Contribution of Myelin Content to the PET-Measured Amyloid Burden

Off-target binding to white matter myelin is well established in amyloid-β (Aβ) PET. Whether tracer binding to intracortical myelin influences cortical PET quantification remains unknown. We tested whether accounting for myelin water fraction (MWF), an MRI measure of myelin, improves the correlation between Aβ PET and the Alzheimer disease (AD) plasma biomarker phosphorylated tau 217 (p-tau217). Methods: This study included 114 participants with and without AD who underwent Aβ PET with ¹¹C-Pittsburgh compound B (n = 60) or ¹⁸F-florbetaben (n = 54), multiecho fast T2 MRI to quantify MWF, and semiquantitative in vitro diagnostic immunoassay to measure plasma p-tau217 levels. Cortical Aβ burden was quantified using SUV ratio and Centiloids. Nested regression models predicted PET signal using age and p-tau217 level, with and without cortical MWF. Results: MWF independently predicted PET-measured Aβ signal and improved model fit by approximately 6% in both the combined and tracer-specific cohorts. Conclusion: Intracortical myelin contributes to Aβ PET signal. Incorporating MWF may improve Aβ PET quantification, with implications for AD diagnosis, patient selection, and monitoring response to anti-Aβ therapies.