Increased glial fibrillary acidic protein (GFAP) in blood, a biomarker of reactive astrogliosis and astrocytic injury, was observed in a variety of neurological disorders. However, the causal relationship between plasma GFAP and neurological disorders remains unclear.
Objective
We aim to investigate causal association between plasma GFAP levels and neurological disorders using bidirectional Mendelian randomization (MR).
Methods
The genome-wide association studies for neurological disorders, including neurodegenerative diseases, neuroimmune disorders, cerebrovascular diseases, and epilepsy, were collected. Genetic variables associated with plasma GFAP levels were obtained from the UK Biobank Pharma Proteomics Project. Inverse variance weighted or Wald ratio method was used as the main analysis to assess the causal association.
Results
Genetically predicted higher plasma GFAP levels were found to be associated with an increased risk of encephalitis (odds ratio [OR] = 2.52; 95% confidence interval [CI] = 1.67–3.47; p = 1.22 × 10–5). Furthermore, we found that Alzheimer's disease (β = 0.05; standard error [SE] = 0.01; p = 6.63 × 10–8), frontotemporal dementia (β = 0.12; SE = 0.01; p = 5.10 × 10–16), and dementia with Lewy bodies (β = 0.08; SE = 0.02; p = 5.45 × 10–5) were causally linked to an increase in plasma GFAP levels. Even after controlling for the influence of aging, these associations remained significant.
Conclusions
Our study found that higher plasma GFAP levels may increase the risk of encephalitis, while neurodegenerative dementia may enhance the plasma GFAP levels, supporting the clinical utility of blood GFAP as a reliable biomarker in neurological diseases.
AbdelhakAFoschiMAbu-RumeilehS, et al.Blood GFAP as an emerging biomarker in brain and spinal cord disorders. Nat Rev Neurol2022; 18: 158–172.
2.
PelkmansWShekariMBrugulat-SerratA, et al.Astrocyte biomarkers GFAP and YKL-40 mediate early Alzheimer’s disease progression. Alzheimers Dement2024; 20: 483–493.
3.
SandovalYAppleFSMahlerSA, et al.High-sensitivity cardiac troponin and the 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guidelines for the evaluation and diagnosis of acute chest pain. Circulation2022; 146: 569–581.
4.
EscartinCGaleaELakatosA, et al.Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci2021; 24: 312–325.
5.
PereiraJBJanelidzeSSmithR, et al.Plasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer’s disease. Brain2021; 144: 3505–3516.
6.
AskenBMElahiFMLa JoieR, et al.Plasma glial fibrillary acidic protein levels differ along the spectra of amyloid burden and clinical disease stage. J Alzheimers Dis2021; 80: 471–474.
7.
ChatterjeePPedriniSStoopsE, et al.Plasma glial fibrillary acidic protein is elevated in cognitively normal older adults at risk of Alzheimer’s disease. Transl Psychiatry2021; 11: 27.
8.
BenedetALMilà-AlomàMVrillonA, et al.Differences between plasma and cerebrospinal fluid glial fibrillary acidic protein levels across the Alzheimer disease continuum. JAMA Neurol2021; 78: 1471–1483.
9.
O’ConnorAAbelEBenedetAL, et al.Plasma GFAP in presymptomatic and symptomatic familial Alzheimer’s disease: a longitudinal cohort study. J Neurol Neurosurg Psychiatry2023; 94: 90–92.
10.
ChatterjeePVermuntLGordonBA, et al.Plasma glial fibrillary acidic protein in autosomal dominant Alzheimer’s disease: associations with Aβ-PET, neurodegeneration, and cognition. Alzheimers Dement2023; 19: 2790–2804.
11.
NicholsNRDayJRLapingNJ, et al.GFAP mRNA increases with age in rat and human brain. Neurobiol Aging1993; 14: 421–429.
12.
CronjéHTLiuXOddenMC, et al.Serum NfL and GFAP are associated with incident dementia and dementia mortality in older adults: the cardiovascular health study. Alzheimers Dement2023; 19: 5672–5680.
SunBBChiouJTraylorM, et al.Plasma proteomic associations with genetics and health in the UK biobank. Nature2023; 622: 329–338.
15.
KunkleBWGrenier-BoleyBSimsR, et al.Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet2019; 51: 414–430.
16.
Van DeerlinVMSleimanPMAMartinez-LageM, et al.Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet2010; 42: 234–239.
17.
ChiaRSabirMSBandres-CigaS, et al.Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture. Nat Genet2021; 53: 294–303.
18.
NallsMABlauwendraatCVallergaCL, et al.Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol2019; 18: 1091–1102.
19.
NicolasAKennaKPRentonAE, et al.Genome-wide analyses identify KIF5A as a novel ALS gene. Neuron2018; 97: 1268–1283.e6.
20.
International Multiple Sclerosis Genetics Consortium. Multiple sclerosis genomic map implicates peripheral immune cells and microglia in susceptibility. Science2019; 365: eaav7188.
21.
EstradaKWhelanCWZhaoF, et al.A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica. Nat Commun2018; 9: 1929.
22.
MalikRChauhanGTraylorM, et al.Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet2018; 50: 524–537.
23.
International League Against Epilepsy Consortium on Complex Epilepsies. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat Commun2018; 9: 5269.
24.
HeQWangWXuD, et al.Causal association of iron status with functional outcome after ischemic stroke. Stroke2024; 55: 423–431.
25.
ChenLPetersJEPrinsB, et al.Systematic Mendelian randomization using the human plasma proteome to discover potential therapeutic targets for stroke. Nat Commun2022; 13: 6143.
26.
DongM-HZhouL-QTangY, et al.CSF sTREM2 in neurological diseases: a two-sample Mendelian randomization study. J Neuroinflammation2022; 19: 79.
27.
BurgessSBowdenJFallT, et al.Sensitivity analyses for robust causal inference from Mendelian randomization analyses with multiple genetic variants. Epidemiology2017; 28: 30–42.
28.
BowdenJDavey SmithGBurgessS. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol2015; 44: 512–525.
29.
VerbanckMChenC-YNealeB, et al.Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet2018; 50: 693–698.
30.
McCartneyDLMinJLRichmondRC, et al.Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging. Genome Biol2021; 22: 194.
31.
Gravier-DumonceauAAmeliRRogemondV, et al.Glial fibrillary acidic protein autoimmunity: a French cohort study. Neurology2022; 98: e653–e668.
32.
ZuzaALBarrosHLSde Mattos Silva OliveiraTF, et al.Astrocyte response to St. Louis encephalitis virus. Virus Res2016; 217: 92–100.
33.
StudahlMRosengrenLGüntherG, et al.Difference in pathogenesis between herpes simplex virus type 1 encephalitis and tick-borne encephalitis demonstrated by means of cerebrospinal fluid markers of glial and neuronal destruction. J Neurol2000; 247: 636–642.
34.
GrahnAHagbergLNilssonS, et al.Cerebrospinal fluid biomarkers in patients with varicella-zoster virus CNS infections. J Neurol2013; 260: 1813–1821.
35.
VejeMGriškaVPakalnienėJ, et al.Serum and cerebrospinal fluid brain damage markers neurofilament light and glial fibrillary acidic protein correlate with tick-borne encephalitis disease severity-a multicentre study on Lithuanian and Swedish patients. Eur J Neurol2023; 30: 3182–3189.
36.
ChengPHuangWYangM, et al.Autoimmune GFAP astrocytopathy after viral encephalitis: a case report of bimodal overlapping encephalitis. Front Immunol2023; 14: 1258048.
37.
VerberkIMWLaarhuisMBvan den BoschKA, et al.Serum markers glial fibrillary acidic protein and neurofilament light for prognosis and monitoring in cognitively normal older people: a prospective memory clinic-based cohort study. Lancet Healthy Longev2021; 2: e87–e95.
38.
SanchezEWilkinsonTCoughlanG, et al.Association of plasma biomarkers with cognition, cognitive decline, and daily function across and within neurodegenerative diseases: results from the Ontario Neurodegenerative Disease Research Initiative. Alzheimers Dement2024; 20: 1753–1770.
39.
OecklPHalbgebauerSAnderl-StraubS, et al.Glial fibrillary acidic protein in serum is increased in Alzheimer’s disease and correlates with cognitive impairment. J Alzheimers Dis2019; 67: 481–488.
40.
FangTDaiYHuX, et al.Evaluation of serum neurofilament light chain and glial fibrillary acidic protein in the diagnosis of Alzheimer’s disease. Front Neurol2024; 15: 1320653.
41.
GuoYShenX-NWangH-F, et al.The dynamics of plasma biomarkers across the Alzheimer’s continuum. Alzheimers Res Ther2023; 15: 31.
42.
WojdałaALBellomoGGaetaniL, et al.Trajectories of CSF and plasma biomarkers across Alzheimer’s disease continuum: disease staging by NF-L, p-tau181, and GFAP. Neurobiol Dis2023; 189: 106356.
43.
LvXChengZWangQ, et al.High burdens of phosphorylated tau protein and distinct precuneus atrophy in sporadic early-onset Alzheimer’s disease. Sci Bull (Beijing)2023; 68: 2817–2826.
44.
CousinsKAQIrwinDJChen-PlotkinA, et al.Plasma GFAP associates with secondary Alzheimer’s pathology in Lewy body disease. Ann Clin Transl Neurol2023; 10: 802–813.
45.
Hsiao-NakamotoJChiuC-LVandeVredeL, et al.Alterations in lysosomal, glial and neurodegenerative biomarkers in patients with sporadic and genetic forms of frontotemporal dementia. bioRxiv 2024; DOI:10.1101/2024.02.09.579529 [Preprint]. Posted February 12, 2024.
46.
HellerCFoianiMSMooreK, et al.Plasma glial fibrillary acidic protein is raised in progranulin-associated frontotemporal dementia. J Neurol Neurosurg Psychiatry2020; 91: 263–270.
47.
WuYShaoWToddTW, et al.Microglial lysosome dysfunction contributes to white matter pathology and TDP-43 proteinopathy in GRN-associated FTD. Cell Rep2021; 36: 109581.
48.
HartnellIJWoodhouseDJasperW, et al.Glial reactivity and T cell infiltration in frontotemporal lobar degeneration with tau pathology. Brain2024; 147: 590–606.
49.
JiwajiZHardinghamGE. Good, bad, and neglectful: astrocyte changes in neurodegenerative disease. Free Radic Biol Med2022; 182: 93–99.
ZhangSWuMPengC, et al.GFAP Expression in injured astrocytes in rats. Exp Ther Med2017; 14: 1905–1908.
52.
De BastianiMABellaverBBrumWS, et al.Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies. Brain Behav Immun2023; 110: 175–184.
53.
ScofieldMDKalivasPW. Astrocytic dysfunction and addiction: consequences of impaired glutamate homeostasis. Neuroscientist2014; 20: 610–622.
54.
Gomez-ArboledasAFonsecaMIKramarE, et al.C5ar1 signaling promotes region- and age-dependent synaptic pruning in models of Alzheimer’s disease. Alzheimers Dement2024; 20: 2173–2190.
55.
BallabhPBraunANedergaardM. The blood-brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis2004; 16: 1–13.
56.
Ayala-GuerreroLGarcía-delaTorrePSánchez-GarcíaS, et al.Serum levels of glial fibrillary acidic protein association with cognitive impairment and type 2 diabetes. Arch Med Res2022; 53: 501–507.
57.
YueQHoiMPM. Emerging roles of astrocytes in blood-brain barrier disruption upon amyloid-beta insults in Alzheimer’s disease. Neural Regen Res2023; 18: 1890–1902.
58.
KaurDSharmaVDeshmukhR. Activation of microglia and astrocytes: a roadway to neuroinflammation and Alzheimer’s disease. Inflammopharmacology2019; 27: 663–677.
59.
CicognolaCMattsson-CarlgrenNvan WestenD, et al.Associations of CSF PDGFRβ with aging, blood-brain barrier damage, neuroinflammation, and Alzheimer disease pathologic changes. Neurology2023; 101: e30–e39.
LiTChenXZhangC, et al.An update on reactive astrocytes in chronic pain. J Neuroinflammation2019; 16: 140.
62.
VollmuthCFiesslerCMontellanoFA, et al.Incremental value of serum neurofilament light chain and glial fibrillary acidic protein as blood-based biomarkers for predicting functional outcome in severe acute ischemic stroke. Eur Stroke J2024; 9: 751–762.
63.
GalenkoOJacobsVKnightS, et al.Circulating levels of biomarkers of cerebral injury in patients with atrial fibrillation. Am J Cardiol2019; 124: 1697–1700.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
