Plasma Biomarker Profiles in a Colombian Cohort of Heterozygous APOE3-Christchurch Carriers

Objectives To determine whether the rare APOE3 Christchurch (APOE3 ^Ch ) variant, known to delay clinical onset in PSEN1 ^E280A -associated autosomal-dominant Alzheimer's disease (ADAD), also attenuates age-related changes in plasma biomarkers of neurodegeneration and neuroinflammation. Methods In this cross-sectional study, plasma Aβ42/40, phosphorylated tau 181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were quantified in 134 members of the Colombian PSEN1 ^E280A kindred, including eight heterozygous APOE3 ^Ch -PSEN1 ^E280A carriers and 14 APOE3 ^Ch -only carriers. Results APOE3 ^Ch heterozygosity was associated with significantly attenuated age-related increases in GFAP (f²=0.247), p-tau181 (f²=0.133), and NfL (f²=0.133) among PSEN1 ^E280A carriers. No significant effect was observed for Aβ42/40, nor among non-carriers. Elevated GFAP and NfL concentrations correlated with poorer memory performance in mutation carriers. Discussion APOE3 ^Ch -associated resilience is measurably reflected in plasma biomarker trajectories, indicating attenuation of both neuroinflammatory and neurodegenerative processes. Plasma GFAP, p-tau181, and NfL emerge as candidate pharmacodynamic markers for clinical trials targeting APOE3 ^Ch -mediated mechanisms. These findings open a new avenue for monitoring resilience-based therapeutic strategies in ADAD.