Plasma and cerebrospinal fluid glial fibrillary acidic protein levels in adults with Down syndrome: a longitudinal cohort study.

Abstract

BACKGROUND:

The diagnosis of symptomatic Alzheimer's disease is a clinical challenge in adults with Down syndrome. Blood biomarkers would be of particular clinical importance in this population. The astrocytic Glial Fibrillary Acidic Protein (GFAP) is a marker of astrogliosis associated with amyloid pathology, but its longitudinal changes, association with other biomarkers and cognitive performance have not been studied in individuals with Down syndrome.

METHODS:

We performed a three-centre study of adults with Down syndrome, autosomal dominant Alzheimer's disease and euploid individuals enrolled in Hospital Sant Pau, Barcelona (Spain), Hospital Clinic, Barcelona (Spain) and Ludwig-Maximilians-Universität, Munich (Germany). Cerebrospinal fluid (CSF) and plasma GFAP concentrations were quantified using Simoa. A subset of participants had PET 18F-fluorodeoxyglucose, amyloid tracers and MRI measurements.

FINDINGS:

This study included 997 individuals, 585 participants with Down syndrome, 61 Familial Alzheimer's disease mutation carriers and 351 euploid individuals along the Alzheimer's disease continuum, recruited between November 2008 and May 2022. Participants with Down syndrome were clinically classified at baseline as asymptomatic, prodromal Alzheimer's disease and Alzheimer's disease dementia. Plasma GFAP levels were significantly increased in prodromal and Alzheimer's disease dementia compared to asymptomatic individuals and increased in parallel to CSF Aβ changes, ten years prior to amyloid PET positivity. Plasma GFAP presented the highest diagnostic performance to discriminate symptomatic from asymptomatic groups (AUC = 0.93, 95% CI 0.9-0.95) and its concentrations were significantly higher in progressors vs non-progressors (p < 0.001), showing an increase of 19.8% (11.8-33.0) per year in participants with dementia. Finally, plasma GFAP levels were highly correlated with cortical thinning and brain amyloid pathology.

INTERPRETATION:

Our findings support the utility of plasma GFAP as a biomarker of Alzheimer's disease in adults with Down syndrome, with possible applications in clinical practice and clinical trials.

FUNDING:

AC Immune, La Caixa Foundation, Instituto de Salud Carlos III, National Institute on Aging, Wellcome Trust, Jérôme Lejeune Foundation, Medical Research Council, Alzheimer's Association, National Institute for Health Research, EU Joint Programme-Neurodegenerative Disease Research, Alzheimer's Society, Deutsche Forschungsgemeinschaft, Stiftung für die Erforschung von Verhaltens, Fundación Tatiana Pérez de Guzmán el Bueno & European Union's Horizon 2020 und Umwelteinflüssen auf die menschliche Gesundheit.

• Authors: Laia Montoliu-Gaya, Daniel Alcolea, Nicholas J Ashton, Jordi Pegueroles, Johannes Levin, Beatriz Bosch, Juan Lantero-Rodriguez, María Carmona-Iragui, Olivia Wagemann, Mircea Balasa, Przemyslaw Radoslaw Kac, Isabel Barroeta, Albert Lladó, Wagner S Brum, Laura Videla, Fernando Gonzalez-Ortiz, Bessy Benejam, Javier José Arranz Martínez, Thomas K Karikari, Georg Nübling, Alexandre Bejanin, Andrea L Benedet, Rafael Blesa, Alberto Lleó, Kaj Blennow, Raquel Sánchez-Valle, Henrik Zetterberg, Juan Fortea
• Journal: EBioMedicine (EBioMedicine) Vol. 90 Pg. 104547 (Apr 2023) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 37002988 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.

Chemical References

• Amyloid beta-Peptides
• Glial Fibrillary Acidic Protein
• Biomarkers
• tau Proteins

Topics

• Adult
• Humans
• Alzheimer Disease (metabolism)
• Down Syndrome (epidemiology)
• Longitudinal Studies
• Amyloid beta-Peptides (metabolism)
• Neurodegenerative Diseases
• Glial Fibrillary Acidic Protein
• Cohort Studies
• Biomarkers
• tau Proteins (metabolism)