Association of glial fibrillary acid protein, Alzheimer's disease pathology and cognitive decline

Débora E Peretti; Cecilia Boccalini; Federica Ribaldi; Max Scheffler; Moira Marizzoni; Nicholas J Ashton; Henrik Zetterberg; Kaj Blennow; Giovanni B Frisoni; Valentina Garibotto

doi:10.1093/brain/awae211

Association of glial fibrillary acid protein, Alzheimer's disease pathology and cognitive decline

Brain. 2024 Jun 28:awae211. doi: 10.1093/brain/awae211. Online ahead of print.

Authors

Débora E Peretti¹, Cecilia Boccalini¹, Federica Ribaldi^{2

3}, Max Scheffler⁴, Moira Marizzoni⁵, Nicholas J Ashton^{6

7

8

9}, Henrik Zetterberg^{9

10

11

12

13

14}, Kaj Blennow^{7

12

15

16}, Giovanni B Frisoni^{2

3}, Valentina Garibotto^{1

17

18}

Affiliations

¹ Laboratory of Neuroimaging and Innovative Molecular Tracers (NIMTlab), Geneva University Neurocentre and Faculty of Medicine, University of Geneva, Geneva 1205, Switzerland.
² Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva 1205, Switzerland.
³ Geneva Memory Centre, Department of Rehabilitation and Geriatrics, Geneva University Hospitals, Geneva 1205, Switzerland.
⁴ Division of Radiology, Geneva University Hospitals, Geneva 1205, Switzerland.
⁵ Biological Psychiatry Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia 25125, Italy.
⁶ Centre for Age-Related Medicine, Stavanger University Hospital, Stavanger 4011, Norway.
⁷ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal 413 90, Sweden.
⁸ King's College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, London SE5 9RX, UK.
⁹ NIHR Biomedical Research Centre for Mental Health & Biomedical Research Unit for Dementia at South London & Maudsley NHS Foundation, London SE5 8AF, UK.
¹⁰ UK Dementia Research Institute at UCL, London WC1E 6BT, UK.
¹¹ Department of Neurodegenerative Disease, UCL Institute of Neurology, London WC1N 3BG, UK.
¹² Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal 413 45, Sweden.
¹³ Hong Kong Centre for Neurodegenerative Diseases, Clear Water Bay, Hong Kong Units 1501-1502, 1512-1518, China.
¹⁴ Wisconsin Alzheimer's Disease Research Centre, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792, USA.
¹⁵ Paris Brain Institute, ICM, Pitié Salpêtrière Hospital, Sorbonne University, Paris 75013, France.
¹⁶ Neurodegenerative Disorder Research Centre, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei 230001, China.
¹⁷ Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospitals, Geneva 1205, Switzerland.
¹⁸ Centre for Biomedical Imaging, University of Geneva, Geneva 1205, Switzerland.

PMID: 38940331
DOI: 10.1093/brain/awae211

Abstract

Increasing evidence shows that neuroinflammation is a possible modulator of tau spread effects on cognitive impairment in Alzheimer's disease. In this context, plasma levels of the glial fibrillary acidic protein (GFAP) have been suggested to have a robust association with Alzheimer's disease pathophysiology. This study aims to assess the correlation between plasma GFAP and Alzheimer's disease pathology, and their synergistic effect on cognitive performance and decline. A cohort of 122 memory clinic subjects with amyloid and tau positron emission tomography, MRI scans, plasma GFAP, and Mini-Mental State Examination (MMSE) was included in the study. A subsample of 94 subjects had a follow-up MMSE score at least one year after baseline. Regional and voxel-based correlations between Alzheimer's disease biomarkers and plasma GFAP were assessed. Mediation analyses were performed to evaluate the effects of plasma GFAP on the association between amyloid and tau PET, and tau PET and cognitive impairment and decline. GFAP was associated with increased tau PET ligand uptake in the lateral temporal and inferior temporal lobes in a strong left-sided pattern independently of age, gender, education, amyloid, and APOE status (β=0.001, p < 0.01). The annual rate of MMSE change was significantly and independently correlated with both GFAP (β=0.006, p < 0.01) and global tau SUVR (β=4.33, p < 0.01), but not with amyloid burden. Partial mediation effects of GFAP were found on the association between amyloid and tau pathology (13.7%), and between tau pathology and cognitive decline (17.4%), but not on global cognition at baseline. Neuroinflammation measured by circulating GFAP is independently associated with tau Alzheimer's disease pathology and with cognitive decline, suggesting neuroinflammation as a potential target for future disease-modifying trials targeting tau pathology. Peretti et al. show that a circulatory marker of neuroinflammation-glial fibrillary acidic protein-is associated with tau pathology in lateral temporal and frontal regions in patients with Alzheimer's disease, independent of amyloid load. Neuroinflammation appears to modulate the association between amyloid and tau biomarkers.

Keywords: Alzheimer’s disease biomarkers; cognitive decline; glial fibrillary acidic protein; neurofibrillary tau tangles; positron emission tomography.