Total tau protein and neurofilament light chain have emerged as candidate blood-based biomarkers of neurodegeneration. Studies have shown that cross-sectionally and longitudinally, elevated levels of plasma T-tau and NfL are associated with worse cognition and neuroimaging measures of cortical thickness, cortical atrophy, white matter hyperintensity, or white matter integrity. Studies have not compared how these biomarkers cross-sectionally or longitudinally associate with cognition and neuroimaging measures.

We compared plasma total tau (T-tau) and neurofilament light (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.

We included 995 participants without dementia who were enrolled in the Mayo Clinic Study on Aging. 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 HD-1 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.

Baseline plasma NfL, compared to T-tau, was more strongly associated with cognitive and neuroimaging outcomes in all analyses. The combination of having both elevated NfL and T-tau at baseline, however, 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. Longitudinally, T-tau did not add to the prognostic value of NfL. Analyses using ADNI had similar results.

Overall, plasma NfL had better utility as a prognostic marker of cognitive decline and neuroimaging changes. Plasma T-tau adds cross-sectional value to NfL in specific contexts.