CSF complement proteins are elevated in prodromal to moderate Alzheimer's disease patients and are not altered by the anti‐tau antibody semorinemab

• Published in: Alzheimer's & dementia 2024-11, Vol.20 (11), p.7940-7953
• Main Authors: Sandoval, Cosme, Lee, Julie, Toth, Balazs, Nagaraj, Rajini, Schauer, Stephen P., Hoffman, Jennifer, Calderon, Emilia, Kollmorgen, Gwendlyn, Sanabria Bohórquez, Sandra M., Monteiro, Cecilia, Teng, Edmond, Hanson, Jesse E., Yeh, Felix L., Gutierrez, Johnny, Biever, Anne
• Format: Article
• Language: English
• Subjects: Aged; Alzheimer Disease - cerebrospinal fluid; Alzheimer's disease; Antibodies, Monoclonal, Humanized - therapeutic use; anti‐tau semorinemab; biomarkers; Biomarkers - cerebrospinal fluid; cerebrospinal fluid; complement proteins; Complement System Proteins - cerebrospinal fluid; Complement System Proteins - metabolism; Female; Humans; Male; Middle Aged; Prodromal Symptoms; tau Proteins - cerebrospinal fluid
• ISSN: 1552-5260; 1552-5279; 1552-5279
• DOI: 10.1002/alz.14271

INTRODUCTION Growing evidence suggests a role for neuroinflammation in Alzheimer's disease (AD). We investigated complement pathway activity in AD patient cerebrospinal fluid (CSF) and evaluated its modulation by the anti‐tau antibody semorinemab. METHODS Immunoassays were applied to measure CSF complement proteins C4, factor B (FB), C3 and their cleavage fragments C4a, C3a, and factor Bb (Bb) in AD patients and a separate cognitively unimpaired (CU) cohort. RESULTS All measured CSF complement proteins were increased in AD versus CU subjects, with C4a displaying the most robust increase. Finally, semorinemab did not have a significant pharmacodynamic effect on CSF complement proteins. DISCUSSION Elevated levels of CSF C4a, C4, C3a, C3, Bb, and FB are consistent with complement activation in AD brains. Despite showing a reduction in CSF soluble tau species, semorinemab did not impact complement protein levels or activity. Further studies are needed to determine the value of complement proteins as neuroinflammation biomarkers in AD. Highlights Cerebrospinal fluid (CSF) complement proteins C4a, C3a, Bb, C4, C3, and factor B levels were increased in Alzheimer's disease (AD) patients compared to a separate cognitively unimpaired (CU) cohort. Baseline CSF complement protein levels were correlated with neuro‐axonal degeneration and glial activation biomarkers in AD patients. The investigational anti‐tau antibody semorinemab did not impact CSF complement protein levels or activity relative to the placebo arm.