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Alzheimer’s disease is characterized by certain key changes in the brain. Among them are the development of two kinds of protein deposits: clumps made up of amyloid beta and tangles of tau.
These changes can be identified in a few ways. Medical professionals and scientists can see the extent of these protein deposits in the brain using sophisticated and expensive neuroimaging. Another diagnostic option involves measuring amyloid beta and certain modified forms of tau in the cerebrospinal fluid that surrounds the brain and spinal cord, but collecting this fluid requires a lumbar puncture, which many people find too invasive.
A newly approved test measures levels of amyloid beta and pTau217, an altered version of tau that is one of the markers of Alzheimer’s disease, in a blood sample. From the time this particular marker was identified, researchers realized it could help detect “preclinical Alzheimer’s disease,” that is, the presence of amyloid beta brain pathology prior to any symptoms. But in a twist, scientists are finding this protein marker of neurodegeneration in unexpected places.
A new study in the journal Brain Communications reports that pTau217 is elevated among healthy newborns. In fact, these infants had higher levels than people with Alzheimer’s disease. This discovery indicates that the protein changes that characterize this devastating disorder are reversible in certain circumstances—hinting at new possibilities for treatment.
Normal tau protein is involved in binding and stabilizing the network of proteins that give a neuron its structure. Tau molecules can attach to phosphate groups (molecules made up of oxygen and phosphorus) through a process called phosphorylation. When that happens, the neuronal structure that tau supports can destabilize in ways that contribute to the formation of tangles. In fact, pTau217 is a tau molecule that has undergone phosphorylation at a position that scientists call 217.
In the new study, an international research team measured levels of pTau217 in blood samples from two groups of healthy newborns and compared them with levels found in teenagers, adults aged 18 to 25, and seniors aged 70 to 77. None of these study participants reported any cognitive difficulties or showed any impairments when tested. Although there were no significant differences in the modified tau levels between the teenage and adult subjects, the newborns had pTau217 levels that were more than five times higher than those of the older groups.
The research team also tested blood samples from “extremely preterm” infants, meaning babies born before 28 weeks of gestation, following up with the infants over the course of 40 weeks. In many cases, these children had even higher levels of blood pTau217 than babies born at the expected delivery date. Levels of pTau217 appeared to decrease as both preterm infants grew older and, by about 20 weeks after birth, reached the levels found among healthy young adults.
To compare infants with people with Alzheimer’s disease, the researchers tested an additional cohort for pTau217. Some people in this group had Alzheimer’s dementia, others had what is called mild cognitive impairment of the Alzheimer’s type (which is sometimes a precursor to the disease), while another group with no evidence of dementia or cognitive decline served as a control. All the diagnoses in this set of participants were confirmed with the invasive lumbar procedure and cognitive testing. The researchers found that people with either mild cognitive impairment or dementia had pTau217 levels that were higher than otherwise healthy adults but were still less than half of what was found among healthy newborns.
In addition, the team discovered that plasma total tau—not just the modified pTau217 form—was elevated in newborns. This is consistent with earlier studies showing high levels of total tau in fetal brains with peak levels at around four to five months of gestation and then decreasing two-fold by the sixth month after birth.
Assessments of other proteins provided nuance. For example, the researchers also found lower levels of amyloid beta in blood samples from healthy newborns than in older study participants. And, curiously, a protein called neurofilament light chain, often linked to brain injury, was elevated in newborns compared with teens and adults—but not as high as what was found in elderly people. That last finding in babies may be explained by developmental processes in the newborn brain and by cranial compression during birth, which, especially in the case of vaginal delivery, leads to increased levels of that protein.
These findings are remarkable given the close association between pTau217 and the amyloid beta pathology of Alzheimer’s disease. Researchers have also seen elevated pTau217 in people with a few rare neurological diseases, including Creutzfeld-Jakob disease, Niemann-Pick disease type C, and amyotrophic lateral sclerosis (better known as Lou Gehrig’s disease or ALS). In addition, a specific mutation in the tau gene increases pTau217 levels. Although this is the first time elevations of the Alzheimer’s disease marker pTau217 have been observed in newborns, extensive phosphorylation of tau has previously been reported in the developing brain. Significantly, there is no evidence that the same tangles arise in a fetus or newborn despite the occurrence of similarly modified tau proteins.
In addition to modifications of the Tau protein, such as phosphorylation, there are also several known forms of the molecule (isoforms) which differ from one another by the inclusion or exclusion of specific stretches of protein sequence. The adult brain typically has six isoforms of tau, but the fetus has a distinct fetal isoform that may support important processes during development. It’s possible fetal tau is somehow protective or resilient in ways that allow baby brains to avoid the formation of tangles linked to toxic outcomes in older adults.
This study cannot fully determine that point, however, in part because the methods used do not discriminate between fetal tau and other isoforms—more research will be needed to explore that possibility.
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