For plasma P-tau181, a step-wise increase with disease severity has been reported [46], and similar data have been reported for plasma NfL (with the caveat that this biomarker is not specific to AD progression) [56], but this is less clear for the other biomarkers; the CSF Aβ42/Aβ40 ratio, for example, appears to be a bimodal marker (normal or abnormal) without a clear relationship between the degree of change and the extent of the pathology [14]. The gene discussed is NEFL; the disease is Alzheimer disease.