Abstract Background The Colombian kindred affected by the autosomal dominant AD causative mutation PSEN1 E280A are an invaluable population in determining the utility of blood biomarkers (BB) and how additional risk factors may affect BB years to decades prior to symptom onset. Neurofilament light (NfL) (Quiroz et al., 2020) and phospho‐tau 217 (p‐tau217) (Palmqvist et al., 2020) diverge about 20 years prior to onset of clinical symptoms in carriers compared to non‐carriers. How APOE4 carriage may influence NfL and p‐tau217 in the kindred is unknown. We assessed cross‐sectional effects of APOE4 carriage on plasma NfL and p‐tau217 in the PSEN1 E280A kindred. Method We used a single molecule array immunoassay to quantify plasma NfL and a Meso Scale Discovery based plasma immunoassay to quantify p‐tau217. 1428 persons (age 18 to 75, mean 35.8, 23% APOE4 carriers, 54% PSEN1 E280A carriers) had available data for NfL analyses. A total of 612 persons (age 18 to 60, mean 35.9, 25% APOE4 carriers, 62% PSEN1 E280A carriers) had available data for p‐tau217 analyses. Age related trajectories were derived from cross‐sectional log‐transformed p‐tau217 and NfL concentrations modelled using a restricted cubic spline model. Model parameters were estimated using a Hamiltonian Markov chain Monte Carlo method in E280A mutation and APOE4 carriage defined groups. The primary comparison was made between APOE4 carrier and noncarriers within E280A carriers and noncarriers separately. Result In PSEN1 E280A mutation carriers, plasma NfL concentrations begin to differentiate those who were APOE4 carriers from non‐carriers at age 47.4 (figure 1). Plasma NfL concentrations did not differentiate APOE4 carriers versus non‐carriers in those without the PSEN1 E280A mutation though concentration of NfL trended higher in APOE4 carriers in the higher age range of the sample. Plasma p‐tau217 concentrations did not differentiate APOE4 carriers from non‐carriers in PSEN1 E280A mutation carriers or non‐carriers. Conclusion APOE4 carriage results in accelerated NfL plasma increases in PSEN1 E280A mutation carriers starting at about the age of symptom onset. The inability to detect APOE4‐related ptau217 and NfL differences in the other groups may be related to the younger age of participants and limitations in statistical power.