October 6, 2022

A study led by University of California, San Diego (UCSD), scientists has provided new evidence to support their suggestion that elevated levels of an enzyme called phosphoglycerate dehydrogenase (PHGDH) in the blood of older adults could be an early warning sign of Alzheimer’s disease (AD). The newly reported results of the team’s analysis of human brain tissue have demonstrated a trend consistent with their previous findings from blood samples, and showed that expression levels of the gene coding for PHGDH were higher in adults with different stages of AD, even at the early stages, before cognitive symptoms manifested.

The latest study findings also caution against the use of dietary supplements that contain the amino acid serine as a potential remedy for AD. PHGDH is a key enzyme in the production of serine, and the increased PHGDH expression found in Alzheimer’s patients suggests that the rate of serine production in the brain is also increased. Taking additional serine may therefore not be beneficial, the researchers warned.

“It’s exciting that our previous discovery of a blood biomarker is now corroborated with brain data,” said research co-lead Sheng Zhong, PhD, a professor of bioengineering at the UCSD Jacobs School of Engineering. “Now we have strong evidence that the changes we see in human blood are directly correlated to changes in the brain in Alzheimer’s disease.” Added Riccardo Calandrelli, PhD, a research associate in Zhong’s lab, “Anyone looking to recommend or take serine to mitigate Alzheimer’s symptoms should exercise caution.” Calandrelli is co-first author of the researchers’ published paper in Cell Metabolism, titled, “PHGDH expression increases with progression of Alzheimer’s disease pathology and symptoms.”

Serine is a modulator of synaptic plasticity, and human mutations in the PHGDH that is involved in serine synthesis can cause abnormal brain development due to serine deficiency, the authors noted. Studies in animal models have also shown that knocking out PHGDH in the hippocampus region of the brain impairs synaptic plasticity and spatial memory. Given the importance of synaptic pathophysiology to AD, these findings point to the possibility that abnormalities in PHGDH expression might be associated with AD pathogenesis, the investigators continued. However, they acknowledged, “A missing key to this question is the direction of change of either serine level or PHGDH expression levels in AD. Despite extensive efforts, changes in L- or D-serine level have not been unequivocally correlated with AD, making it particularly important to assess changes in PHGDH expression that may occur in AD.”

The new study, which was co-led by Xu Chen, PhD, a professor of neurosciences at UCSD School of Medicine, builds on earlier work by Zhong and colleagues that had first identified PHGDH as a potential blood biomarker for AD. The researchers had analyzed blood samples of older adults and found a steep increase in PHGDH gene expression in Alzheimer’s patients, as well as in healthy individuals approximately two years before they were diagnosed with the disease.

The researchers were curious to find out if this increase could be linked back to the brain. They analyzed genetic data collected from post-mortem human brains from subjects in four different research cohorts, each made up of 40 to 50 individuals who were 50 years and older. The subjects consisted of Alzheimer’s patients, asymptomatic individuals (people without cognitive problems and without an Alzheimer’s diagnosis, but whose post-mortem brain analyses showed early signs of Alzheimer’s-related changes), and healthy controls.

The results showed a consistent increase in PHGDH expression among Alzheimer’s patients and asymptomatic individuals in all four cohorts compared to the healthy controls. Moreover, expression levels were higher the more advanced the disease. This trend was also observed in two different mouse models of AD. The investigators wrote: “We report that PHGDH mRNA and protein levels are increased in the brains of two mouse models of AD and/or tauopathy, and are also progressively increased in human brains with no, early, and late AD pathology, as well as in people with no, asymptomatic, and symptomatic AD … We reanalyzed 80,660 single-nucleus transcriptomes from 24, 15, and 9 individuals with no, early, and late AD pathology.”

The researchers also compared the subjects’ PHGDH expression levels with their scores on two different clinical assessments: the Dementia Rating Scale, which rates a person’s memory and cognitive ability, and Braak staging, which rates the severity of Alzheimer’s disease based on the brain’s pathology. The results showed that the worse the scores, the higher the expression of PHGDH in the brain. “These data suggest an increase in PHGDH protein expression during both pathological and symptomatic progression of AD,” they wrote.

“The fact that this gene’s expression level directly correlates with both a person’s cognitive ability and disease pathology is remarkable,” said Zhong. “Being able to quantify both of these complex metrics with a single molecular measurement could potentially make diagnosis and monitoring progression of Alzheimer’s disease much simpler.”

The findings come with implications for the use of serine supplements, which are advertised to improve memory and cognitive function. The key player responsible for making serine in the body is PHGDH. Some researchers have proposed that PHGDH expression is reduced in AD, and that boosting serine intake could help with treatment and prevention. Clinical trials are already underway to test serine treatments in older adults experiencing cognitive decline.

But with their data consistently showing increased PHGDH expression in Alzheimer’s, Zhong et al., posit that serine production may likely be increased in this disease, contrary to what some other research groups have claimed. The team, therefore, suggests that other researchers’ claims that oral L-serine could represent “a ready-to-use therapy to AD,” warrants precaution. And as the UCSD investigators further noted, some reported evidence also suggests that long-term use of D-serine contributes to neuronal death in AD through excitotoxicity. “Furthermore, D-serine, as a coagonist of NMDAR, would be expected to oppose NMDAR antagonists, which have proven clinical benefits in treating AD.”

The researchers are looking to study how changing PHGDH gene expression will affect disease outcomes. New insights could potentially lead to new therapeutics for Alzheimer’s. And as the authors noted in their paper, PHGDH could also have diagnostic utility. “Together, these data nominate circulating PHGDH exRNA as a possible diagnostic biomarker of late-onset AD.”

Zhong is the co-founder of a San Diego-based biotechnology startup, Genemo, which is working to develop a PHGDH blood test for early detection of Alzheimer’s disease.