Discordant cerebrospinal fluid and positron emission tomography amyloid biomarkers in an APP mutation carrier presenting corticobasal syndrome

Abstract

INTRODUCTION: While amyloid cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers are considered interchangeable indicators of Alzheimer's disease (AD) pathology, biomarker discrepancies can occur but remain poorly characterized. METHODS: We evaluated 18F-florbetapir amyloid PET, 18F-Florzolotau PET (tau pathology), magnetic resonance imaging (MRI) findings, and CSF biomarkers in a 59-year-old man carrying the pathogenic APP p.K687Q mutation, who presented with possible corticobasal syndrome. RESULTS: CSF analysis revealed reduced amyloid beta (Aβ)1-42 (503.44 pg/mL) and Aβ1-42/Aβ1-40 ratio (0.044), indicating amyloid pathology. Conversely, 18F-florbetapir PET was visually negative (standardized uptake value ratio [SUVR] 0.97; −11.8 Centiloids). 18F-Florzolotau PET demonstrated AD-typical tau deposition, whereas MRI revealed extensive white matter hyperintensities, enlarged perivascular spaces, and a temporal microbleed. DISCUSSION: The observed discordance suggests that CSF and PET amyloid biomarkers can diverge in certain patients. Potential mechanisms include polymorphic Aβ fibrils lacking 18F-florbetapir binding sites, excess non-fibrillar aggregates, low fibril density, or contributions from cerebral amyloid angiopathy. Highlights: CSF Aβ and 18F-florbetapir PET findings showed a mismatch in a patient with an APP mutation. Amyloid pathology should not be excluded despite negative 18F-florbetapir PET findings. Mismatch may reflect altered ligand binding or fibril structural variants. Comorbid cerebral amyloid angiopathy may contribute to biomarker discrepancies.