ApoE E4 Attenuates The Association Between Plasma P-tau217 And Amyloid Pathology In Alzheimer’s Disease:

Author Block:Han-Kyeol Kim¹, Jae-Hoon Lee², Joong-Hyun Chun³, Mina Park⁴, You Jin Kim⁵, Daniel Connell⁶, Joel Braunstein⁶, Young Hoon Ryu², Chul Hyoung Lyoo⁵, Hanna Cho⁵.
¹Department of Neurology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Korea, Republic of, ²Department of Nuclear Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, Republic of, ³Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, Republic of, ⁴Department of Radiology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, Republic of, ⁵Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea, Republic of, ⁶C2N Diagnostics, LLC, St Louis, MO, USA.

Abstract:
Background: This study aimed to investigate the differential association between plasma p-tau217 and amyloid burden across Apolipoprotein E (APOE) genotypes.
Methods:: A total of 234 participants were included in the study, undergoing ¹⁸F-florbetaben (FBB), ¹⁸F-flortaucipir (FTP) PET, and plasma biomarker assessments, including %p-tau217, p-tau217, and APS2. Participants were categorized based on their APOE genotype: E2+ (E2/E2, E2/E3), E3/E3, and E4+ (E3/E4, E4/E4). The relationship between FBB centiloid values, FTP temporal meta-region-of-interest (ROI) SUVR values, and plasma biomarkers was analyzed across these genotypes, and differences in correlations were assessed using Fisher’s Z test. Longitudinal cognitive trajectories were analyzed using linear mixed-effects models, and mediation analyses assessed indirect pathways linking APOE genotype to cognitive decline.
Results: The association between plasma p-tau217 and amyloid burden varied significantly across APOE genotypes. Correlations between amyloid Centiloid and plasma biomarkers were strongest in E2+ carriers (APS2 r=0.923; %p-tau217 r=0.868; p-tau217 r=0.826), intermediate in E3/E3 homozygotes, and significantly attenuated in E4+ carriers (p-tau217 r=0.538; all p<0.05 vs. E2+ and E3/E3). In contrast, correlations between plasma p-tau217 and tau PET SUVRs did not differ significantly across genotypes. Longitudinally, both E3/E3 and E4+ groups exhibited faster cognitive decline than E2+ carriers after adjustment for baseline p-tau217, with E4+ carriers showing the steepest decline in MMSE and increase in CDR-SB. Mediation analysis demonstrated that the effect of E4 on cognitive decline was almost entirely indirect, operating through amyloid-driven tau accumulation, while plasma p-tau217 showed no independent mediating effect on cognitive decline.
Conclusion: The association between plasma p-tau217 and amyloid burden varies by APOE genotype, being strongest in E2 and E3 carriers and significantly attenuated in E4 carriers. Although APOE E4 carriers showed more rapid cognitive decline, mediation analyses indicate that this effect is primarily driven by downstream amyloid-related tau pathology rather than plasma p-tau217 levels, supporting a role for p-tau217 as an upstream pathological correlate rather than a direct mediator of neurodegeneration.