Amyloid, pTau, NfL, and GFAP as biomarkers for Alzheimer’s disease

Abstract

AbstractBackgroundAlzheimer's disease (AD) is a multifactorial disease, with ongoing amyloid and tau accumulation, axonal damage and astrocytosis. Blood‐based biomarkers reflecting these processes are potentially valuable for patient selection for clinical trials, for monitoring disease progression and treatment effects, and for the differential diagnosis of AD. Several studies have shown that plasma amyloid beta (Abeta) 42 and 40 concentrations, phosphorylated tau (pTau) at amino acid 181 or 217, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) are changed in AD. Therefore, our studies are driven by the idea that combination of several markers will provide a more complete picture of the full complexity of AD.MethodThe results presented were obtained in several retrospective clinical cohort studies in memory clinics. Plasma Abeta 42 and 40, GFAP, and NfL were measured with Simoa technology, using homebrew assays (Amyblood, ADx), and commercial kits (Quanterix). pTau181 and 217 were measured using MSD technology with Lilly antibodies. Based on positive Amyblood and GFAP results, a novel 4‐plex assay was developed (AUMC, Quanterix, ADx). Results will be presented on the use pTau217 and of the measurement of combinations of Abeta isoforms, GFAP, and NfL for differential diagnosis of AD, Lewy body dementia, and Frontotemporal lobar degeneration (FTLD).ResultThe plasma markers are analyzed in over 1100 subjects. The Abeta 42/40 ratio decreased 1.2 fold in cases in the AD spectrum with a positive amyloid‐PET status, compared to amyloid negative cases. pTau181 concentrations were increased 2.4 fold in cases with tau accumulation measured with FTP‐PET, and pTau181 was increased 2.3 fold in AD compared to FTLD. NfL was increased 1.4‐2.3 fold in AD and FTLD patients compared to controls. GFAP levels were increased 1.8 fold in amyloid‐PET cases. Combining GFAP and the Abeta 42/40 ratio together with APOE e4 carriership resulted in an AUC of 88% differentiating amyloid‐PET positive from negative cases.ConclusionIndividual blood‐based biomarkers reflect different physiological processes in the brain. Creating a panel of t markers could provide a more complete picture of ongoing pathological processes and likely increases diagnostic accuracy to be suitable for blood‐based screening of AD and enable personalized medicine.