Association Between Longitudinal Rate of Change in CSF Biomarkers and Subsequent Tau PET Burden in Early Braak Stages

Changes in CSF and tau PET biomarkers of Alzheimer disease (AD) emerge years before clinical symptoms are observed. However, few studies have examined the temporal relationship between these measures. This study investigated whether longitudinal changes in CSF AD biomarkers were associated with ¹⁸F-MK6240 tau PET measures in early Braak stage subregions.

This study involved a retrospective analysis of cognitively unimpaired participants from the longitudinal observational Biomarkers of Cognitive Decline Among Normal Individuals cohort (NIH and Johns Hopkins University). Phosphorylated tau (p-tau) 181, total tau (t-tau), and β-amyloid (Aβ)₄₂/Aβ₄₀) measures were obtained from CSF collected biennially over a mean of 12.8 years before tau PET acquisition. Linear mixed-effect models examined how previous CSF biomarker levels and rates of change in these measures related to subsequent tau deposition corresponding to Braak stages I and II.

A total of 120 cognitively unimpaired individuals (baseline age range 32-78 years; mean age 57 years; 60% female) were included in the analysis, including 78 participants with longitudinal CSF data (424 observations) and 42 additional participants contributing to cross-sectional analyses of initial CSF levels only. Results showed that higher levels of CSF p-tau₁₈₁ (β = 0.567 [0.411-0.724]; β = 0.508 [0.344-0.671]) and t-tau (β = 0.411 [0.260-0.562]; β = 0.393 [0.240-0.547]), as well as steeper previous rates of increase in p-tau₁₈₁ (β = 0.016 [0.008-0.024]; β = 0.018 [0.011-0.025]) and t-tau (β = 0.015 [0.009-0.022]; β = 0.016 [0.010-0.022]), were significantly associated with subsequent higher tau PET burden in Braak stages I and II. By contrast, although lower Aβ₄₂/Aβ₄₀ levels were associated with subsequent tau burden (β = -0.556 [-0.706 to -0.406]; β = -0.503 [-0.653 to -0.353]), the rate of change in Aβ₄₂/Aβ₄₀ over time was not.

These findings show that tau PET burden in Braak stage I and II subregions is associated with increases in CSF tau and p-tau over time, offering important insights into the relationships among key biomarkers for the diagnosis and staging of AD, although tau PET was collected at only a single time point, limiting inferences about the temporal evolution of PET-CSF relationships.