Normalization of CSF pTau measurement by Aβ40improves its performance as a biomarker of Alzheimer's disease

Abstract

Background: Alzheimer's disease (AD)-related tauopathy can be measured with CSF phosphorylated tau (pTau) and tau PET. We aim to investigate the associations between these measurements and their relative ability to predict subsequent disease progression. Methods: In 219 cognitively unimpaired and 122 impaired Alzheimer's Disease Neuroimaging Initiative participants with concurrent amyloid-β (Aβ) PET (18F-florbetapir or 18F-florbetaben), 18F-flortaucipir (FTP) PET, CSF measurements, structural MRI, and cognition, we examined inter-relationships between these biomarkers and their predictions of subsequent FTP and cognition changes. Results: The use of a CSF pTau/Aβ40 ratio eliminated positive associations we observed between CSF pTau alone and CSF Aβ42 in the normal Aβ range likely reflecting individual differences in CSF production rather than pathology. Use of the CSF pTau/Aβ40 ratio also increased expected associations with Aβ PET, FTP PET, hippocampal volume, and cognitive decline compared to pTau alone. In Aβ+ individuals, abnormal CSF pTau/Aβ40 only individuals (26.7%) were 4 times more prevalent (p < 0.001) than abnormal FTP only individuals (6.8%). Furthermore, among individuals on the AD pathway, CSF pTau/Aβ40 mediates the association between Aβ PET and FTP PET accumulation, but FTP PET is more closely linked to subsequent cognitive decline than CSF pTau/Aβ40. Conclusions: Together, these findings suggest that CSF pTau/Aβ40 may be a superior measure of tauopathy compared to CSF pTau alone, and CSF pTau/Aβ40 enables detection of tau accumulation at an earlier stage than FTP among Aβ+ individuals.