Pathologic and clinical correlates of region-specific brain GFAP in Alzheimer’s disease

• Published in: Acta neuropathologica 2024-11, Vol.148 (1), p.69, Article 69
• Main Authors: Phillips, Jared M., Winfree, Rebecca L., Seto, Mabel, Schneider, Julie A., Bennett, David A., Dumitrescu, Logan C., Hohman, Timothy J.
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Autopsies; Autopsy; Biomarkers; Biomarkers - metabolism; Blood levels; Brain - metabolism; Brain - pathology; Caudate nucleus; Cerebral amyloid angiopathy; Cognitive ability; Cognitive Dysfunction - genetics; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - pathology; Cortex (cingulate); Female; Gene expression; Glial fibrillary acidic protein; Glial Fibrillary Acidic Protein - metabolism; Humans; Lewy bodies; Male; Medicine; Medicine & Public Health; Neurodegenerative diseases; Neurosciences; Original Paper; Pathology; Prefrontal cortex; Proteins; Proteomics; Tau protein; tau Proteins - metabolism; β-Amyloid
• ISSN: 1432-0533; 0001-6322; 1432-0533
• DOI: 10.1007/s00401-024-02828-5

Plasma glial fibrillary acidic protein (GFAP) is an emerging biomarker of Alzheimer’s disease (AD), with higher blood GFAP levels linked to faster cognitive decline, particularly among individuals with high brain amyloid burden. However, few studies have examined brain GFAP expression to clarify if peripheral associations reflect brain changes. This study aimed to correlate region-specific GFAP mRNA expression ( n  = 917) and protein abundance (n=386) with diverse neuropathological measures at autopsy in the Religious Orders Study and Rush Memory and Aging Project (ROS/MAP) and to characterize the interaction between brain GFAP and brain amyloid burden on downstream outcomes. We assessed GFAP gene expression in the dorsolateral prefrontal cortex, caudate nucleus, and posterior cingulate cortex with respect to core AD pathology (amyloid-β and tau), cerebrovascular (microinfarcts, macroinfarcts, and cerebral amyloid angiopathy [CAA]), proteinopathic (TDP-43, Lewy bodies), and cognitive outcomes. These associations were further examined at the protein level using tandem-mass tag proteomic measurements from the dorsolateral prefrontal cortex. We also assessed GFAP interactions with AD neuropathology on downstream outcomes. Cortical GFAP gene and protein expression were significantly upregulated in participants with a neuropathologically confirmed AD diagnosis at autopsy (all P FDR   0.05). Higher cortical GFAP levels were associated with increased amyloid pathology, CAA pathology, and faster cognitive decline (all P FDR