Soluble P-tau217 reflects both amyloid and tau pathology in the human brain and mediates the association of amyloid with neocortical tau

Abstract

Alzheimer’s disease is characterized by β-amyloid plaques and tau tangles. Plasma levels of phospho-tau217 (P-tau217) accurately differentiate Alzheimer’s disease dementia from other dementias, but it is unclear to what degree this reflects β-amyloid plaque accumulation, tau tangle accumulation, or both. In a cohort with post-mortem neuropathological data (N=88), both plaque and tangle density contributed independently to higher P-tau217. Several findings were replicated in a cohort with PET imaging (“BioFINDER-2”, N=426), where β-amyloid and tau PET were independently associated to P-tau217. P-tau217 correlated with β-amyloid PET (but not tau PET) in early disease stages, and with both β-amyloid and (more strongly) tau PET in late disease stages. Finally, P-tau217 mediated the association between β-amyloid and tau in both cohorts, especially for tau outside of the medial temporal lobe. These findings support the hypothesis that plasma P-tau217 is increased by both β-amyloid plaques and tau tangles and is congruent with the hypothesis that P-tau is involved in β-amyloid-dependent formation of neocortical tau tangles.

Progress regarding the context-of-use of tau as biomarker of Alzheimer’s disease and other neurodegenerative diseases

“…Several studies, performed in AD and NDDs, indicate that plasma p-tau217 is a reliable predictor of tau pathology (as assessed through tau-PET) [210], amyloid-β-mediated tau pathophysiology, longitudinal cortical/subcortical atrophy and AD-like cognitive decline. These findings coupled with the evidence that p-tau217 discriminates AD from non-AD conditions [30,31] explain why plasma p-tau217 will be used as exploratory marker in different COU, including patients' selection and follow-up in clinical trials. The evidence about plasma p-tau217 also support its integration in the ATN matrix for disease diagnosis, prognosis and progression monitoring in clinical practice [31].…”

“…These findings coupled with the evidence that p-tau217 discriminates AD from non-AD conditions [30,31] explain why plasma p-tau217 will be used as exploratory marker in different COU, including patients' selection and follow-up in clinical trials. The evidence about plasma p-tau217 also support its integration in the ATN matrix for disease diagnosis, prognosis and progression monitoring in clinical practice [31]. not yet available A better understanding of time-trajectories of these alternative phosphorylation sites of p-tau mayis mandatory to help understand the more adequate context-ofuse of each isoform from preclinical to full-blown AD.…”

“…These findings coupled with the evidence that p-tau217 discriminates AD from non-AD conditions [30,31] explain why plasma p-tau217 will be used as exploratory marker in different COU, including patients' selection and follow-up in clinical trials. The evidence about plasma p-tau217 also support its integration in the ATN matrix for disease diagnosis, prognosis and progression monitoring in clinical practice [31].…”

“…Single Molecule Array (Simoa), a fully-automated ELISA relying on antibody-coated magnetic beads, has been used to assess t-tau, p-tau [22][23][24] and N-terminal tau fragments [25] in blood samples of AD patients (Table 1). On the other hand, Electrochemiluminescence immunoassays (ECLIA) provide a quantification of t-tau [26], p-tau181 [27][28][29] and p217-taup-tau217 [30,31] in patients with AD, with high accuracy even in low sample volumes (Table 1). An upgrade of standard mass spectrometry (MS), combining immunoprecipitation reactions with MS [32,33], tracks different phosphorylated tau isoforms like p217-taup-tau217 and p-tau181 in plasma [33](Table 1).…”