👤 Gary Marano

In recent years, lecanemab received regulatory approval from several regulatory agencies. The safety profile, particularly the risk of amyloid-related imaging abnormalities (ARIA), necessitates post-marketing surveillance. From a public health perspective, generating robust real-world evidence (RWE) is essential. This study aims to inform policy and clinical decision-makers by analyzing prescribing information, literature evidence, and the FDA Adverse Events Reporting System (FAERS) pharmacovigilance reports. This study employed a mixed-method approach. First, prescribing information for lecanemab was collected and compared across four regulatory agencies. Second, a systematic literature review was conducted in MEDLINE and Embase to identify RWE studies reporting adverse events (AEs), symptoms, or management strategies in patients treated with lecanemab. Finally, post-marketing safety data from the FAERS database were analyzed. Four regulatory agencies have approved lecanemab through different pathways, each requiring confirmation of amyloid pathology and careful assessment of ARIA risk, particularly in Apolipoprotein E (ApoE) ε4 homozygotes. Notable differences exist across agencies regarding indications, contraindications, monitoring protocols, and criteria for treatment suspension, resumption, or discontinuation. All authorities mandate post-marketing programs to ensure ongoing monitoring of safety and effectiveness. A bibliographic search identified 26 studies. Nine cohort studies included between 19 and 407 participants and reported follow-up periods ranging from 6 to 14 months; in a few studies, lecanemab was administered to individuals with moderate or severe AD. As expected, infusion-related reactions (IRRs) and ARIA were the most frequent adverse events, predominantly occurring within the first seven infusions. Some studies reported preliminary efficacy outcomes, although attrition bias may have affected these findings. Seventeen case reports described nineteen individuals aged 57–82, with most AEs arising between the 3rd and 7th infusion and primarily consisting of ARIA; serious events such as stroke, seizures, and two fatalities were also noted. In most cases, lecanemab was paused or permanently discontinued. Analysis of the FAERS database identified 1,286 reports revealing 2,627 AEs, of which 30% were classified as serious, including forty-six deaths. The most reported AEs were headache, ARIA-E, ARIA-H, and chills. ARIA-E and ARIA-H have similar demographics, onset timing, and severity profiles. This study highlights the complexity of lecanemab’s safety profile and the variability in regulatory prescribing recommendations. While ARIA, especially in ApoE ε4 homozygotes, remains the most frequent adverse event, its severity ranges from mild to, in rare cases, severe or fatal. These findings underscore the need for robust post-marketing surveillance and harmonized recommendations to ensure safe and effective clinical use. The online version contains supplementary material available at 10.1007/s10072-026-08829-4. Show less

Amyloid related imaging abnormalities (ARIA) are the most significant risk associated with the use of anti-amyloid monoclonal antibodies (MAB) for Alzheimer's disease (AD). Currently, the presence of the APOE ε4 allele is the best predictor for the development of ARIA. However, the degree of baseline memory impairment has not been fully explored as a risk factor for ARIA. Here, we examined MAB outcomes in a memory clinic population and compared patients with AD who developed ARIA to a case-matched group who did not develop ARIA. Participants who developed ARIA had greater numbers of recall intrusions and false positives, both markers for memory consolidation, at baseline than those who did not develop ARIA. We also observed greater baseline hippocampal and supplementary motor cortical atrophy with ARIA. These differences remained when controlling for the APOE ε4 allele and the presence of pretreatment microhemorrhages. Further investigation of memory impairment and associated brain atrophy is warranted to understand ARIA risk and MAB outcomes in AD. Show less

In budding yeast, overcoming of a critical size to enter S phase and the mitosis/mating switch--two central cell fate events--take place in the G1 phase of the cell cycle. Here we present a mathematical model of the basic molecular mechanism controlling the G1/S transition, whose major regulatory feature is multisite phosphorylation of nuclear Whi5. Cln3-Cdk1, whose nuclear amount is proportional to cell size, and then Cln1,2-Cdk1, randomly phosphorylate both decoy and functional Whi5 sites. Full phosphorylation of functional sites releases Whi5 inhibitory activity, activating G1/S transcription. Simulation analysis shows that this mechanism ensures coherent release of Whi5 inhibitory action and accounts for many experimentally observed properties of mitotically growing or conjugating G1 cells. Cell cycle progression and transcriptional analyses of a Whi5 phosphomimetic mutant verify the model prediction that coherent transcription of the G1/S regulon and ensuing G1/S transition requires full phosphorylation of Whi5 functional sites. Show less