New Clarity AD Analysis Reveal How Lecanemab Engages and Clears Neurotoxic Protofibrils in Alzheimer Disease

Researchers recently developed a sensitive immunoassay using lecanemab (Leqembi; Eisai), an antiamyloid therapy approved for Alzheimer disease (AD), to selectively quantify amyloid-β protofibrils (Aβ-PF) in the cerebrospinal fluid (CSF). Newly presented findings from an analysis of the phase 3 Clarity AD trial (NCT03887455) implementing the created immunoassay demonstrated that treatment with lecanemab led to increased Aβ-PF levels in the CSF among patients with AD, further validating the drug’s target engagement and pharmacodynamic effect.¹

Presented at the 18th Clinical Trials on Alzheimer’s Disease (CTAD) Conference, held December 1-4, 2025, in San Diego, California, a total of 410 participants (placebo, n = 207; lecanemab, n = 203) had CSF samples at baseline, and 253 participants (placebo, n = 127; lecanemab, n = 126) had both baseline and at least 1 post baseline sample over the 18-month core study period. At baseline, CSF Aβ-PF were positively correlated with neurogranin, a marker of synaptic dysfunction (r = 0.153, P = .0127), and negatively correlated with amyloid PET centiloid (r = -0.202, P = .0005).

In the lecanemab-treated group, findings showed that total CSF Aβ-PF levels, including both free and bound forms, increased relative to placebo at all post baseline assessments (P = .0126 at 12 months and numerically higher at 18 months). Among participants who achieved amyloid negativity (Centiloid less than 30) at 18 months, researchers observed that those receiving lecanemab had a greater percent change of CSF Aβ-PF from baseline compared with participants who remained amyloid positive (Centiloid less than 30).

“Clarity AD results confirmed previously demonstrated positive correlation of soluble Aβ-PF with neurodegeneration biomarkers. In contrast, we found that soluble Aβ-PF is negatively correlated with amyloid-PET, suggesting that Aβ-PF is a toxic species generated upstream of plaques in the amyloid cascade,” lead author Kanta Horie, PhD, MEng, head of the human biology creation hub at Eisai and voluntary research associate professor in the Department of Neurology at Washington University School of Medicine, and colleagues wrote.²

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In the study, investigators characterized CSF Aβ-PF in the Clarity AD trial by assessing levels at baseline and evaluating Aβ-PF as a target engagement biomarker of lecanemab. The analysis also examined longitudinal changes in the placebo arm and analyzed associations between changes from baseline in CSF Aβ-PF and neurodegenerative biomarkers. Additional biomarker assessments, including amyloid PET and CSF measures of total tau (t-tau), phosphorylated tau at residue 181 (p-tau181), neurogranin, and microtubule-binding region tau containing residue 243 (MTBR-tau243), were performed as previously described and used for correlation analyses.

In the placebo arm, researchers reported that CSF Aβ-PF levels increased from baseline. These increases were significantly positively correlated with changes in CSF neurodegenerative biomarkers, including total tau (t-tau; r = 0.286, P = 0.0069) and neurogranin (r = 0.262, P = 0.0138). Positive correlations were also observed with tau-related biomarkers associated with AD, including phosphorylated tau at residue 181 (p-tau181; r = 0.304, P = 0.0040) and MTBR-tau243 (r = 0.252, P = 0.0155). In the lecanemab-treated arm, total CSF Aβ-PF levels increased; however, no significant associations were observed between changes in Aβ-PF and neurodegenerative or tau-related biomarkers.

“The observed increase in total CSF Aβ-PF levels with lecanemab-treatment demonstrates target engagement, and mobilization of Aβ-PF from amyloid plaques (pharmacodynamic effect), confirming the unique dual mechanism of lecanemab targeting Aβ-PF and plaques,” Horie et al noted.² “Finally, we demonstrated that lecanemab treatment disrupts the association between CSF Aβ-PF and AD biomarkers changes observed in the placebo arm, suggesting neutralization of Aβ-PF toxicity by lecanemab.”

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REFERENCES
1. New Data Presented at CTAD 2025 Confirms Pharmacological Effect of LEQEMBI® (lecanemab-irmb) on Neurotoxic Aβ Protofibrils in CSF. News release. Eisai. December 2, 2025. Accessed December 3, 2025. https://www.eisai.com/news/2025/news202584.html
2. Horie K, Koyama A, Sachdev P, et al. The Effects Of Lecanemab Treatment On Soluble CSF Aβ Protofibrils In Clarity AD.. Presented at: 2025 Clinical Trials on Alzheimer Disease conference. December 1-5; San Diego, CA. Abstract OC05.