Biomarker linked to Alzheimer’s disease detected at high levels in newborns

Babies are born with high levels of proteins linked to Alzheimer’s disease in their brains

By Robert Martone edited by Daisy Yuhas

Alzheimer’s disease is characterized by certain key changes in the brain. Among them are the development of two types of protein deposits: clumps made of beta-amyloid and tau tangles.

These changes can be identified in several ways. Medical professionals and scientists can measure the extent of these protein deposits in the brain using sophisticated and expensive neuroimaging. Another diagnostic option is to measure beta-amyloid and some modified forms of tau in the spinal fluid that surrounds the brain and spinal cord, but collecting this fluid requires a lumbar puncture, which many people find too invasive.

A recently approved test measures levels of beta-amyloid and pTau217, a modified version of the tau protein 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 brain pathology before any symptoms. But by chance, scientists are discovering this protein marker of neurodegeneration in unexpected places.

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A new study in the journal Brain communications reports that pTau217 is elevated in healthy newborns. In fact, these infants had higher levels than people with Alzheimer’s disease. This finding indicates that the protein changes that characterize this devastating disorder are reversible in certain circumstances, opening up new treatment possibilities.

Normal tau 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 of oxygen and phosphorus) through a process called phosphorylation. When this happens, the neuronal structure supported by the Tau protein can become destabilized in ways that contribute to the formation of tangles. In fact, pTau217 is a tau molecule that has undergone phosphorylation 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 to levels found in adolescents, adults aged 18 to 25, and people aged 70 to 77. None of these study participants reported cognitive difficulties or showed any impairments on testing. Although there were no significant differences in altered tau levels between adolescent and adult subjects, newborns had pTau217 levels more than five times higher than those in older groups.

The research team also tested blood samples from “extremely premature” infants, meaning babies born before 28 weeks of gestation, by following them for 40 weeks. In many cases, these children had even higher blood levels of pTau217 than babies born on their due date. Levels of pTau217 appeared to decrease as the two preemies grew, and by about 20 weeks after birth, they reached levels seen in 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’s 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 set of participants were confirmed by invasive lumbar procedure and cognitive testing. The researchers found that people with mild cognitive impairment or dementia had higher levels of pTau217 than otherwise healthy adults, but still less than half of those found in healthy newborns.

Additionally, the team found that total Tau protein in plasma, not just the modified pTau217 form, was elevated in newborns. This is consistent with previous studies showing high levels of total tau in the brains of fetuses, with levels peaking around four to five months of gestation and then decreasing twofold by the sixth month after birth.

Evaluations of other proteins have provided nuance. For example, researchers also found lower levels of beta-amyloid in blood samples from healthy newborns than in older study participants. And, interestingly, a protein called neurofilament light chain, often linked to brain damage, was elevated in newborns compared to adolescents and adults, but not as elevated as that found in older adults. This latest finding in babies may be explained by developmental processes in the newborn’s brain and cranial compression during childbirth which, especially in the case of vaginal delivery, leads to increased levels of this protein.

These results are remarkable given the close association between pTau217 and amyloid-beta pathology in Alzheimer’s disease. Researchers also observed 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). Additionally, a specific mutation in the tau gene increases pTau217 levels. Although this is the first time that elevations of the Alzheimer’s disease marker pTau217 have been observed in newborns, significant phosphorylation of tau protein has previously been reported in the developing brain. Significantly, there is no evidence that the same tangles occur in a fetus or newborn despite the presence 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 specific segments of the 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 that fetal tau is somehow protective or resilient, allowing babies’ brains to avoid the formation of tangles linked to toxic effects in older people. This study cannot fully determine this, however, in part because the methods used do not distinguish between fetal tau and other isoforms. Further research will be needed to explore this possibility.

And there are still other circumstances in which tau hyperphosphorylation is reversed. Research in species such as the ground squirrel shows that hyperphosphorylation of tau occurs in torporous brains during hibernation, then reverses when the animals wake up. A more intrepid experiment revealed similar changes in hibernating black bears. The researchers hypothesized that phosphorylation in this context might have a protective effect, essentially limiting cellular activity during periods of metabolic stress.

In another line of research, scientists have discovered that anesthesia in mice can induce phosphorylation of the Tau protein through mechanisms at least partially linked to hypothermia. This brain change is generally reversible unless mice undergo repeated anesthesia, which itself may increase the risk of Alzheimer’s dementia in humans.

The new research highlights the challenges of understanding the biology of Alzheimer’s disease. A newborn and a 60-year-old adult who notice forgetfulness or disorientation may both test positive for pTau217, but no one will conclude that the baby has Alzheimer’s disease. Yet there East a lively debate over whether or not it makes sense to define Alzheimer’s disease in a way that emphasizes these protein markers in adults, instead of relying primarily on clinical assessment for diagnosis. The new finding does not settle this debate, but it does suggest that continued study of tau and the processes that reverse its accumulation could reveal insights that interventions against Alzheimer’s disease can exploit.

Are you a scientist specializing in neuroscience, cognitive science or psychology? And have you read a recent peer-reviewed article that you would like to write about for Mind Matters? Please send your suggestions to Scientific AmericanDaisy Yuhas, editor-in-chief of Mind Matters, at dyuhas@sciam.com.

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