TY - JOUR
T1 - Basic Science and Pathogenesis
AU - Barthélemy, Nicolas R.
AU - He, Yingxin
AU - Salvadó, Gemma
AU - Janelidze, Shorena
AU - Li, Yan
AU - Ghoshal, Nupur
AU - Mukherjee, Soumya
AU - Horie, Kanta
AU - Spina, Salvatore
AU - VandeVrede, Lawren
AU - Paterson, Ross W.
AU - Perrin, Richard J.
AU - Benzinger, Tammie L.S.
AU - Boxer, Adam L.
AU - Gabelle, Audrey
AU - Sato, Chihiro
AU - Schindler, Suzanne
AU - McDade, Eric
AU - Gordon, Brian
AU - Hansson, Oskar
AU - Bateman, Randall
N1 - Publisher Copyright:
© 2024 The Alzheimer's Association. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
PY - 2024/12/1
Y1 - 2024/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85214534262&partnerID=8YFLogxK
U2 - 10.1002/alz.089427
DO - 10.1002/alz.089427
M3 - Article
C2 - 39751143
AN - SCOPUS:85214534262
SN - 1552-5260
VL - 20
SP - e089427
JO - Alzheimer's & dementia : the journal of the Alzheimer's Association
JF - Alzheimer's & dementia : the journal of the Alzheimer's Association
ER -