Comparison of plasma neurofilament light and total tau as neurodegeneration markers: associations with cognitive and neuroimaging outcomes

Background: Total tau protein (T-Tau) and neurofilament light chain (NfL) have emerged as candidate plasma biomarkers of neurodegeneration, but studies have not compared how these biomarkers cross-sectionally or longitudinally associate with cognitive and neuroimaging measures. We therefore compared plasma T-Tau and NfL as cross-sectional and longitudinal markers of (1) global and domain-specific cognitive decline and (2) neuroimaging markers of cortical thickness, hippocampal volume, white matter integrity, and white matter hyperintensity volume. Methods: We included 995 participants without dementia who were enrolled in the Mayo Clinic Study of Aging cohort. All had concurrent plasma NfL and T-tau, cognitive status, and neuroimaging data. Follow-up was repeated approximately every 15 months for a median of 6.2 years. Plasma NfL and T-tau were measured on the Simoa-HD1 Platform. Linear mixed effects models adjusted for age, sex, and education examined associations between baseline z-scored plasma NfL or T-tau and cognitive or neuroimaging outcomes. Analyses were replicated in Alzheimer’s Disease Neuroimaging Initiative (ADNI) among 387 participants without dementia followed for a median of 3.0 years. Results: At baseline, plasma NfL was more strongly associated with all cognitive and neuroimaging outcomes. The combination of having both elevated NfL and T-tau at baseline, compared to elevated levels of either alone, was more strongly associated at cross-section with worse global cognition and memory, and with neuroimaging measures including temporal cortex thickness and increased number of infarcts. In longitudinal analyses, baseline plasma T-tau did not add to the prognostic value of baseline plasma NfL. Results using ADNI data were similar. Conclusions: Our results indicate plasma NfL had better utility as a prognostic marker of cognitive decline and neuroimaging changes. Plasma T-tau added cross-sectional value to NfL in specific contexts. Trial registration: Not applicable.