Association of amyloid-beta CSF/PET discordance and tau load 5 years later

Objective To investigate the association between discordant beta-amyloid (A beta) PET and CSF biomarkers at baseline and the emergence of tau pathology 5 years later. Methods We included 730 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants without dementia (282 cognitively normal, 448 mild cognitive impairment) with baseline [F-18]florbetapir PET and CSF A beta(42) available. A beta CSF/PET status was determined at baseline using established cutoffs. Longitudinal data were available for [18F]florbetapir (A beta) 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 modeling to study the association between A beta CSF/PET status and tau pathology measured in CSF or using PET. We calculated the proportion of CSF+/PET-participants who during follow-up (1) progressed to A beta CSF+/PET+ or (2) became taupositive based on [18F]flortaucipir PET. Results A beta 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-participants, 21/64 (33%) progressed to A beta CSF+/PET+, whereas only one (3%, difference p < 0.05) became tau-positive based on [18F]flortaucipir PET. Conclusions A beta load detectable by both CSF and PET seems to precede substantial tau deposition. Compared to participants with abnormal A beta levels on both PET and CSF, the CSF+/PET-group has a distinctly better prognosis.