Amyloid-β CSF/PET discordance vs tau load 5 years later: It takes two to tangle

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 [ 18 F]Florbetapir PET and CSF Aβ42 available. Amyloid-β CSF/PET status was determined at baseline using established cut-offs. Longitudinal data was available for [ 18 F]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 [ 18 F]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 [ 18 F]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, [ 18 F]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 [ 18 F]flortaucipir PET. CONCLUSIONS Sufficient amyloid-β load detectable by both CSF and PET is required before substantial tau deposition emerges. Compared to participants with abnormal amyloid-β levels on PET and CSF, the CSF+/PET-group has a distinctly better prognosis.