The potential dual role of tau phosphorylation: plasma phosphorylated-tau217 in newborns and Alzheimer's disease

Tau phosphorylation plays an important role in brain physiology and pathology. During foetal development, it supports microtubule dynamics and neuroplasticity, whereas in Alzheimer's disease (AD), it drives pathological tau aggregation and tangle formation. In this multicentre study (n = 462), we measured plasma phosphorylated-tau217 in healthy newborns, premature infants, patients with AD and healthy controls across various age groups. Plasma phosphorylated-tau217 levels were significantly higher in newborns compared to healthy individuals of any age group and even exceeded levels observed in patients with AD. In newborns, plasma phosphorylated-tau217 levels inversely correlated with perinatal factors such as gestational age. Longitudinal analysis of preterm infants demonstrated a decline in serum phosphorylated-tau217 levels over the first months of life, approaching levels observed in young adults. In contrast, elevated plasma phosphorylated-tau217 in older individuals was associated with AD pathology. Our findings corroborate the crucial role of tau phosphorylation in early brain development. However, in AD, tau phosphorylation transitions into a pathological mechanism. The high levels of blood-based phosphorylated-tau217 observed at birth and subsequent clearance might indicate distinct regulatory mechanisms that prevent tau aggregation in early life. Further studies are needed to explore the shared mechanisms of tau phosphorylation in newborns and AD.