Plasma p-tau181 accurately predicts Alzheimer’s disease pathology at least 8 years prior to post-mortem and improves the clinical characterisation of cognitive decline

Abstract

The neuropathological confirmation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFT) remains the gold standard for a definitive diagnosis of Alzheimer's disease (AD). Nowadays, the in vivo diagnosis of AD is greatly aided by both cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers. Although highly accurate, their broad implementation is restricted by high cost, limited accessibility and invasiveness. We recently developed a high-performance, ultrasensitive immunoassay for the quantification of tau phosphorylated at threonine-181 (p-tau181) in plasma, which identifies AD pathophysiology with high accuracy. However, it remains unclear whether plasma p-tau181, measured years before the death, can predict the eventual neuropathological confirmation of AD, and successfully discriminates AD from non-AD dementia pathologies. We studied a unique cohort of 115 individuals with longitudinal blood collections with clinical evaluation at 8, 4 and 2 years prior to neuropathological assessment at death. The results demonstrate that plasma p-tau181 associates better with AD neuropathology and Braak staging than a clinical diagnosis 8 years before post-mortem. Moreover, while all patients had a diagnosis of AD dementia during life, plasma p-tau181 proved to discriminate AD from non-AD pathologies with high accuracy (AUC = 97.4%, 95% CI = 94.1-100%) even 8 years before death. Additionally, the longitudinal trajectory of plasma p-tau181 was assessed in all patients. We found that the main increases in plasma p-tau181 occurred between 8 and 4 years prior to death in patients with AD neuropathology and later plateauing. In contrast, non-AD pathologies and controls exhibited minor, albeit significant, increases in p-tau181 up until death. Overall, our study demonstrates that plasma p-tau181 is highly predictive and specific of AD neuropathology years before post-mortem examination. These data add further support for the use of plasma p-tau181 to aid clinical management in primary care and recruitment for clinical trials.

Diagnostic value of plasma neurofilament light: A multicentre validation study

“…Our < 65-year plasma NfL cut-offs (19.4 pg/mL, 21.5 pg/mL, 30.0 pg/mL) were substantially lower as to compared older cut-offs (38.0 pg/mL, 46.0 pg/mL, 54.8 pg/mL) and when this was applied, EOAD patients had the equivalent rate of abnormal plasma NfL as typical AD dementia -consistent with the reported literature on familial AD 56,57 . We also observed that age-related cut-offs may be more sensitive to neurodegeneration related to Aβ deposition, although it is clear that recent developments in plasma p-tau181 or p-tau217 would be a superior measure of Aβ and tau pathologies 10,11,14,15,51,58 . In individuals < 65 years, rates of abnormal plasma NfL were 3-fold higher in Aβ + controls as compared to Aβ-controls and also higher in MCI Aβ + than MCI Aβ-.…”

Moving fluid biomarkers for Alzheimer’s disease from research tools to routine clinical diagnostics

“…Most data currently available suggest that P-tau217 is earlier and more strongly associated with AD pathology than plasma P-tau181 [ 47 , 48 ], but more head-to-head comparisons are needed before a conclusion can be reached. As an example, while plasma P-tau217 measured by the ECL immunoassay showed an AUC of 0.89 to differentiate neuropathologically defined AD from non-AD in blood samples taken during life in one cohort [ 47 ], the corresponding number for plasma P-tau181 measured using Single molecule array (Simoa™) was 0.97 in another [ 49 ]. These findings call for further studies comparing different P-tau biomarkers in the same cohort.…”

Association between polygenic risk score of Alzheimer’s disease and plasma phosphorylated tau in individuals from the Alzheimer’s Disease Neuroimaging Initiative

“…Results from Karikari et al [ 3 ] indicate that plasma p-tau181 increases during early stages of tau pathology accumulation, but reaches a plateau in cases with moderate to severe pathology. In agreement, the performance of plasma p-tau to identify AD pathology is very high in later disease stages [ 7 ]. In view of these results, one could hypothesize that genetic risk factors for AD, especially those with smaller effect than APOE , are of greater importance in relation to p-tau181 during the time when the level of the biomarker changes the most.…”

“…This indicates that having MCI and being Aβ-positive is the most vulnerable combination in relation to the association between genetic risk for AD beyond APOE and plasma p-tau181. Previous studies have shown that p-tau181 increases already in response to Aβ pathology and then further in a stepwise manner with more advanced Braak stage [ 3 – 5 , 7 ]. P-tau181 signaling already in response to Aβ positivity is in line with our results for the non- APOE PRSs (i.e., association with ptau181 in MCI and Aβ positive individuals).…”

“…It identifies AD with the same accuracy as tau PET [ 3 – 5 ] and CSF p-tau181 [ 4 ] and associates with development of AD dementia in cognitively unimpaired (CU) individuals and in those with mild cognitive impairment (MCI) [ 4 ], as well as in carriers of mutations causing familial AD [ 6 ]. Furthermore, plasma p-tau181 accurately discriminates AD from non-AD neurodegenerative disorders with post-mortem confirmation [ 7 ]. The relation between plasma p-tau181 and genetic risk for sporadic AD is, however, uninvestigated.…”