A Popular Alzheimer’s Biomarker Found at High Levels in Newborns

By Deborah Borfitz

July 16, 2025 | In recent years, phosphorylated tau has garnered so much attention as one of the “bad guys” of Alzheimer’s disease (AD) that the scientific community may have developed a bit of tunnel vision. A medical doctor in Sweden seeks to remedy the situation as a “champion” of the biomarker based on the critical if forgotten physiological role it plays in the healthy human brain. 

Context matters, says Fernando Gonzalez-Ortiz, M.D., Ph.D., a researcher at the University of Gothenburg and Sahlgrenska University Hospital. Fresh evidence comes from a new study finding that phosphorylated tau at threonine (p-tau217) plays a potential dual role in AD and newborns (Brain Communications, DOI: 10.1093/braincomms/fcaf221).  

As expected, elevated plasma p-tau217 was associated with AD pathology in older adults. The kicker is that levels of the biomarker were higher still in newborns, in whom p-tau217 inversely correlated with perinatal factors such as gestational age, Gonzalez-Ortiz says. And in preterm infants, p-tau217 levels approached those seen in young adults over the first few months of life. 

The study examined plasma samples from over 400 individuals, including healthy newborns, premature infants, patients with AD, and healthy controls across various age groups, by measuring five biomarkers—neurofilament light chain (NfL), p-tau217, total tau, amyloid42 and amyloid40. In the ALzheimer's for FAmilies (ALFA) age cohort from Spain, which included umbilical cord blood samples, amyloid levels were lower and NfL only slightly higher than in the other age groups. “Only the tau forms showed these extreme increases in newborns,” he notes. 

That p-tau217 might have some applications for newborns came as the biggest surprise to Gonzalez-Ortiz. To validate this, he reports that he will next examine new plasma samples from babies born healthy as well as those who had problems at birth and were subsequently followed for the next 20 years.   

The goal here is to determine how p-tau217 levels at birth predict future changes in development of individuals as well as the differences between tau isoforms in the blood of newborns and adults with AD, says Gonzalez-Ortiz. If all goes well, this could lead to insights useful in generating more “physiologically grounded” therapies. 

As suggested by the latest study and prior work with other neurodegenerative disorders, amyloid plaques may not be the main driver of increases in p-tau217 as has been commonly believed. Gonzalez-Ortiz says he suspects that the same biological process is happening in both newborns and adults with AD, but that the AD population has a poorer means of eliminating the protein. 

One of his quests has therefore become better understanding the clearance mechanisms in newborns that allows them to quickly get rid of high levels of p-tau217 before it has a chance to accumulate into paired helical filaments and aggregate to form neurofibrillary tangles—the chain of events seen with the tauopathy that can develop later in life. 

Colleagues in Australia doing the data analysis for the latest published study discovered the biomarker’s inverse correlation with gestational age on their own, Gonzalez-Ortiz points out. “We measured the biomarkers and then sent results to the owners of the samples; we didn’t know which patients were young, old, or had any kind of condition. We were completely blinded to the clinical results.”   

Birth of a Study

It has long been established that phosphorylation of tau is a critical physiological process in the human brain, but AD studies have also repeatedly shown that p-tau217 levels in control groups are not zero, says Gonzalez-Ortiz. “Proteins like tau and amyloid are not in our brains just to tell us who has AD or not.” 

Gonzalez-Ortiz’s curiosity was stirred a few years ago after examining some cerebrospinal fluid samples from newborns, otherwise destined for disposal, and learning their p-tau17 levels were “extremely high” relative to that seen in AD cohorts and other controls. When it came to light that these were in fact patients with pathological conditions such as intraventricular bleeding after birth, some of his colleagues became disheartened thinking that no meaningful conclusions could be drawn, he recalls.   

But Gonzalez-Ortiz couldn’t shake the thought that they were missing something. Yes, the newborns weren’t healthy, he reasoned, but could that account for p-tau217 readings that were 10 or 20 times higher than people with AD? 

Not long thereafter umbilical cord samples were received from a healthy newborn cohort in Australia, for the purpose of running general NfL and total tau measurements, and it was subsequently agreed that researchers could use the same samples to check their p-tau217 levels as well, says Gonzalez-Ortiz. This constituted one of the cohorts in the latest study, which as reported had significantly higher levels of this biomarker than the AD cohort.   

A repeat analysis with a completely different set of reagents in a new cohort confirmed this finding, he adds. Gonzalez-Ortiz and his team then gained access to the Spanish ALFA age cohort comprising newborns and individuals across different age groups to complete the validation exercise. 

Reading Tau

The clinical relevance of p-tau217 in the brains of newborns is potentially vast, but Gonzalez-Ortiz says he is particularly interested in exploring how the marker associates with neurodevelopment after birth, including any future pathological conditions. “If phosphorylated tau is a key player in the development of the brain, it makes sense that the more premature the baby, the higher the levels of phosphorylated tau in the blood will be” as synaptic connections continue to form and mature. 

Currently, clinical scales are used to assess the maturity of a baby after birth, but “an objective measurement like p-tau217 could potentially give us more [clinically meaningful] information,” he says. But perhaps the more exciting possibility is what can be learned from the physiological process in the brain of newborns that could potentially lead to new and better ways of treating the tau pathology in AD. 

With birth comes the transition from fetal tau to adult tau, which are two distinct isoforms expressed at different periods of life, he notes. Immunoassays currently used to measure p-tau217 can’t distinguish between the two versions. So, it remains to be investigated whether it is the fetal form rather than the adult isoform that the research team found to be highly phosphorylated in the newborns. 

If the decreasing levels of p-tau217 seen in the blood of premature babies in the study represents the transition from the fetal to the adult forms of the protein, then “what we are measuring... is a reflection of this neurodevelopmental process more directly,” says Gonzalez-Ortiz. He and his team plan to develop a fetal tau immunoassay, but it is also possible to use more antibody-free methods like mass spectrometry to determine which isoform of tau is present.  

His background in internal medicine has worked in his favor, Gonzalez-Ortiz says. “We know biomarkers have limitations, but when I started working in the AD field, I noticed people would think... you don’t need anything else because you have p-tau217, and that is not the case.” Biomarkers “should only guide our clinical evaluations, not replace it.” 

At the AD/PD International Conference in Vienna a few months ago, there were probably 100 presentations on p-tau217 alone, says Gonzalez-Ortiz, including a talk he gave on how such biomarker levels “mean nothing without a proper clinical investigation by your physician.” Elevated p-tau217 could be due to other circumstances, quite possibly “a physiological process that we don’t yet understand.”