The antagonistic pleiotropy of tau phosphorylation: plasma tau species in newborns and Alzheimer's disease
Year: 2026
Type: article
Study design: Observational Study
Abstract: Tau phosphorylation is essential for early brain development but is also central to Alzheimer’s disease pathogenesis, suggesting an antagonistic pleiotropy model in which the same biology is beneficial early in life and harmful in aging. Here we investigate whether healthy term newborns exhibit higher concentrations of multiple phosphorylated tau species in plasma and compare their profiles against older adults and Alzheimer’s disease patients. In this multicenter study, we used the Simoa HD-X platform to measure plasma phospho-tau (p-tau) species (p-tau217 and p-tau205), Glial fibrillary acidic protein (GFAP), Neurofilament light (NfL) and amyloid-β species (Aβ1-40 and Aβ1-42), in healthy term newborns (n= 42), aged controls (n= 41), and patients with Alzheimer’s disease (n=73). Perinatal associations were examined using multivariable regression adjusted for gestational age and birth weight. In an exploratory subset analysis comprising 12 aged controls and 27 term newborns, 220 analytes were measured using the Central Nervous System panel on the NULISA proteomics platform. Group comparisons were performed using either linear regression or Welch t-tests with Benjamini-Hochberg correction for multiple testing. In the Simoa analysis, plasma p-tau217 and p-tau205 showed a stepwise increase from controls to Alzheimer’s disease and from Alzheimer’s disease to newborns. Mean p-tau217 concentrations were 2.6 pg/mL in controls, 8.6 pg/mL in Alzheimer’s disease, and 17 pg/mL in newborns; corresponding p-tau205 concentrations were 0.5, 0.7, and 3.3 pg/mL. All pairwise differences for both tau species were significant. Correlations between p-tau markers differed across groups. Newborns showed a strong correlation (r= 0.81, p<0.001), whereas correlations were weaker in AD (r= 0.44, p<0.001). Newborns also had the highest GFAP concentrations, whereas NfL was highest in Alzheimer’s disease and lowest in newborns. Mode of delivery affected GFAP and NfL levels, but not p-tau217 or p-tau205, arguing against birth stress as the main driver of neonatal tau phosphorylation. The NULISA analysis independently supported broad neonatal enrichment of tau. Phosphorylated tau species were markedly higher in newborns than controls, and multiple epitopes, including the brain-derived forms of p-tau181, p-tau205, p-tau212, p-tau217 and p-tau231, clustered among proteins with positive newborn-control differences and strong statistical significance. Our findings identify a high early-life phospho-tau state across multiple epitopes that exceeds Alzheimer’s disease levels but occurs outside of the amyloid/neurodegenerative biomarker profile. The results support the hypothesis that tau phosphorylation has divergent biological meanings across the lifespan and motivate mechanistic studies of how the developing brain tolerates high phospho-tau without an amyloid/neurodegenerative biomarker profile.
Source: Brain Communications
Authors: Fernando Gonzalez-Ortiz, Bjørn-Eivind Kirsebom, Cristiano Santos, Burak Arslan, Julia K Gundersen, Hlin Kvartsberg, Karin Sävman, Michael Turton, Peter Harrison, Helena Sophia Coley Gleerup, Kristian Steen Frederiksen, Steen Gregers Hasselbalch, Anja Hviid Simonsen, Tormod Fladby, Helena Barreto Henriksson, Sofia Frandberg, Ann Hellström, Floris Groenendaal, Michel N Nafash, Ella N Klaus, Xuemei Zeng, Thomas K Karikari, Henrik Zetterberg, Ulrika Sjöbom
Institutions: Royal College of Physicians of Edinburgh, University of Gothenburg, University Hospital of North Norway, Akershus University Hospital, UiT The Arctic University of Norway, Sahlgrenska University Hospital, Copenhagen University Hospital, Rigshospitalet, University of Copenhagen, University of Oslo, Region Västra Götaland, Utrecht University, University Medical Center Utrecht, Wilhelmina Children's Hospital, University of Pittsburgh, University of Pittsburgh Medical Center, University of Wisconsin–Madison, UK Dementia Research Institute, National Hospital for Neurology and Neurosurgery, UCL Queen Square Institute of Neurology, University College London, Indian Institute of Science Bangalore
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,024
Funders: Alzheimer's Association, Alzheimer's Drug Discovery Foundation, Familjen Erling-Perssons Stiftelse, Cure Alzheimer's Fund, Stiftelsen för Gamla Tjänarinnor, National Institute for Health and Care Research, University College London, European Commission, Hjärnfonden, Vetenskapsrådet, Rigshospitalet, Alzheimerfonden, UK Dementia Research Institute, Demensfonden, HORIZON EUROPE Framework Programme
Awards: G1057200632, G1451607819, G150733400, G1546555014, G1551449788, G1588116593, G1710774808, G1771944843, G1833008592, G1928552717, G196098375, G201353144, G2057385626, G2081597990, G2224941001, G2256555670, G237833635, G2475953241, G2543812357, G2799940023, G292763017, G3241251457, Fluid biomarkers for neurodegenerative dementias, G3509189227, G3809224024, G3842727039, G3903502641, G4166693258, G4228906844, G4234328627, G4244943609, G4260843567, G4377393254, G4786159458, G506008078, G516766298, Fluid biomarkers for neurodegenerative dementias, G5576250680, G5712520100, CASCADE: CAuSe or Consequence in Alzheimer DiseasE?, G6158734006, G6207287561, G6252389079, G6289970089, G6544145387, Multi-omics Interdisciplinary Research Integration to Address DEmentia diagnosis, G6701856265, G6745400708, G691317373, G7075164165, G7293611571, G7907773732
OpenAlex ID: W7224270362