Amyloid-beta levels and cognitive trajectories in non-demented pTau181-positive subjects without amyloidopathy

In a long-term observational study, Oberstein et al. find that the biomarker constellation of increased pTau181, A beta 40 and A beta 42 in CSF is not associated with dementia. Further investigation of this biomarker profile may provide insights into the circumstances under which A beta becomes pathological. Phosphorylated Tau181 (pTau181) in CSF and recently in plasma has been associated with Alzheimer's disease. In the absence of amyloidopathy, individuals with increased total Tau levels and/or temporal lobe atrophy experience no or only mild cognitive decline compared with biomarker-negative controls, leading to the proposal to categorize this constellation as suspected non-Alzheimer's disease pathophysiology (SNAP). We investigated whether the characteristics of SNAP also applied to individuals with increased CSF-pTau181 without amyloidopathy. In this long-term observational study, 285 non-demented individuals, including 76 individuals with subjective cognitive impairment and 209 individuals with mild cognitive impairment, were classified based on their CSF levels of pTau181 (T), total Tau (N), amyloid-beta(42) (A beta(42)) and A beta(42)/A beta(40) ratio (A) into A+T+N +/-, A+T-N +/-, A-T+N +/-, and A-T-N-. The longitudinal analysis included 154 subjects with a follow-up of more than 12 months who were followed to a median of 4.6 years (interquartile range = 4.3 years). We employed linear mixed models on psychometric tests and region of interest analysis of structural MRI data. Cognitive decline and hippocampal atrophy rate were significantly higher in A+T+N +/- compared to A-T+N +/-, whereas there was no difference between A-T+N +/- and A-T-N-. Furthermore, there was no significant difference between A-T+N +/- and controls in dementia risk [hazard ratio 0.3, 95% confidence interval (0.1, 1.9)]. However, A-T+N +/- and A-T-N- could be distinguished based on their A beta(42) and A beta(40) levels. Both A beta(40) and A beta(42) levels were significantly increased in A-T+N +/- compared to controls. Long term follow-up of A-T+N +/- individuals revealed no evidence that this biomarker constellation was associated with dementia or more severe hippocampal atrophy rates compared to controls. However, because of the positive association of pTau181 with A beta in the A-T+N +/- group, a link to the pathophysiology of Alzheimer's disease cannot be excluded in this case. We propose to refer to these individuals in the SNAP group as 'pTau and A beta surge with subtle deterioration' (PASSED). The investigation of the circumstances of simultaneous elevation of pTau and A beta might provide a deeper insight into the process under which A beta becomes pathological.