High levels of an enzyme called PHGDH in the blood of older people could be a warning sign of Alzheimer’s disease, and a study led by the University of California, San Diego provides new supporting evidence of this statement. By analyzing brain tissue, the researchers observed a pattern consistent with their previous findings in blood samples: expression levels of the gene encoding PHGDH were consistently higher in adults at different stages of Alzheimer’s disease. , even the early stages before cognitive symptoms manifest.

The findings also urge caution against using dietary supplements containing the amino acid serine as a remedy for Alzheimer’s disease. Because PHGDH is a key enzyme in serine production, the increased expression of PHGDH found in Alzheimer’s disease patients suggests that the rate of serine production in the brain is also increased, and therefore, taking supplemental serine may not be beneficial, the researchers warned.

Researchers led by Sheng Zhong, professor of bioengineering at UC San Diego Jacobs School of Engineering, and Xu Chen, professor of neuroscience at UC San Diego School of Medicine, published their findings May 3 in Cell metabolism.

The new study builds on previous work by Zhong and colleagues that first identified PHGDH as a potential blood biomarker for Alzheimer’s disease. The researchers analyzed blood samples from the elderly and found a sharp increase in the expression of the PHGDH gene in patients with Alzheimer’s disease, as well as in healthy people about two years before they were born. are diagnosed with the disease.

The results were promising, and the researchers were curious if this increase could be related to the brain. In their new study, they show that this is indeed the case.

“It’s exciting that our previous discovery of a blood biomarker is now supported by brain data,” Zhong said. “Now we have strong evidence that the changes we see in human blood directly correlate with changes in the brain in Alzheimer’s disease.”

The researchers analyzed genetic data collected from post-mortem human brains of subjects from four different research cohorts, each consisting of 40 to 50 people aged 50 and over. The subjects were composed of Alzheimer’s patients, so-called “asymptomatic” individuals (people without cognitive problems and without an Alzheimer’s diagnosis, but whose post-mortem brain analyzes showed early signs of changes related to Alzheimer’s disease), and healthy controls.

The results showed a consistent increase in PHGDH expression in Alzheimer’s disease patients and asymptomatic individuals in all four cohorts compared to healthy controls. Moreover, the expression levels were all the higher as the disease was advanced. This trend was also observed in two different mouse models of Alzheimer’s disease.

The researchers also compared the subjects’ PHGDH expression levels with their scores on two different clinical assessments: the Dementia Rating Scale, which assesses a person’s memory and cognitive abilities, and the dementia staging. Braak, which assesses the severity of Alzheimer’s disease based on brain pathology. The results showed that the worse the scores, the higher the expression of PHGDH in the brain.

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

The Case Against Serine

The findings have implications for serine supplements, which are advertised to improve memory and cognitive function. The main player responsible for making serine in the body is PHGDH. Some researchers have proposed that PHGDH expression is reduced in Alzheimer’s disease and that increasing serine intake may aid in treatment and prevention. Clinical trials are already underway to test serine treatments in older adults with cognitive decline.

But with their data consistently showing increased expression of PHGDH in Alzheimer’s disease, the researchers posit that serine production could likely be increased in this disease, contrary to what some other groups claim.

“Anyone looking to recommend or take serine for easing symptoms of Alzheimer’s disease should exercise caution,” said co-first author Riccardo Calandrelli, who is a research associate in Zhong’s lab.

Next steps

Researchers are looking to study how altering the expression of the PHGDH gene will affect disease outcomes. This approach could lead to new therapies for Alzheimer’s disease.

A San Diego-based biotech startup co-founded by Zhong called Genemo is working to develop a PHGDH blood test for the early detection of Alzheimer’s disease.

Reference: Chen X, Calandrelli R, Girardini J, et al. The expression of PHGDH increases with the progression of the pathology and the symptoms of Alzheimer’s disease. Cell metabolism. 2022;34(5):651-653. doi:10.1016/j.cmet.2022.02.008

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