Abstract

Over the last several years, there has been a surge in blood biomarker studies examining the value of plasma or serum neurofilament light (NfL) as a biomarker of neurodegeneration for Alzheimer’s disease (AD). However, there have been limited efforts to combine existing findings to assess the utility of blood NfL as a biomarker of neurodegeneration for AD. In addition, we still need better insight into the specific aspects of neurodegeneration that are reflected by the elevated plasma or serum concentration of NfL.

In this review, we survey the literature on the cross-sectional and longitudinal relationships between blood-based NfL levels and other, neuroimaging-based, indices of neurodegeneration in individuals on the Alzheimer’s continuum. Then, based on the biomarker classification established by the FDA-NIH Biomarker Working group, we determine the utility of blood-based NfL as a marker for monitoring the disease status (i.e., monitoring biomarker) and predicting the severity of neurodegeneration in older adults with and without cognitive decline (i.e., a prognostic or a risk/susceptibility biomarker). The current findings suggest that blood NfL exhibits great promise as a monitoring biomarker because an increased NfL level in plasma or serum appears to reflect the current severity of atrophy, hypometabolism, and the decline of white matter integrity, particularly in the brain regions typically affected by AD. Longitudinal evidence indicates that blood NfL can be useful not only as a prognostic biomarker for predicting the progression of neurodegeneration in patients with AD but also as a susceptibility/risk biomarker predicting the likelihood of abnormal alterations in brain structure and function in cognitively unimpaired individuals with a higher risk of developing AD (e.g., those with a higher amyloid beta).

There are still limitations to current research, as discussed in this review. Nevertheless, the extant literature strongly suggests that blood NfL can serve as a valuable prognostic and susceptibility biomarker for AD-related neurodegeneration in clinical settings, as well as in research settings.