Current state of Alzheimer's fluid biomarkers

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.

Keywords: Alzheimer’s disease; Amyloid; Biomarker; Blood; Cerebrospinal fluid; Tau.

Fig. 1

Pathological mechanisms implicated in AD and associated fluid biomarkers. In this figure, the arrows reflect hypothetical relationships, not direct causal links between the pathological mechanisms and neurodegeneration. Only select pathological mechanisms (and associated biomarkers) of AD are represented. Aβ38 amyloid beta 38, Aβ40 amyloid beta 40, Aβ42 amyloid beta 42, AD Alzheimer’s disease, BACE1 β-site amyloid precursor protein cleaving enzyme 1, hFABP heart-type fatty acid-binding protein, IP-10 interferon-γ-induced protein 10, NF-L neurofilament light, P-tau phosphorylated tau, SNAP-25 synaptosome-associated protein 25, TDP-43 transactive response DNA-binding protein 43, TREM2 triggering receptor expressed on myeloid cells 2, T-tau total tau, VILIP-1 visinin-like protein 1