Objective: To investigate the association between discordant amyloid-β PET and CSF biomarkers at baseline and the emergence of tau pathology 5 years later.

Methods: We included 730 ADNI participants without dementia (282 cognitively normal, 448 mild cognitive impairment) with baseline [18F]Florbetapir PET and CSF Aβ42 available. Amyloid-β CSF/PET status was determined at baseline using established cut-offs. Longitudinal data was available for [18F]florbetapir (Aβ) PET (baseline to 4.3±1.9 years), CSF (p)tau (baseline to 2.0±0.1 years), cognition (baseline to 4.3±2.0 years), and [18F]flortaucipir (tau) PET (measured 5.2±1.2 years after baseline to 1.6±0.7 years later). We used linear mixed modelling to study the association between amyloid-β CSF/PET status and tau pathology measured in CSF or using PET. Additionally, we calculated the proportion of CSF+/PET- participants who during follow-up (i) progressed to amyloid-β CSF+/PET+, and/or (ii) became tau-positive based on [18F]flortaucipir PET.

Results: Amyloid-β CSF+/PET+ (N=318) participants had elevated CSF (p)tau levels and worse cognitive performance at baseline, while CSF+/PET- (N=80) participants were overall similar to the CSF-/PET- (N=306) group. Five years after baseline, [18F]flortaucipir PET uptake in the CSF+/PET- group (1.20±0.13) did not differ from CSF-/PET- (1.18±0.08, p=0.69), but was substantially lower than CSF+/PET+ (1.48±0.44, p<0.001). Of the CSF+/PET- subjects, 21/64 (33%) progressed to amyloid-β CSF+/PET+, whereas only one (3%, difference p<0.05) became tau-positive based on [18F]flortaucipir PET. 

Conclusions: Amyloid-β load detectable by both CSF and PET seems to precede substantial tau deposition. Compared to participants with abnormal amyloid-β levels on both PET and CSF, the CSF+/PET- group has a distinctly better prognosis.