The antagonistic pleiotropy of tau phosphorylation: plasma tau species in newborns and Alzheimer's disease

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.