The findings also raise concerns about using serine-containing dietary supplements as a treatment for Alzheimer's disease. Because PHGDH is a critical enzyme in the creation of serine, the researchers concluded that higher PHGDH expression in Alzheimer's patients indicates that the rate of serine production in the brain is also increased and that consuming more serine may not be useful.
The findings were published in the journal Cell Metabolism on May 3, 2022, by a team led by Sheng Zhong, a professor of bioengineering at the UC San Diego Jacobs School of Engineering, and Xu Chen, a professor of neurosciences at the UC San Diego School of Medicine.
The current research relies on prior work by Zhong and colleagues, who discovered PHGDH as a possible Alzheimer's disease blood biomarker. The researchers looked at blood samples from elderly people and discovered a significant rise in PHGDH gene expression in Alzheimer's patients as well as healthy people two years before they were diagnosed.
The findings were encouraging, and the researchers wondered if the rise could be attributed to the brain. They show in their latest study that this is the case.
"It's wonderful that our prior finding of a blood biomarker now has brain data to back it up," Zhong added. "Now we have good evidence that alterations in human blood are linked to changes in the brain in Alzheimer's disease."
The researchers looked examined genetic data from post-mortem human brains from four separate research cohorts, each consisting of 40 to 50 people aged 50 and higher. Alzheimer's patients, so-called "asymptomatic" persons (those who did not have cognitive impairments or an Alzheimer's diagnosis but whose post-mortem brain examinations revealed early indicators of Alzheimer's-related alterations), and healthy controls were the participants.
PHGDH expression was consistently higher in Alzheimer's patients and asymptomatic persons in all four cohorts when compared to healthy controls. Furthermore, the more advanced the illness, the greater the expression levels. This pattern was also seen in two separate Alzheimer's disease mice models.
The researchers then compared the individuals' PHGDH expression levels to their scores on two clinical assessments: the Dementia Rating Scale, which measures a person's memory and cognitive skills, and Braak staging, which ranks the severity of Alzheimer's disease based on brain pathology. The results revealed that the higher the expression of PHGDH in the brain, the lower the scores.
"It's amazing that the degree of expression of this gene corresponds with both cognitive performance and disease pathology," Zhong added. "Being able to quantify both of these complicated criteria with a single molecular assay should make Alzheimer's disease diagnosis and monitoring considerably easier."
The case against serine
Serine pills, which are claimed to help memory and cognitive function, may be affected by the findings. PHGDH is the primary actor in the production of serine in the body. PHGDH expression is thought to be decreased in Alzheimer's disease, and that increasing serine intake might aid with therapy and prevention. Clinical studies for serine therapies in older persons with cognitive impairment are currently begun.
However, because their data regularly shows higher PHGDH expression in Alzheimer's, the researchers believe that, contrary to what some other groups state, serine synthesis is likely to be enhanced in this illness.
“Anyone looking to recommend or take serine to mitigate Alzheimer’s symptoms should exercise caution,” said co-first author Riccardo Calandrelli, who is a research associate in Zhong’s lab.
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