Associations of plasma GFAP, NfL, and p‐tau231 with early‐onset Alzheimer’s Disease pathology

Abstract Background Increased levels of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), and phosphorylated tau 231 (p‐tau231) in plasma have been associated with late‐onset Alzheimer’s Disease (AD). The impact of these biomarkers in early‐onset AD (EOAD) is unclear and the novel plasma biomarker, p‐tau231, has not been studied in this population. We aimed to demonstrate the effect of each biomarker on EOAD pathology by investigating their associations with amyloid burden, tau burden, and gray matter density (GMD). Method 183 EOAD participants from the Longitudinal EOAD study with available baseline plasma GFAP, NfL, p‐tau231, MRI, amyloid PET, and tau PET data were included (mean age = 58.7, 55.2% female, 54.1% APOE‐ε4 carrier, mean MMSE = 21.9). Voxel‐wise multiple linear regression models of amyloid PET, tau PET, and T1‐weighted MRI images yielded statistical maps with GFAP, NfL, or p‐tau231 as predictors. Covariates were hierarchically added: Model 1: age, sex; Model 2: age, sex and APOE‐ε4 ; Model 3: age, sex, APOE‐ε4 and MMSE. All models are displayed at a family‐wise error adjustment of p<.05. Result Higher levels of GFAP, NfL, and p‐tau231 were significantly associated with greater amyloid burden and tau burden. Higher levels of GFAP and NfL were also significantly associated with lower GMD. No significant associations were found for p‐tau231 and GMD (Figures 1, 2 & 3). When controlling for APOE‐ε4 carrier status, the effect of GFAP on amyloid burden was no longer significant (Figure 1). After additionally controlling for MMSE, the effects of NfL and p‐tau231 on amyloid burden were no longer significant, while the effects of all three biomarkers on tau burden were reduced but remained significant. In terms in of GMD, the effect of NfL survived correction for dementia severity, while the effect of GFAP did not. Conclusion These results suggest that all three plasma biomarkers show stronger associations with neurodegeneration (cortical atrophy and/or tau burden) than with amyloid burden. Furthermore, this study highlights the importance of plasma biomarkers for AD diagnosis and monitoring. Future work should investigate longitudinal associations and the mediational role of APOE‐ε4 and dementia severity.