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

Autor: Phillips JM; Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.; Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA., Winfree RL; Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA., Seto M; Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA., Schneider JA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA., Bennett DA; Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA., Dumitrescu LC; Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA., Hohman TJ; Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA. timothy.j.hohman@vumc.org.; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA. timothy.j.hohman@vumc.org.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2024 Nov 24; Vol. 148 (1), pp. 69. Date of Electronic Publication: 2024 Nov 24.
DOI: 10.1007/s00401-024-02828-5
Abstrakt: 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  < 3.5e-4), but not in individuals positive for tau pathology and negative for amyloid pathology (all P FDR  > 0.05). Higher cortical GFAP levels were associated with increased amyloid pathology, CAA pathology, and faster cognitive decline (all P FDR  < 3.3e-3). GFAP's associations with phosphorylated tau burden and cognition were influenced by amyloid burden, being most pronounced among amyloid-positive individuals, confirming previous in vivo biomarker observations. No associations were observed between GFAP gene expression and outcomes in the caudate nucleus. Our results support previous biomarker findings and suggest that higher brain GFAP levels are associated with higher brain amyloid burden and faster cognitive decline among amyloid-positive individuals.
Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Ethical approval and consent to participate: This study adhered to the principles outlined in the Declaration of Helsinki. All protocols received approval from the Rush University Medical Center Institutional Review Board, and written informed consent, including the Anatomical Gift Act, was obtained from all participants. The secondary analyses were approved by the Vanderbilt University Medical Center Institutional Review Board under protocol number 170135. Consent for publication: All authors have given consent to the publication of this manuscript.
(© 2024. The Author(s).)
Databáze: MEDLINE
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