OUP accepted manuscript

The biological definition of Alzheimer's disease using CSF biomarkers requires both abnormal amyloid (A) and p-tau (T) levels. However, biomarkers and corresponding cutoffs may not always reflect the presence or absence of pathology. Previous studies suggest that up to 32% of autopsy-confirmed Alzheimer's disease individuals show normal CSF p-tau levels in vivo, but these studies are sparse and had small sample sizes. Therefore, we studied in three independent autopsy cohorts whether CSF A+T- excluded Alzheimer's disease based on autopsy or not. We included 215 individuals with ante-mortem CSF collection and autopsy performed from three cohorts: the Amsterdam Dementia Cohort (n = 80, 37 (46%) Alzheimer's disease at autopsy, time between CSF collection and death 4.5±2.9 years); from the Antwerp Dementia Cohort (n = 92, 84 (91%) Alzheimer's disease at autopsy, time CSF collection to death 1.7±2.3 years); and from the Alzheimer's Disease Neuroimaging Initiative (n = 43, 31 (72%) Alzheimer's disease at autopsy, time CSF collection to death 5.1±2.5 years). Biomarker profiles were based on dichotomized CSF Aβ1-42 and p-tau levels. Accuracy of CSF AT profiles to detect autopsy-confirmed Alzheimer's disease was assessed. Lastly, we investigated whether the concordance of AT profiles with autopsy diagnosis improved when CSF was collected closer to death in 9 (10%) Antwerp Dementia Cohort and 30 (70%) Alzheimer's Disease Neuroimaging Initiative individuals with repeated CSF measurements available. In total, 50-73% of A+T- individuals and 100% of A+T+ individuals had Alzheimer's disease at autopsy. Amyloid status showed the highest accuracy to detect autopsy-confirmed Alzheimer's disease (accuracy, sensitivity and specificity in Amsterdam Dementia Cohort: 88%, 92% and 84%; in Antwerp Dementia Cohort: 87%, 94% and 12%; and in Alzheimer's Disease Neuroimaging Initiative: 86%, 90% and 75% respectively). The addition of CSF p-tau did not further improve these estimates. We observed no differences in demographics or on degree of Alzheimer's disease neuropathology between A+T- and A+T+ individuals with autopsy-confirmed Alzheimer's disease. All individuals with repeated CSF measurements remained stable in Aβ1-42 status during follow-up. None of the Alzheimer's disease individuals with a normal p-tau status changed to abnormal, however four (44%) Antwerp Dementia Cohort individuals and two (7%) Alzheimer's Disease Neuroimaging Initiative individuals changed from abnormal to normal p-tau status over time, and all had Alzheimer's disease at autopsy. In summary, we found that up to 73% of A+T- individuals did have Alzheimer's disease at autopsy. This should be taken into account in both research and clinical settings.