The mediating role of plasma glial fibrillary acidic protein in amyloid and tau pathology in Down's syndrome

Anna H Boerwinkle; Julie K Wisch; Benjamin L Handen; Elizabeth Head; Mark Mapstone; Michael S Rafii; Sid E O'Bryant; Sharon J Krinsky-McHale; Florence Lai; H Diana Rosas; Shahid Zaman; Ira T Lott; Dana Tudorascu; Matthew Zammit; Adam M Brickman; Joseph H Lee; Beau M Ances; Alzheimer's Biomarker Consortium‐Down Syndrome

doi:10.1002/alz.14359

The mediating role of plasma glial fibrillary acidic protein in amyloid and tau pathology in Down's syndrome

Alzheimers Dement. 2024 Nov 13. doi: 10.1002/alz.14359. Online ahead of print.

Authors

Anna H Boerwinkle¹, Julie K Wisch², Benjamin L Handen³, Elizabeth Head⁴, Mark Mapstone⁵, Michael S Rafii⁶, Sid E O'Bryant⁷, Sharon J Krinsky-McHale⁸, Florence Lai⁹, H Diana Rosas¹⁰, Shahid Zaman¹¹, Ira T Lott¹², Dana Tudorascu³, Matthew Zammit¹³, Adam M Brickman¹⁴, Joseph H Lee^{14

15}, Beau M Ances²; Alzheimer's Biomarker Consortium‐Down Syndrome

Affiliations

¹ McGovern Medical School, University of Texas in Houston, Houston, Texas, USA.
² Department of Neurology, Washington University in St. Louis, St. Louis, Missouri, USA.
³ Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
⁴ Department of Pathology, Gillespie Neuroscience Research Facility, University of California - Irvine, Irvine, California, USA.
⁵ Department of Neurology, University of California Irvine School of Medicine, Orange, California, USA.
⁶ Alzheimer's Therapeutic Research Institute, Keck School of Medicine of USC, Los Angeles, California, USA.
⁷ Institute for Translational Research Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, Texas, USA.
⁸ Department of Psychology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, New York, USA.
⁹ Department of Radiology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹⁰ Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA.
¹¹ Cambridge Intellectual and Developmental Disabilities Research Group, University of Cambridge, Cambridge, UK.
¹² Department of Pediatrics, University of California Irvine School of Medicine, Orange, California, USA.
¹³ Department of Medical Physics and Psychiatry, University of Wisconsin Madison, Madison, Wisconsin, USA.
¹⁴ Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA.
¹⁵ Department of Epidemiology, Columbia University Irving Medical Center, New York, New York, USA.

PMID: 39535359
DOI: 10.1002/alz.14359

Abstract

Introduction: Development of Alzheimer's disease (AD) pathology in Down's syndrome (DS) occurs within a compressed timeline compared to sporadic or other genetic forms of AD.

Methods: Plasma glial fibrillary acidic protein (GFAP) and plasma pTau-217 levels were compared by AD pathophysiology (amyloid (A+) and tau (T+) positron emission tomography [PET]) in persons with DS (N = 348) and sibling controls (N = 42). Plasma GFAP, plasma pTau-217, amyloid-PET, and tau-PET levels were compared with regard to estimated years to onset of clinical symptoms (52.5 years old). We evaluated if plasma GFAP mediated the relationship between amyloid PET and plasma pTau-217 or tau PET.

Results: Plasma GFAP, a measure of astrogliosis, was elevated in A+/T- and A+/T+ individuals with DS. Plasma pTau-217 was elevated in A+/T+ individuals with DS. GFAP partially mediated the relationship between amyloid-PET and tau-PET (15.3%) and amyloid-PET and plasma pTau-217 (42.1%).

Discussion: Astrogliosis is a key component in the advancement of preclinical AD pathophysiology in DS.

Highlights: Amyloid may be a necessary precursor for stimulating astrocytes. Astrogliosis may play a key role in modifications to tau phosphorylation. Targeting neuroinflammation may only aid amyloid positive individuals. Alzheimer's disease timecourse is compressed in individuals with Down's syndrome.

Keywords: Alzheimer's disease; Down's syndrome; biomarkers; plasma.

Abstract

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