Longitudinal plasma biomarkers and multimodal PET across APOE ε4 genotypes: a prospective cohort study

Abstract Background In preclinical Alzheimer's disease (AD), longitudinal trajectories of blood-based biomarkers and their relationship to brain amyloid pathology, synaptic density and neuroinflammation in cognitively unimpaired individuals stratified by apolipoprotein E ( APOE ) ε4 genotype remain poorly characterized. Methods We measured plasma tau phosphorylated at threonine 217 (p-tau217), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), synaptosomal-associated protein 25 (SNAP25) and neurogranin (NRGN) using the nucleic acid-linked immuno-sandwich assay (NULISA) platform at baseline (n = 60) and after 4.4 years (n = 45) in cognitively unimpaired older adults ( APOE ε4/ε4, n = 19; ε4/ε3, n = 21; ε3/ε3, n = 20 at baseline). Longitudinal biomarker changes were analyzed using linear mixed-effects models. Associations with [ 11 C]PiB (amyloid) and [ 11 C]PK11195 (neuroinflammation) positron emission tomography (PET) at baseline and [ 11 C]UCB-J (synaptic density) PET were examined using multiple linear regression. Results GFAP increased over time in all genotype groups and NfL in the ε4/ε4 and ε3/ε3 groups, with no group differences in rate of change. Plasma p-tau217 was the only biomarker robustly associated with amyloid burden at both timepoints. Synaptic markers showed minimal longitudinal change and no association with synaptic density PET. Conclusions These findings support a model in which p-tau217 specifically tracks amyloid-driven pathological progression, while markers of neurodegeneration reflect broader age-related processes that are not associated with APOE genotype.