of current and emerging Alzheimer’s disease therapies “in the wild.” Real-world impact remains uncertain. The initial amyloid-centred approach prioritised the amyloid biological target over other targets and clinical context. This prompts a re-evaluation of the amyloid hypothesis, urging the development of person-centred care models that integrate disease heterogeneity, comorbidities, and patient goals.

1. Bruno M, et al. Rejection and approval: Lecanemab and the future of anti-amyloid treatments. SPS09_1, EAN Congress 2025, 21-24 June 2025, Helsinki, Finland.

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Posted on 3 September 20253 September 2025