Plasma glial fibrillary acidic protein detects Alzheimer pathology and predicts future conversion to Alzheimer dementia in patients with mild cognitive impairment

Cicognola, Claudia; Bateman, Randall J.; Hertze, Joakim; Zetterberg, Henrik; Blennow, Kaj; Mattsson‐Carlgren, Niklas; Hansson, Oskar

doi:10.1186/s13195-021-00804-9

Cited by 163 publications

(172 citation statements)

References 40 publications

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“…80 82-84 Notably, the diagnostic performance improved with the inclusion of plasma Aβ42/Aβ40 ratio and other AD risk factors such as age, gender and/or APOE ε4 (AUC increased from 0.84 to 0.92). [82][83][84] Altogether, these results indicate that blood GFAP may be an early biomarker of reactive astrogliosis associated with Aβ pathology in the predementia phase. Moreover, higher baseline blood GFAP levels in non-demented elderly were associated with progression to dementia and steeper rates of cognitive decline, 84 85 with effect sizes greater than NfL, 85 implying that GFAP could be a better prognostic marker for incident dementia than NfL.…”

Section: Multi-marker Approach Towards Ad Biomarkersmentioning

confidence: 68%

Blood-based high sensitivity measurements of beta-amyloid and phosphorylated tau as biomarkers of Alzheimer’s disease: a focused review on recent advances

Chong

Ashton

Karikari

et al. 2021

J Neurol Neurosurg Psychiatry

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Discovery and development of clinically useful biomarkers for Alzheimer’s disease (AD) and related dementias have been the focus of recent research efforts. While cerebrospinal fluid and positron emission tomography or MRI-based neuroimaging markers have made the in vivo detection of AD pathology and its consequences possible, the high cost and invasiveness have limited their widespread use in the clinical setting. On the other hand, advances in potentially more accessible blood-based biomarkers had been impeded by lack of sensitivity in detecting changes in markers of the hallmarks of AD, including amyloid-β (Aβ) peptides and phosphorylated tau (P-tau). More recently, however, emerging technologies with superior sensitivity and specificity for measuring Aβ and P-tau have reported high concordances with AD severity. In this focused review, we describe several emerging technologies, including immunoprecipitation-mass spectrometry (IP-MS), single molecule array and Meso Scale Discovery immunoassay platforms, and appraise the current literature arising from their use to identify plaques, tangles and other AD-associated pathology. While there is potential clinical utility in adopting these technologies, we also highlight the further studies needed to establish Aβ and P-tau as blood-based biomarkers for AD, including validation with existing large sample sets, new independent cohorts from diverse backgrounds as well as population-based longitudinal studies. In conclusion, the availability of sensitive and reliable measurements of Aβ peptides and P-tau species in blood holds promise for the diagnosis, prognosis and outcome assessments in clinical trials for AD.

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Section: Multi-marker Approach Towards Ad Biomarkersmentioning

confidence: 68%

Blood-based high sensitivity measurements of beta-amyloid and phosphorylated tau as biomarkers of Alzheimer’s disease: a focused review on recent advances

Chong

Ashton

Karikari

et al. 2021

J Neurol Neurosurg Psychiatry

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“…Although emerging evidence suggests that inflammation has a causal role in AD, [11][12][13][14][15][16][17][18] the detection of inflammatory markers has not yet been established as a valuable method for the early diagnosis and monitoring of AD patients. 1 Our findings show that plasma GFAP holds great potential as an early and specific marker of Aβ deposition even during the earliest stages of AD.…”

Section: Discussionmentioning

confidence: 99%

“…In particular, the recent assays that allow measuring the concentrations of GFAP in the blood have already demonstrated the potential of plasma GFAP in distinguishing different stages of AD and detecting Aβ positivity on positron emission tomography (PET). [10][11][12][13][14][15][16][17][18] However, no study has yet assessed whether plasma GFAP is also associated with tau-PET burden. Moreover, to this date, it is not known whether astrocytosis is independently related to Aβ or tau pathology, respectively, in vivo.…”

Section: Introductionmentioning

confidence: 99%

Plasma glial fibrillary acidic protein is an early marker of Aβ pathology in Alzheimer’s disease

Bateman

Smith

et al. 2021

Preprint

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Although recent clinical trials targeting amyloid in Alzheimers disease (AD) have shown promising results, there is increasing evidence suggesting that understanding alternative disease pathways that interact with amyloid metabolism and amyloid pathology might be important to halt the clinical deterioration. In particular, there is evidence supporting a critical role of astroglial activation and astrocytosis in AD. However, to this date, no studies have assessed whether astrocytosis is independently related to amyloid or tau pathology, respectively, in vivo. To address this question, we determined the levels of the astrocytic marker glial fibrillary acidic protein (GFAP) in plasma and cerebrospinal fluid (CSF) of 217 amyloid-negative cognitively unimpaired individuals, 71 amyloid-positive cognitively unimpaired individuals, 78 amyloid-positive cognitively impaired individuals, 63 amyloid-negative cognitively impaired individuals and 75 patients with a non-AD neurodegenerative disorder from the Swedish BioFINDER-2 study. Subjects underwent longitudinal amyloid (18F-flutemetamol) and tau (18F-RO948) positron emission tomography (PET) as well as cognitive testing. We found that plasma GFAP concentration was significantly increased in all amyloid-positive groups compared with subjects without amyloid pathology (p<0.01). In addition, there were significant associations between plasma GFAP with higher amyloid-PET signal in all amyloid-positive groups, but also in cognitively normal individuals with normal amyloid values (p<0.001), which remained significant after controlling for tau-PET signal. Furthermore, plasma GFAP could predict amyloid-PET positivity with an area under the curve of 0.76, which was greater than the performance achieved by CSF GFAP (0.69) and other glial markers (CSF YKL-40: 0.64, sTREM2: 0.71). Although correlations were also observed between tau-PET and plasma GFAP, these were no longer significant after controlling for amyloid-PET. In contrast to plasma GFAP, CSF GFAP concentration was significantly increased in non-AD patients compared to other groups (p<0.05) and correlated with amyloid-PET only in amyloid-positive cognitively impaired individuals (p=0.005). Finally, plasma GFAP was associated with both longitudinal amyloid-PET and cognitive decline, and mediated the effect of amyloid-PET on tau-PET burden, suggesting that astrocytosis secondary to amyloid aggregation might promote tau accumulation. Altogether, these findings indicate that plasma GFAP is an early marker associated with brain amyloid pathology but not tau aggregation, even in cognitively normal individuals with a normal amyloid status. This suggests that plasma GFAP should be incorporated in current hypothetical models of AD pathogenesis and be used as a non-invasive and accessible tool to detect early astrocytosis secondary to amyloid pathology.

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“…Current findings on plasma biomarkers have generated new enthusiasm in the blood biomarker field, particularly plasma neurofilament light (NfL), Aβ42/40, p-tau 181 and 217, and glial fibrillary acidic protein (GFAP; Nakamura et al, 2018 ; Karikari et al, 2020 , 2021 ; Mattsson-Carlgren et al, 2020 ; Sugarman et al, 2020 ; Thijssen et al, 2020 ; Chatterjee et al, 2021 ; Cicognola et al, 2021 ; Clark et al, 2021 ; Janelidze et al, 2021 ). However, the samples in these studies were clinical trial populations, the performance of these biomarkers in community-based populations was much worse.…”

Section: Discussionmentioning

confidence: 99%

Plasma Proteomic Biomarkers Relating to Alzheimer’s Disease: A Meta-Analysis Based on Our Own Studies

Shi

Buckley

Bos

et al. 2021

Front. Aging Neurosci.

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Background and Objective: Plasma biomarkers for the diagnosis and stratification of Alzheimer’s disease (AD) are intensively sought. However, no plasma markers are well established so far for AD diagnosis. Our group has identified and validated various blood-based proteomic biomarkers relating to AD pathology in multiple cohorts. The study aims to conduct a meta-analysis based on our own studies to systematically assess the diagnostic performance of our previously identified blood biomarkers.Methods: To do this, we included seven studies that our group has conducted during the last decade. These studies used either Luminex xMAP or ELISA to measure proteomic biomarkers. As proteins measured in these studies differed, we selected protein based on the criteria that it must be measured in at least four studies. We then examined biomarker performance using random-effect meta-analyses based on the mean difference between biomarker concentrations in AD and controls (CTL), AD and mild cognitive impairment (MCI), MCI, and CTL as well as MCI converted to dementia (MCIc) and non-converted (MCInc) individuals.Results: An overall of 2,879 subjects were retrieved for meta-analysis including 1,053 CTL, 895 MCI, 882 AD, and 49 frontotemporal dementia (FTD) patients. Six proteins were measured in at least four studies and were chosen for meta-analyses for AD diagnosis. Of them, three proteins had significant difference between AD and controls, among which alpha-2-macroglobulin (A2M) and ficolin-2 (FCN2) increased in AD while fibrinogen gamma chain (FGG) decreased in AD compared to CTL. Furthermore, FGG significantly increased in FTD compared to AD. None of the proteins passed the significance between AD and MCI, or MCI and CTL, or MCIc and MCInc, although complement component 4 (CC4) tended to increase in MCIc individuals compared to MCInc.Conclusions: The results suggest that A2M, FCN2, and FGG are promising biomarkers to discriminate AD patients from controls, which are worthy of further validation.

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Plasma glial fibrillary acidic protein detects Alzheimer pathology and predicts future conversion to Alzheimer dementia in patients with mild cognitive impairment

Cited by 163 publications

References 40 publications

Blood-based high sensitivity measurements of beta-amyloid and phosphorylated tau as biomarkers of Alzheimer’s disease: a focused review on recent advances

Blood-based high sensitivity measurements of beta-amyloid and phosphorylated tau as biomarkers of Alzheimer’s disease: a focused review on recent advances

Plasma glial fibrillary acidic protein is an early marker of Aβ pathology in Alzheimer’s disease

Plasma Proteomic Biomarkers Relating to Alzheimer’s Disease: A Meta-Analysis Based on Our Own Studies

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