Basic Science and Pathogenesis.

Background: P-tau217 has emerged as a compelling alternative to long-established p-tau181 to accurately measure tau modifications in biofluids in response to brain Abeta and tau deposition in Alzheimer's disease (AD). Understanding the specificity and significance of p-tau217 changes over AD stages is critical to interpret its potential response to treatments against Abeta and tau aggregation.

Methods: We measured p-tau217 phosphorylation by mass spectrometry. We analyzed brain, cerebrospinal fluid (CSF) and plasma samples from participants with late-onset AD (LOAD), dominantly-inherited AD (DIAD) and primary tauopathies.

Results: Soluble and insoluble tau species extracted from LOAD and DIAD brains are p-tau217 hyperphosphorylated [1-2]. P-tau217 abundance in insoluble tau extracts from AD and most primary tauopathies associates with brain tau aggregates level. In LOAD CSF and plasma, slight p-tau217 phosphorylation changes are detected in response to early Abeta deposition in participants without cognitive symptoms [3-4]. Early Abeta-associated changes are observed in DIAD around 20 years before symptoms onset [5]. Subsequently, p-tau217 increases with brain Abeta build-up until cognitive symptoms onset. At asymptomatic stages, CSF and plasma p-tau217/tau ratio better associates with Abeta PET than p-tau concentration [3,6]. While brain Abeta deposition plateaus at symptoms onset, we observe p-tau217 increases and significantly associates with Tau PET. This association weakens then disappears at dementia stage when p-tau217 decreases. Finally, abnormal soluble p-tau217 is observed sporadically in participants with primary tauopathies in absence of Abeta positivity [7].

Conclusions: P-tau217 is a highly accurate marker of Abeta deposition. The strong association between p-tau217 and Abeta PET, when tau PET remains negative, supports tau hyperphosphorylation is a neuronal response to Abeta pathology independent from tau aggregation. On the other hand, p-tau217 associates with tau-PET at prodromal AD stage and occasionally changes in participants with primary tauopathies free of amyloid deposition. This corroborates soluble p-tau217 also increases because of the presence of brain tau aggregates. The duality of p-tau217 response to amyloid and tau pathology in AD complicates its utility as marker of tau aggregation. Lastly, plasma p-tau217 use as a single marker of Abeta positivity may expose to risk of false positive AD diagnosis for patients with primary tauopathies.