Serum GFAP differentiates Alzheimer's disease from frontotemporal dementia and predicts MCI-to-dementia conversion.

Reactive astrogliosis is a hallmark of Alzheimer's disease (AD) and frontotemporal dementia (FTD) but differences between the diseases and time course are unclear. Here, we used serum levels of the astroglial marker glial fibrillary acidic protein (GFAP) to investigate differences in patients with AD dementia, mild cognitive impairment (MCI)-AD and behavioural variant FTD (bvFTD). This multicentre study included serum samples from patients diagnosed with AD dementia (n=230), MCI-AD (n=111), bvFTD (n=140) and controls (n=129). A subgroup of patients with MCI-AD (n=32) was longitudinally followed-up for 3.9±2.6 years after sample collection. Serum levels of GFAP, neurofilament light chain (NfL) and pTau181 were measured by Simoa (Quanterix) and Ella (ProteinSimple). In total, samples from 610 individuals from four clinical centres were investigated in this study. Serum GFAP levels in AD dementia were increased (median 375 pg/mL, IQR 276-505 pg/mL) compared with controls (167 pg/mL, IQR 108-234 pg/mL) and bvFTD (190 pg/mL, IQR 134-298 pg/mL, p<0.001). GFAP was already increased in the early disease phase (MCI-AD, 300 pg/mL, IQR 232-433 pg/mL, p<0.001) and was higher in patients with MCI-AD who developed dementia during follow-up (360 pg/mL, IQR 253-414 pg/mL vs 215 pg/mL, IQR 111-266 pg/mL, p<0.01, area under the curve (AUC)=0.77). Diagnostic performance of serum GFAP for AD (AUC=0.84, sensitivity 98%, specificity 60%, likelihood ratio 2.5) was comparable to serum pTau181 (AUC=0.89, sensitivity 80%, specificity 87%, likelihood ratio 6.0) but superior to serum NfL (AUC=0.71, sensitivity 92%, specificity 49%, likelihood ratio 1.8). Our data indicate a different type of reactive astrogliosis in AD and bvFTD and support serum GFAP as biomarker for differential diagnosis and prediction of MCI-to-dementia conversion.

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Competing interests: PO received research support from the Michael J. Fox Foundation for Parkinsons Research (Grant ID: MJFF-010349) and Alzheimer Forschung Initiative e.V. (20059CB). CAFVA received research support from Roche Diagnostics, personal speaker honoraria from Biogen, Roche Diagnostics and Dr Willmar Schwabe GmbH & Co. KG, personal funding for attending meetings and travel from Biogen and Roche Diagnostics and personal fees for the scientific advisory boards of Biogen, Roche and Dr Willmar Schwabe GmbH & Co. KG. IB received a contract with Sanofi/Genzyme, a grant by Grupo de estudos e Envelhecimento Cerebral and payment for scientific lecturers by Merck. JD-S received funding from German Ministry of Research and Education, consulting fee by Pfizer and speaker fee by Roche. TG received grants to institution from Actelion and Novartis, consulting fees from AbbVie, Anavex, Biogen, Bracket, Eli Lilly, Functional Neuromodulation, Iqvia/Quintiles, Novartis, Novo Nordisk, NuiCare, Roche Pharma, Toyama and Vivoryon and lecture fees from Actelion, B. Braun, Biogen, Eli Lilly, Life Molecular Imaging, Novartis, Parexel and Roche Pharma. IS received personal grants from webinars promoted by pharma, personal consulting fees as member of national Ethics Committee, personal payments for presentations, personal fees for advisory board of pharma. MMV is supported by the BIONIC project (no. 733050822, which has been made possible by ZonMW within the framework of Memorabel, the research and innovation programme for dementia, as part of the Dutch national Deltaplan for Dementia: zonmw.nl/dementiaresearch), the CAFC project (the National Institutes of Health, USA, grant number 5R01NS104147-02) and by a grant from the Selfridges Group Foundation. ACL received funding from the state Baden-Württemberg, Payments were made to me 2018: Desitin 2019: Desitin Roche Teva Biogen Novartis Pharma 2020: Biogen Roche Pharma Biologix 2021: Biogen Roche Pharma Alector Neuroforum Springer. Payments for expert witness at courts/insurances. Payments from Advisory Boards, President German Society for Neurosciences, Scientific Board German Society for Neuromuscle Disease, Thierry Latran Foundation. MO received consulting fees from Axon, Biogen and Roche. SA-S, SH, AMK, ML, TMM, MOr, PS and AEV report no conflict of interest.