Fig. 2 |. Longitudinal serum NfL distinguishes mutation carriers from non-carriers very early in the presymptomatic disease process, with the NfL rate of change peaking in individuals converting from the presymptomatic to the symptomatic phase.

a, Spaghetti plot showing longitudinal serum NfL for non-carriers (blue, n = 63) and mutation carriers (red, n = 133) as a function of EYO. The displayed x axis range is limited to −27.5 until +12.5 years before or after EYO, respectively, to maintain blinding of some individuals contributing to this dataset. In addition, again to maintain blinding, the EYO of two participants (one mutation carrier and one non-carrier) was set to the mean of both EYO values. A logarithmic version of the spaghetti plot is shown in Extended Data Fig. 3a to better appreciate that changes between mutation carriers and non-carriers already occur at presymptomatic levels. b, Estimated rate of change per year in serum NfL (see Methods for calculation) plotted against baseline EYO for mutation carriers and non-carriers (shown is −27.5 until +12.5 years). Individual random effect slope estimates are plotted as colored symbols. The shaded areas represent the 99% credible intervals around the model estimates. The curves and credible intervals are drawn from the actual distributions of model fits derived with the Hamiltonian Markov chain Monte Carlo analyses. The first EYO where groups (non-carriers and mutation carriers) differed was determined to be the first point where the 99% credible intervals around the difference distribution between non-carriers and mutation carriers did not overlap 0 (−16.2 years before EYO; see Extended Data Fig. 3b). An even earlier deviation of the two curves was calculated when linear regression analyses were performed (Extended Data Fig. 3c). c, Rate of change per year in serum NfL across four groups differing by mutation and cognitive status: non-carriers (blue, n = 63); presymptomatic (Presym) mutation carriers (yellow, n = 65) are individuals who scored as CDR= 0 across all visits; converters (orange, n = 13) are mutation carriers who scored as CDR= 0 at baseline and CDR> 0 at subsequent visits; symptomatic (Sym) mutation carriers (red, n = 55) are individuals who scored as CDR> 0 across all visits. The boxes map to the median, 25th and 75th quintiles, and the whiskers extend to 1.5 × interquartile range (IQR). Comparisons were done with LMEMs. Presymptomatic mutation carriers had a significantly higher annual rate of change compared to non-carriers (B(s.e.m.) = 0.009(0.003), P = 6.71 × 10⁻⁴). Converters had significantly higher rate of change compared to both non-carriers (B(s.e.m.) = 0.024(0.004), P = 3.05 × 10⁻⁷) and presymptomatic mutation carriers (B(s.e.m.) = 0.015(0.005), P = 1.19 × 10⁻³). Symptomatic mutation carriers had significantly higher rates of change compared to both non-carriers (B(s.e.m.) = 0.020(0.003), P = 8.78 × 10⁻¹²) and presymptomatic mutation carriers (B(s.e.m.) = 0.011(0.003), P = 1.51 × 10⁻⁴). There was no difference between converters and symptomatic mutation carriers (B(s.e.m.) = −0.004(0.005), P = 0.445).