Lecanemab in symptomatic PSEN1 p.Met233Val early‐onset Alzheimer's disease: Neuroimaging safety, regional amyloid‐PET dynamics, and longitudinal plasma biomarkers

Abstract

Abstract Introduction The presenilin 1 (PSEN1) p.Met233Val variant is a Dominantly Inherited Alzheimer Network–Trials Unit (DIAN‐TU)–eligible autosomal‐dominant Alzheimer's disease (ADAD) variant for which lecanemab response data are unavailable. Methods A 34‐year‐old symptomatic PSEN1 p.Met233Val carrier (APOE ε3/ε3) was prospectively followed through 26 lecanemab infusions over 12 months, with serial magnetic resonance imaging (MRI), amyloid positron emission tomography (PET), and plasma biomarkers. Results No amyloid‐related imaging abnormalities occurred. Composite Centiloid increased modestly (+7.2), masking regional divergence: basal ganglia (−24.5) and medial temporal cortex (−22.1) declined, whereas posterior cortical regions accrued amyloid. Plasma amyloid beta (Aβ) 42/40 rose to 122% by T22, with concurrent decreases in phosphorylated tau at threonine 217 (p‐tau217), p‐tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Global Clinical Dementia Rating (CDR) score remained 0.5; caregiver reports noted improvements in spasticity, dystonia, and affective features. Discussion Lecanemab demonstrated neuroimaging safety and evidence of biological target engagement in this symptomatic PSEN1 p.Met233Val ADAD carrier. These longitudinal neuroimaging and plasma biomarker findings may help inform interpretation of treatment responses in genetically defined ADAD.