Plasma p-tau181 and p-tau217 in discriminating PART, AD and other key neuropathologies in older adults

Abstract

We examined whether plasma p-tau181 and p-tau217 are specific biomarkers of pathologically confirmed Alzheimer's disease (AD). In particular, we investigated the utility of plasma p-tau for differentiating AD from primary age-related tauopathy (PART), as well as AD with mixed pathologies. Data came from 269 older adults who participated in the Religious Orders Study or the Rush Memory and Aging Project. Blood samples were collected during annual clinical evaluations. Participants died and underwent brain autopsy. P-tau181 and p-tau217 were quantified in the plasma samples proximate to death (average interval before death: 1.4 years) using Lilly-developed MSD immunoassays. Uniform neuropathologic evaluations assessed AD, PART, and other common degenerative and cerebrovascular conditions. Plasma p-tau217 was more strongly correlated with brain β-amyloid and paired helical filament tau (PHFtau) tangles than p-tau181. Both p-tau markers were associated with greater odds of AD, but p-tau217 had higher accuracy (area under the ROC curve (AUC): 0.83) than p-tau181 (AUC: 0.76). Plasma p-tau markers were almost exclusively associated with AD pathologic indices with the exception of cerebral amyloid angiopathy. Compared to p-tau181, p-tau217 showed a higher AUC (0.82 versus 0.74) in differentiating AD from PART. For either p-tau, we did not observe a level difference between individuals with AD alone and those with mixed AD pathologies. In summary, plasma p-tau181and p-tau217 were specifically associated with AD pathological changes. Further, our data provide initial evidence that p-tau217 may be able to differentiate between AD and PART in individuals with comparable burdens of tau tangle pathology. These results demonstrate the specificity of p-tau217 for AD, supporting its use to identify patients suitable for anti-AD therapies including β-amyloid immunotherapies.

Keywords: Alzheimer’s disease; Mixed pathologies; PART; Plasma p-tau217; p-tau181.

Fig. 1

shows the burden of mixed pathologies in the aging brain. The bar chart on the lower left corner shows the frequencies of individual neuropathologic indices investigated in this study. The connected black dots on the x-axis indicate the specific combination of neuropathology represented (top 35 combinations shown). The histograms in the main panel show the frequencies of mixed neuropathologies, ordered by their frequency. The height of each bar corresponds to the number of persons with each combination

Fig. 2

shows the areas under the receiver operating characteristic (ROC) curves for classifying AD versus PART. Within each panel, the black curve represents the estimated ROC for the model with demographics only. The orange curve on a represents the ROC for p-tau181, and the blue curve on b represents the ROC for p-tau217

Fig. 3

shows the levels of plasma p-tau measures by mixed AD groups (A: AD only, B: AD mixed with vascular conditions, C: AD mixed with other degenerative conditions, and D: AD mixed with vascular and other degenerative conditions). Each panel, with plasma p-tau181 on the left (a) and p-tau217 on the right (b), is a boxplot with the height of each box representing the interquartile range and line segment inside the box representing the median