Alzheimer’s-Related Biomarker Found at Elevated Levels in Newborns

Babies are born with high levels of proteins linked to Alzheimer's disease in the brain

TO Robert Martone edited by Daisy Yuhasz

Alzheimer's disease is characterized by certain key changes in the brain. These include the development of two types of protein deposits: clumps composed of beta-amyloid and tau tangles.

These changes can be detected in several 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 beta-amyloid and some modified forms of tau in the cerebrospinal fluid surrounding the brain and spinal cord, but collecting this fluid requires a lumbar puncture, which many people find too invasive.

Recently approved test measures levels of beta-amyloid and pTau217, an altered version of tau that is one of the markers of Alzheimer's disease, in a blood sample. From the moment this particular marker was identified, researchers realized that it could help detect “preclinical Alzheimer's disease,” that is, the presence of beta-amyloid pathology in the brain before any symptoms appear. But, oddly enough, scientists are finding this neurodegeneration marker protein in unexpected places.

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New study in the journal Brain Communications reports that pTau217 increased among healthy newborns. In fact, these babies had higher levels than people with Alzheimer's disease. This discovery indicates that the protein changes that characterize this devastating disease are reversible under certain circumstances, pointing to new treatment options.

Normal tau protein is involved in binding and stabilizing the network of proteins that give the neuron its structure. Tau molecules can attach to phosphate groups (molecules made of oxygen and phosphorus) through a process called phosphorylation. When this happens, the neural structure that tau supports can become destabilized. ways that promote to the formation of mats. In fact, pTau217 is a tau molecule that has been phosphorylated at a position scientists call 217.

In the new study, an international research team measured pTau217 levels in blood samples from two groups of healthy newborns and compared them with levels found in adolescents, adults aged 18 to 25 years, and older adults aged 70 to 77 years. None of the study participants reported any cognitive difficulties or showed any impairment on testing. Although there were no significant differences in modified tau levels between adolescent and adult subjects, newborns had pTau217 levels more than five times higher than the older groups.

The research team also tested blood samples from “extremely preterm” babies, meaning babies born before 28 weeks of pregnancy, and followed the babies for 40 weeks. In many cases, these children had even higher levels of pTau217 in their blood than children born on their expected due date. Levels of pTau217 appeared to decline as both premature infants grew older and reached levels found in healthy young adults approximately 20 weeks after birth.

To compare infants with people with Alzheimer's disease, the researchers tested an additional group for pTau217. Some people in this group had Alzheimer's dementia, others had so-called mild cognitive impairment of the Alzheimer's type (which is sometimes a precursor to the disease), while another group without signs of dementia or cognitive decline served as controls. All diagnoses in this group of participants were confirmed using an invasive lumbar procedure and cognitive testing. The researchers found that people with mild cognitive impairment or dementia had higher levels of pTau217 than healthy adults, but were still less than half of what was found in healthy newborns.

In addition, the team found that total plasma tau, not just the modified form pTau217, was elevated in newborns. This matches earlier research demonstrating high levels of total tau in the fetal brain, with levels peaking around four to five months of pregnancy and then declining by half by the sixth month after birth.

Evaluation of other proteins revealed nuances. For example, the researchers also found lower levels of amyloid beta in blood samples from healthy newborns than in older study participants. And, interestingly, levels of a protein called neurofilament light chain, often associated with traumatic brain injury, were elevated in newborns compared to teenagers and adults, but not as high as in older adults. This latest finding in infants may be explained by the development of the newborn's brain and compression of the skull during birth, which, especially in the case of vaginal birth, leads to increased levels of this protein.

These results are remarkable given the strong association between pTau217 and beta-amyloid pathology in Alzheimer's disease. The researchers also observed elevated levels of pTau217 in people with several rare neurological diseases, including Creutzfeldt-Jakob disease, Niemann-Pick disease type C, and amyotrophic lateral sclerosis (better known as Lou Gehrig's disease or ALS). In addition, specific mutation in the tau gene increases the level of pTau217. Although elevation of the Alzheimer's disease marker pTau217 was observed for the first time in newborns, extensive phosphorylation of tau has previously been reported. developing brain. Notably, there is no evidence that the same tangles occur in the 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) that differ from each other by the inclusion or exclusion of certain regions of the protein sequence. The adult brain typically has six tau isoforms, but the fetus has a separate fetal isoform that may support important processes during development.. It is possible that fetal tau is somehow protective or resilient, allowing children's brains to avoid the tangles associated with toxic outcomes in older adults. However, this study cannot fully determine this point, in part because the methods used do not distinguish between fetal tau and other isoforms—more research will be needed to explore this possibility.

There are other circumstances in which tau hyperphosphorylation is reversed. Research with species such as chipmunk shows that tau hyperphosphorylation occurs in the hibernating brain during hibernation and is then reversed when animals awaken. A bolder experiment found similar changes in hibernating blacks. bears. Researchers have suggested that phosphorylation in this context may have a protective function, essentially limiting cellular activity during periods of metabolic stress.

In a separate study, the researchers found that anesthesia in mice can induce tau phosphorylation through mechanisms at least in part related to hypothermia. This brain change is usually reversible unless the mice are re-anesthetized, which itself may increase the risk of Alzheimer's dementia in humans.

A new study highlights challenges in understanding the biology of Alzheimer's disease. A newborn child and a 60-year-old adult who notices forgetfulness or confusion may test positive for pTau217, but no one will conclude that the child has Alzheimer's disease. And yet there is heated debate about whether it makes sense determine Alzheimer's disease in ways that highlight it protein markers in adults, as opposed to relying mainly on clinical assessment for diagnostics. The new discovery does not resolve this debate, but it does suggest that further study of tau and the processes that reverse its accumulation may reveal insights that could be used to treat Alzheimer's disease.

Are you a scientist specializing in neuroscience, cognitive science or psychology? Have you read a recent peer-reviewed article that you would like to write about for Mind Matters? Please send proposals to Scientific AmericanMind Matters Editor Daisy Juhasz on [email protected].

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