Emerging evidence of cerebrospinal fluid biomarkers for disease modifying therapy of Alzheimer disease

Abstract

In 2021, the US Food and Drug Administration approved disease modifying therapy (DMT) for Alzheimer disease (AD), and the DMT era for AD is finally becoming a reality.

AD–related biomarkers have been used in clinical trials of DMT for several context of use, such as diagnosis, judgment of therapeutic effect, and detection of adverse events. Specifically, the intervention targets were selected by amyloid positron emission tomography (PET), the therapeutic effect was evaluated by amyloid PET, tau PET, or cerebrospinal fluid (CSF) Aβ42, phosphorylated tau (p–tau), and neurofilament light chain, and amyloid–related imaging abnormalities, which is anti–Aβ antibodies specific adverse events, was monitored by MRI.

CSF Aβ42 and amyloid PET are grouped as the same A marker, but the former is a state marker that detects the state in which Aβ is likely to be deposited at that time, while the latter is a stage marker that detects Aβ accumulated up to that point. CSF p–tau and tau PET are grouped as the same T marker, but the former is a state marker that detects Aβ–dependent pathological tau metabolism at that time, while the latter is a stage marker which detects tau accumulated up to that time.

Cognitively unimpaired subjects with discordance between CSF and PET biomarkers, i.e., CSF positive/PET negative, possibly have earlier pathology than both markers positive, and are promising targets for future clinical trials.