Identifying Optimal Blood Tau Epitopes for the Detection of Alzheimer’s Disease Neuropathology: An Immunoprecipitation Mass Spectrometry and Autopsy Study
Authors: Montoliu‐Gaya Laia , Alosco Michael L , Yhang Eukyung , Tripodis Yorghos , Ashton Nicholas J. , Rodriguez Juan Lantero , Aparicio Hugo J , Sugarman Michael A , Ally Madeline , Martin Brett M , Palmisano Joseph N , Steinberg Eric , Simkin Irene , Turk Katherine W , Budson Andrew E , Au Rhoda , Farrer Lindsay A. , Jun Gyungah R , Kowall Neil W , Stern Robert A , Killiany Ronald J , Goldstein Lee E , Qiu Wei Qiao , Huber Bertrand R. , Mez Jesse B. , McKee Ann C. , Zetterberg Henrik , Gobom Johan , Stein Thor D. 
Published: December 2023

Background

Plasma‐to‐autopsy studies are essential for validation of plasma biomarkers for the detection of Alzheimer’s disease (AD). Few such studies have been done and those that exist have had limited or no comparison of the different tau epitopes. This plasma‐to‐autopsy study is the first to use immunoprecipitation mass spectrometry (IP‐MS) to compare the accuracy of eight different plasma tau epitopes (six p‐tau, two total tau) in predicting autopsy‐confirmed AD.

Method

The sample included 123 participants from the Boston University Alzheimer’s Disease Research Center who had an available antemortem plasma sample and donated their brain for neuropathological examination. Plasma samples proximate to death were analyzed for six different plasma p‐tau (181+199+202+205+217+231) and two total tau (t‐tau) epitopes (195‐205, 212‐221) simultaneously using IP‐MS. NIA‐Reagan Institute criteria were used for the neuropathological diagnosis of AD. Binary logistic regressions tested the association between each plasma epitope and autopsy‐confirmed AD status. Area under the receiver operating curve (AUC) statistics were generated using predicted probabilities from the logistic regression models. Analyses were repeated stratified by Clinical Dementia Rating (CDR) score (i.e., <1 and ≥1) at the time of blood draw. Odds Ratio (OR) was used to study associations between the different plasma tau species and CERAD and Braak classifications.

Result

Table 1 shows sample characteristics. Sixty‐nine of the 123 (56.1%) brain donors had autopsy‐confirmed AD and the average interval between blood draw and death was ∼5 years. Table 2 summarizes logistic regressions and Figure 1 displays ROC curves. Plasma p‐tau217 (AUC = 89.8), p‐tau231 (AUC = 83.4), and p‐tau205 (AUC = 81.3) all had excellent accuracy in discriminating AD from non‐AD brain donors. Among those with CDR≥1, p‐tau217, p‐tau231, and p‐tau205 had outstanding discrimination and all other epitopes had excellent discrimination. Among those with CDR<1, p‐tau217 (AUC = 86.3) and p‐tau231 (AUC = 80.6) still had excellent discrimination accuracy; p‐tau181, p‐tau205, and t‐tau195‐209 had acceptable discrimination. Furthermore, p‐tau217, p‐tau205 and p‐tau231 were the tau species that showed higher ORs with both CERAD (ORp‐tau217 = 15.29, ORp‐tau205 = 5.05 and ORp‐tau231 = 3.86) and Braak staging (ORp‐tau217 = 14.29, ORp‐tau205 = 5.27 and ORp‐tau231 = 4.02).

Conclusion

Plasma levels of p‐tau217, p‐tau231, and p‐tau205 showed the best discrimination accuracy for AD confirmed neuropathology in both mild and severe cognitive impairment.