Age-adjusted CSF t-tau and NfL do not improve diagnostic accuracy for prodromal Alzheimer's disease

Cerebrospinal fluid total -tau (t -tau) and neurofilament light chain (NfL) are biomarkers of neurodegeneration and are increased in Alzheimer's disease (AD). In order to adjust for age -related increases in t -tau and NfL, crosssectional age -adjusted norms were developed based on amyloid negative cognitively normal (CN) adults aged 41-78 years (CN, n = 137). The age -adjusted norms for t -tau and NfL did not improve receiver operating curve based diagnostic accuracies in individuals with mild cognitive impairment (MCI) due to AD (AD -MCI, n = 144). Furthermore, while NfL was correlated with higher age in AD -MCI, no significant correlation was found for t -tau. The cox proportional hazard models, applied in 429 participants with baseline t -tau and NfL, showed higher hazard ratio of progression to MCI or dementia without age -adjustments (HR = 3.39 for t -tau and HR = 3.17 for NfL), as compared to using our norms (HR = 2.29 for t -tau and HR = 1.89 for NfL). Our results indicate that utilizing normative reference data could obscure significant age -related increases in these markers associated with neurodegeneration and AD leading to a potential loss of overall diagnostic accuracy.