Plasma p-tau212 as a biomarker of sporadic and Down Syndrome Alzheimer's disease
Kac, Przemysław R. (University of Gothenburg)
Alcolea, Daniel (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Montoliu-Gaya, Laia (University of Gothenburg)
Fernández, Susana (Fundació Catalana Síndrome de Down)
Rodriguez, Juan Lantero (University of Gothenburg)
Maure Blesa, Lucia (Fundación Catalana Síndrome de Down)
González-Ortiz, Fernando (Sahlgrenska University Hospital (Mölndal, Suècia))
Benejam, Bessy (Fundación Catalana Síndrome de Down)
Turton, Michael (Bioventix (Farnham, Regne Unit))
Barroeta, Isabel (Fundación Catalana Síndrome de Down)
Harrison, Peter (Bioventix (Farnham, Regne Unit))
Videla Toro, Laura (Fundación Catalana Síndrome de Down)
Ashton, Nicholas J. (King's College London)
Lleó, Alberto (Hospital de la Santa Creu i Sant Pau (Barcelona, Catalunya))
Zetterberg, Henrik (University of Gothenburg)
Carmona Iragui, María (Fundación Catalana Síndrome de Down)
Karikari, Thomas K. (University of Pittsburgh)
Fortea, Juan (Fundación Catalana Síndrome de Down)
Blennow, Kaj (University of Gothenburg)

Data:	2024
Resum:	All individuals with Down Syndrome (DS) will develop full-blown Alzheimeŕs disease (AD) pathology by age 40, decades before the occurrence of sporadic late-onset AD. Understanding this strong biological relation between age and AD pathology risk in DS is important to accelerate diagnostics, disease monitoring, and treatment. Several genes encoded in chromosome 21 including dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) have been proven to contribute to the pathology. A recently validated plasma immunoassay to measure tau phosphorylation at threonine-212 (p-tau212) has very high diagnostic accuracy in detecting AD. P-tau212 is also very sensitive to DYRK1A phosphorylation and is increased in DSAD brain lysates. Here, we assessed the potential of this biomarker in DSAD and sporadic AD. Using Simoa technology, we tested p-tau212 and p-tau181 (n=245 for plasma, n=114 matching cerebrospinal fluid (CSF) samples). We used AUC-ROC to examine diagnostic performance and the DeLong test to compare the AUC-ROC differences between methods. Spearman correlation is used to examine correlations. Fold changes relative to median levels were calculated for their respective asymptomatic groups. ANCOVA followed by Tukey posthoc test was used to calculate differences across groups. LOESS was used to determine the temporality of plasma biomarker changes. We have confirmed that p-tau212 has extremely high accuracy in detecting AD-related changes in euploid controls. For the DS population, we observed a strong correlation between plasma and CSF p-tau212 (r=0. 867; p<0. 001). In prodromal DS (pDS) and dementia DS (dDS), we observed significantly elevated levels of p-tau212 in reference to asymptomatic DS (aDS). The diagnostic accuracy to differentiate between aDS and dDS was AUC=0. 91 and AUC = 0. 86 in discriminating between DS amyloid positive and amyloid negative participants. Plasma p-tau212 started increasing approximately when people became amyloid PET-positive. We have confirmed that the levels of plasma p-tau212 are increased in the DS population and sporadic AD cases including prodromal and MCI states. Plasma p-tau212 might have utility for theragnostic, monitoring therapy efficacy, and as a target engagement biomarker in clinical trials both in sporadic and DSAD.
Ajuts:	Instituto de Salud Carlos III PI20/01473 Instituto de Salud Carlos III PI23/01786 Generalitat de Catalunya SLT006/17/00119
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Alzheimeŕs disease ; Down Syndrome ; Plasma biomarkers ; P-tau212 ; DYRK1A ; DABNI ; SPIN ; Simoa ; CSF biomarkers
Publicat a:	medRxiv, november 2024

DOI: 10.1101/2024.10.31.24316469
PMID: 39574868

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