Logan : Associations of plasma GFAP, NfL, and p-tau231 with early-onset Alzheimer’s Disease pathology
Associations of plasma GFAP, NfL, and p-tau231 with early-onset Alzheimer’s Disease
Indiana University School of Medicine
Paige E. Logan1, Jeffrey L. Dage1, Dustin B. Hammers1, Mohit K. Manchella1, Ani Eloyan2, Nidhi S. Mundada3, Renaud La Joie3, Leonardo Iaccarino3, Anne M. Fagan4, Tatiana M. Foroud1, Henrik Zetterberg5, Kaj Blennow5, Robert A. Koeppe6, Paul Aisen7, Maria C. Carrillo8, Gil D. Rabinovici3, Bradford C. Dickerson9 and Liana G. Apostolova1
(1)Indiana University School of Medicine
(2)Brown University, Providence
(3)University of California, San Francisco
(4)Washington University School of Medicine
(5)The Sahlgrenska Academy at the University of Gothenburg
(6)University of Michigan
(7)University of Southern California, San Diego
(9) Harvard Medical School, Massachusetts General Hospital
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).
183 EOAD participants from the Longitudinal EOAD study were included. 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.
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.
These results suggest that all three plasma biomarkers show stronger associations with neurodegeneration (cortical atrophy and/or tau burden) than with amyloid burden. Future work should investigate longitudinal associations and the mediational role of APOE-ε4 and dementia severity.
Translational/Human Health Impact:
This study highlights the importance of plasma biomarkers for AD diagnosis and disease monitoring.