Normalization of CSF pTau measurement by Aβ40 improves its performance as a biomarker of Alzheimer's disease

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-beta (A beta) PET (F-18-florbetapir or(18)F-florbetaben),F-18-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/A beta(40) ratio eliminated positive associations we observed between CSF pTau alone and CSF A beta(42) in the normal A beta range likely reflecting individual differences in CSF production rather than pathology. Use of the CSF pTau/A beta(40) ratio also increased expected associations with A beta PET, FTP PET, hippocampal volume, and cognitive decline compared to pTau alone. In A beta+ individuals, abnormal CSF pTau/A beta(40) 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/A beta(40) mediates the association between A beta PET and FTP PET accumulation, but FTP PET is more closely linked to subsequent cognitive decline than CSF pTau/A beta(40). Conclusions: Together, these findings suggest that CSF pTau/A beta(40) may be a superior measure of tauopathy compared to CSF pTau alone, and CSF pTau/A beta(40) enables detection of tau accumulation at an earlier stage than FTP among A beta+ individuals.