Plasma P-tau217, GFAP, and NfL as biomarkers for Alzheimer's disease: role in disease stratification, pathological progression, and cognitive decline.

INTRODUCTION: Blood-based phosphorylated tau 217 (p-tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) show promise for Alzheimer's disease (AD), while their links to brain amyloid beta (Aβ)/tau, hippocampal atrophy, and cognitive decline need further investigation. METHODS: A cohort of 1275 participants, representing various cognitive stages, was recruited to examine the links between plasma biomarkers and brain Aβ/tau stages, tau progression, hippocampal atrophy, and cognitive decline. RESULTS: Plasma p-tau217 effectively distinguished A-T-/A-T+ individuals and A+T+Braak III-VI patients, though it identified early A+T-/A+T+Braak I-II stages only in Aβ+ subjects. Plasma GFAP levels plateau beyond a certain tau threshold, while Aβ-induced tau progression occurred only in those with high GFAP. Plasma NfL showed a weak link to brain Aβ and tau pathology, hippocampal atrophy, and typical AD cognitive decline. DISCUSSION: Plasma p-tau217 aids in disease stratification, and GFAP promotes tau progression, while NfL is inadequate as a neuronal injury biomarker for AD. HIGHLIGHTS: Plasma p-tau217 is strongly linked to brain Aβ/tau burdens and effectively differentiates between various Aβ/tau stages. Elevated plasma levels of GFAP consistently contributed to the Aβ-induced tau progression across various Braak stages. Plasma NfL exhibits limited associations with Aβ/tau pathology, AD-specific hippocampal atrophy, and cognitive decline.