One Protein, Two Fates: The Enigma Between Babies And Alzheimer's

Tau protein is essential for brain development, aiding in the growth of neurons. In newborns, it appears in very high levels and is important for healthy brain formation. However, in older adults, abnormal accumulation of this same protein is linked to Alzheimer's disease. A new study has shown that levels of phosphorylated tau in the blood are naturally high in babies but decline over time. Understanding this process could help develop treatments to prevent or combat diseases like Alzheimer's in the future.

Tau protein plays a fundamental role in brain function. It helps maintain the stability of nerve cells, especially in structures called microtubules, which are like tracks that transport nutrients and important substances within cells.

Tau also aids in the growth of neurons during brain development. These functions are regulated by a process called phosphorylation, which consists of adding small molecules (phosphates) to specific sites on the protein, acting as switches that control its activity.

During the fetal stage, the brain primarily produces a simpler form of tau, called 3R tau, which has three microtubule-binding regions. In the adult brain, there is a mixture of the 3R and 4R forms, the latter being slightly longer and with four binding regions, allowing for more complex regulation of tau function.

Furthermore, adult tau can have different variations (called isoforms), depending on the presence or absence of certain insertions at the tip of the protein (0N, 1N, or 2N), which contributes to the diversity of its functions.

In Alzheimer's disease (AD), tau phosphorylation gets out of control. Instead of helping, it begins to disrupt the normal functioning of brain cells. Excessive phosphorylated tau loses its function as a microtubule support and begins to clump together abnormally, forming toxic tangles within neurons. These tangles are one of the hallmarks of AD and directly contribute to brain cell death and the progression of disease symptoms.

Interestingly, elevated levels of phosphorylated tau (p-tau) are also found naturally in the brains of developing fetuses, causing no harm. In fact, at this stage, tau phosphorylation is beneficial and necessary for brain growth and plasticity.

Furthermore, newborns have been found to have increased levels of p-tau in their cerebrospinal fluid (CSF), the fluid that bathes the brain and spinal cord.

What was still unknown was whether this increased amount of p-tau could also be measured in the blood of these babies using modern laboratory tests, and whether these levels might have any clinical significance.

Among the different forms of phosphorylated tau, p-tau217 has emerged as one of the most sensitive markers for identifying Alzheimer's disease, even before symptoms appear.

High levels of this protein in the blood have been strongly associated with the presence of amyloid plaques in the brain (another classic sign of AD) and with disease severity, both in imaging studies (PET) and in autopsy findings. Therefore, many researchers consider p-tau217 an "amyloid-dependent" marker.

However, this idea has been challenged. Recent studies have shown that p-tau217 can also increase in other neurological diseases that do not involve amyloid, such as Niemann-Pick type C, Creutzfeldt-Jakob disease, and amyotrophic lateral sclerosis.

Furthermore, temporary elevated levels of this protein are also seen in acute situations such as head trauma and cardiac arrest, indicating that tau phosphorylation may be a sign of brain stress in general, not just Alzheimer's.

To better understand the role of phosphorylated tau in early and late life, researchers from multiple centers collaborated on a study involving 462 people, including healthy newborns (full-term and premature), young adults, healthy elderly individuals, and Alzheimer's patients. They measured the levels of phosphorylated tau217 in the blood of all participants.

The results were surprising: newborns had the highest levels of p-tau217 in their blood, even higher than those found in Alzheimer's patients. This suggests that the elevated presence of this protein early in life is a natural and healthy part of brain development.

Blood levels of p-tau217 in newborns, healthy controls, and Alzheimer's disease. The figure shows a comparison of plasma p-tau217 concentrations (pg/mL) between four groups.

Furthermore, in premature infants, p-tau217 levels gradually decreased in the first months of life, reaching values similar to those observed in young adults, indicating a natural control over tau phosphorylation after birth.

Conversely, in older individuals with Alzheimer's disease, increased blood levels of p-tau217 were related to the presence of the disease and its severity, reinforcing its role as a diagnostic and prognostic marker.

These findings show that tau phosphorylation has a dual role: during development, it is a healthy and necessary mechanism for brain growth; but in old age, it can become pathological, leading to neuronal degeneration.

Understanding why high levels of p-tau217 early in life do not cause problems, while similar levels later in life lead to Alzheimer's, could help scientists develop ways to prevent or even reverse the damage caused by tau in neurodegenerative diseases.

Therefore, the researchers emphasize the importance of continuing to investigate the mechanisms that regulate tau phosphorylation at different stages of life. The hope is that by learning from the developing brain, we can discover new therapeutic strategies to protect the aging brain.

READ MORE:

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

Fernando Gonzalez-Ortiz, Jakub Vávra, Emma Payne, Bjørn-Eivind Kirsebom, Ulrika Sjöbom, Cristiano Santos, Jordi Júlvez, Kaitlin Kramer, David Zalcberg, Laia Montoliu-Gaya, Michael Turton, Peter Harrison, Ann Hellström, Henrik Zetterberg, Tormod Fladby, Marc Suárez-Calvet, Robert D Sanders, and Kaj Blennow

Brain Communications, Volume 7, Issue 3, 2025, fcaf221

https://doi.org/10.1093/braincomms/fcaf221

Abstract: 

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.