Biomarker A+T−: is this Alzheimer’s disease or not? A combined CSF and pathology study

Abstract

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.

Differences between ante mortem Alzheimer's disease biomarkers in predicting neuropathology at autopsy

“…Previous studies using biomarker evidence for AD have covered only one of these measures of abnormal amyloid in PET or CSF 3,43,44 . However, solely abnormal amyloid deposition may not accurately reflect the presence of AD pathology, and up to 27% of individuals with abnormal amyloid markers but normal tau markers do not have AD at autopsy 8 . Possibly, AD biomarker cutoffs may need recalibration and validation based on autopsy‐confirmed cases.…”

“…Biomarker evidence consistent with AD in the previous study required at least one modality of an abnormal amyloid marker, but not tau measure, 3–5 or defined based on differentiating between clinical diagnosis of AD and controls 6,7 . However, the limitation of the former is that individuals with only abnormal amyloid pathology may not have AD because some individuals who had ante mortem abnormal amyloid markers but normal tau markers were not found to have AD at autopsy 8 . The limitation of the latter is that clinical diagnosis may not be consistent with the pathological diagnosis and may not accurately reflect the presence of AD neuropathology 2 .…”

“…6,7 However, the limitation of the former is that individuals with only abnormal amyloid pathology may not have AD because some individuals who had ante mortem abnormal amyloid markers but normal tau markers were not found to have AD at autopsy. 8 The limitation of the latter is that clinical diagnosis may not be consistent with the pathological diagnosis and may not accurately reflect the presence of AD neuropathology. 2 Ideally, the gold standard autopsy diagnosis should be used to define the diagnosis of AD, but only a few studies have done this.…”

Associations of the A/T/N profiles in PET, CSF, and plasma biomarkers with Alzheimer's disease neuropathology at autopsy

“…Before the A/T/N profile was used in clinical trials and clinical practice, it was crucial to determine the degree to which the A/T/N profile based on PET, CSF, or plasma biomarkers were associated with AD neuropathological changes (ADNC) at autopsy. Previous studies exploring the association between A/T/N biomarkers and AD neuropathology at autopsy typically assessed a single biomarker, 21–23 failed to investigate the correlation between the combination of A/T/N biomarkers and neuropathological changes, or generally focused on one modality among PET, CSF, and plasma without including all three modalities of biomarkers 24–27 …”

“…Previous studies exploring the association between A/T/N biomarkers and AD neuropathology at autopsy typically assessed a single biomarker, [21][22][23] failed to investigate the correlation between the combination of A/T/N biomarkers and neuropathological changes, or generally focused on one modality among PET, CSF, and plasma without including all three modalities of biomarkers. [24][25][26][27] Therefore, the primary aim of this study was to evaluate the concordance between the A/T/N profile in PET, CSF, and plasma and AD neuropathology at autopsy. To achieve this objective, we used PET-, CSF-, and plasma-related A/T/N biomarkers, alone and in combination, to assess their associations with ADNC in a large autopsy cohort.…”