Plasma p‐tau212 is an early biomarker to identify Alzheimer’s Disease pathology in Down Syndrome

Abstract Background The life‐time risk of Alzheimer´s disease (AD) in people with Down Syndrome (DS) is above 95% by the seventh decade of life. Understanding the strong biological relation between those conditions is important to accelerate progress in diagnostics and treatment. Tau phosphorylation at threonine‐212 (p‐tau212) is very sensitive to Dual‐specificity tyrosine phosphorylation‐regulated kinase 1A (DYRK1A), which is encoded in chromosome 21. Published results showed that p‐tau212 was significantly increased in AD‐DS male brains. This suggests a possible involvement of p‐tau212 in early progression to AD in individuals with DS. Here, we assessed the potential of these biomarker in DS and sporadic AD. Method Using SIMOA technology, we tested in‐house developed p‐tau212 immunoassay (n = 245 for plasma, n = 329 for CSF and n = 115 paired samples) and p‐tau181 (n = 459 for plasma, n = 357 for CSF and n = 245 for p‐tau212 paired plasma samples). A subset of participants had amyloid‐PET data. We used AUC‐ROC to examine diagnostic potential and DeLong test for comparison. Spearman correlations were used to establish associations. Age‐related changes of p‐tau212 and p‐tau181 were examined in relation to amyloid positivity in CSF and Amyloid‐PET. Result Plasma/CSF p‐tau212 and p‐tau181 showed excellent analytical performances. Plasma p‐tau212 started increasing around 20 years before people were diagnosed as prodromal AD‐DS (pDS) and CSF p‐tau212 approximately 27 years. Paired plasma and CSF p‐tau212 measurements correlated strongly (r = 0.71;p<0.001). Both plasma biomarkers were successful in differentiating asymptomatic DS (aDS) from dementia‐DS (dDS) with an AUC = 91% for p‐tau212 and AUC = 88% for p‐tau181. Plasma p‐tau212 had greater than p‐tau181 magnitude of change in early stages of AD performing 3.4 vs 2‐fold change for pDS and 3 vs 2.1 for vs mild cognitive impairment (MCI‐AD). Pattern remained the same for dDS, AD and CSF measurements. Moreover, plasma p‐tau212 was 2.4‐fold increased in aDS people, when compared to CN. Aside of great discrimination in DS, plasma p‐tau212 had significantly better performance than p‐tau181 for differentiating CN from MCI‐AD (AUC = 84%‐91%;p = 0.026) and CN from MCI‐AD+AD (AUC = 86%‐93%;p = 0.026). Conclusion Plasma p‐tau212 is useful for early DS and AD differentiation. Blood‐based p‐tau212 will be a cost‐effective and simple‐to‐implement alternative to in vivo and autopsy‐based evaluations for AD changes in DS and sporadic cases.