Researchers found the PHGDH gene directly causes Alzheimer’s and discovered a drug-like molecule, NCT-503, that may help treat the disease early by targeting the gene’s hidden function.
A recent study has revealed that a gene previously identified as a biomarker for Alzheimer’s disease is not just a marker, it is a direct cause of the disease. Researchers at the University of California, San Diego discovered that the gene plays a previously unrecognized secondary role that actively drives the development of Alzheimer’s. Using artificial intelligence, the team was able to uncover this hidden function and identify a potential therapeutic strategy to block the gene’s harmful activity.
The findings were published on April 23 in the journal Cell.
Alzheimer’s disease affects approximately one in nine people aged 65 and older, making it the most common form of dementia. Although certain genetic mutations are known to cause Alzheimer’s, these cases represent only a small fraction of the total. Most individuals with Alzheimer’s do not carry mutations in any of the established disease-causing genes. These sporadic or “spontaneous” cases have long puzzled scientists, as their underlying causes remain largely unknown.
Discovering those causes could ultimately improve medical care.
“Unfortunately, treatment options for Alzheimer’s disease are very limited. And treatment responses are not outstanding at this moment,” said study senior author Sheng Zhong, a professor in the Shu Chien-Gene Lay Department of Bioengineering at the UC San Diego Jacobs School of Engineering.
So Zhong and his team took a closer look at phosphoglycerate dehydrogenase (PHGDH), which they had previously discovered as a potential blood biomarker for early detection of Alzheimer’s disease. In a follow-up study, they later found that expression levels of the PHGDH gene directly correlated with changes in the brain in Alzheimer’s disease; in other words, the higher the levels of protein and RNA produced by the PHGDH gene, the more advanced the disease. That correlation has since been verified in multiple cohorts from different medical centers, according to Zhong.
Intrigued by this reproducible correlation, the research team decided to investigate in this latest study whether there was a causal effect. Using mice and human brain organoids, the researchers found that altering the amounts of PHGDH expression had consequential effects on Alzheimer’s disease: lower levels corresponded to less disease progression, whereas increasing the levels led to more disease advancement. Thus, the researchers established that PHGDH is indeed a causal gene to spontaneous Alzheimer’s disease.
In further support of that finding, the researchers determined, with the help of AI, that PHGDH plays a previously undiscovered role: it triggers a pathway that disrupts how cells in the brain turn genes on and off. And such a disturbance can cause issues, like the development of Alzheimer’s disease.
Moonlighting role
PHGDH creates an enzyme key for the production of serine, an essential amino acid and a neurotransmitter. Because PHGDH’s enzymatic activity was its only known role, the researchers hypothesized that its metabolic function must be connected to an Alzheimer’s outcome. However, all their experiments designed to prove so failed.
“At that time, our study hit a wall, and we didn’t have a clue of what mechanism it is,” said Zhong.
But another Alzheimer’s project in his lab, which did not focus on PHGDH, changed all this. A year ago, that project revealed a hallmark of Alzheimer’s disease: a widespread imbalance in the brain in the process where cells control which genes are turned on and off to carry out their specific roles.
The researchers were curious if PHGDH had an unknown regulatory role in that process, and they turned to modern AI for help.
With AI, they could visualize the three-dimensional structure of the PHGDH protein. Within that structure, they discovered that the protein has a substructure that is very similar to a known DNA-binding domain in a class of known transcription factors. The similarity is solely in the structure and not in the protein sequence.
Zhong said, “It really demanded modern AI to formulate the three-dimensional structure very precisely to make this discovery.”
After discovering the substructure, the team then demonstrated that with it, the protein can activate two critical target genes. That throws off the delicate balance, leading to several problems and eventually the early stages of Alzheimer’s disease. In other words, PHGDH has a previously unknown role, independent of its enzymatic function, that through a novel pathway leads to spontaneous Alzheimer’s disease.
That ties back to the team’s earlier studies: the PHGDH gene produced more proteins in the brains of Alzheimer’s patients compared to the control brains, and those increased amounts of the protein in the brain triggered the imbalance. While everyone has the PHGDH gene, the difference comes down to the expression level of the gene, or how many proteins are made by it.
Treatment option
Now that the researchers uncovered the mechanism, they wanted to figure out how to intervene and thus possibly identify a therapeutic candidate, which could help target the disease.
While many current treatments focus on treating the abnormal buildup of the sticky protein called beta-amyloid in the brain, some studies suggest that treating those plaques may be ineffective: essentially by that stage of accumulation, treatment is too late. But the critical pathway discovered in this study is upstream, so preventing this pathway can reduce amyloid plaque formation in the first place.
Given that PHGDH is such an important enzyme, there are past studies on its possible inhibitors. One small molecule, known as NCT-503, stood out to the researchers because it is not quite effective at impeding PHGDH’s enzymatic activity (the production of serine), which they did not want to change. NCT-503 is also able to penetrate the blood-brain-barrier, which is a desirable characteristic.
They turned to AI again for three-dimensional visualization and modeling. They found that NCT-503 can access that DNA-binding substructure of PHGDH, thanks to a binding pocket. With more testing, they saw that NCT-503 does indeed inhibit PHGDH’s regulatory role.
When the researchers tested NCT-503 in two mouse models of Alzheimer’s disease, they saw that it significantly alleviated Alzheimer’s progression. The treated mice demonstrated substantial improvement in their memory and anxiety tests. These tests were chosen because Alzheimer’s patients suffer from cognitive decline and increased anxiety.
The researchers do acknowledge limitations of their study. One being that there is no perfect animal model for spontaneous Alzheimer’s disease. They could test NCT-503 only in the mouse models that are available, which are those with mutations in those known disease-causing genes.
Still, the results are promising, according to Zhong.
“Now there is a therapeutic candidate with demonstrated efficacy that has the potential of being further developed into clinical tests,” said Zhong. “There may be entirely new classes of small molecules that can potentially be leveraged for development into future therapeutics.”
An advantage of small molecules is that they could even be administered orally, he added, unlike the current treatments that require infusions.
The next steps will be to optimize the compound and subject it to FDA IND-enabling studies.
Reference: “Transcriptional regulation by PHGDH drives amyloid pathology in Alzheimer’s disease” by Junchen Chen, Fatemeh Hadi, Xingzhao Wen, Wenxin Zhao, Ming Xu, Shuanghong Xue, Pei Lin, Riccardo Calandrelli, John Lalith Charles Richard, Zhixuan Song, Jessica Li, Alborz Amani, Yang Liu, Xu Chen and Sheng Zhong, 23 April 2025, Cell.
DOI: 10.1016/j.cell.2025.03.045
The study was funded by the National Institutes of Health.
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14 Comments
Presumably, the PHGDH gene has been a part of the human genome for millennia and it can be triggered to cause Alzheimer’s Disease (AD). However, the global epidemic of AD has only been in progress for a few decades, perhaps just since 1980. What mouse models and AI have yet to learn is that there is a kind of practically harmless individual brief (about six to twelve hours) nearly subclinical non-IgE-mediated food allergy reaction which can be aggravated to become chronic and brain damaging, long-term (months to decades, highly individual), with added artificially cultured “free” (can cross the blood-brain barrier) monosodium glutamate (MSG). 1980 was the year the US FDA approved the expanded use of added MSG. Mainstream medicine still fails to recognize these facts as relevant so how are AI programmers going to know to include them in their programming?
I agree with all you said and add my opinion to the mix. I have always believed that for a condition to arrive into the human condition in a fasttrack way there must be a trigger involved. I believe your math is correct on the 1980 surface date, and I believe that one of the triggers that must be re-evaluated is artificial sweeteners. Introduced in early 70’s and used everywhere now needs further study.
Thanks for the support, Tom. I’d like to support you too, but I (with a family history of dementia, long since) personally became mysteriously, seriously ill in early 1981, the same year the artificial sweetener “aspartame” (Nutrasweet, minimally) was FDA approved. I never knowingly used it but I’ve read it can cause brain tumors.
The global epidemic of AD might be something of a mirage. Consider the lengthening of average lifespan over the past 45 to 50 years, which would translate into increased risk for exposing clinically significant cognitive impairment in people who might very well have otherwise died before that became evident. Societal changes including diet, smoking, exercise, alcohol use, improved treatment for hypertension and blood lipid disorders, etc., have resulted in people living longer and thus more of us entering the risk years for showing AD type symptoms.
Your unexamined assumption is that everyone is living longer, which is false. The ‘increase’ in longevity is an increase in the average age at which a population dies. The average has been increasing because vaccinations for viruses and antibiotics have been especially effective in reducing childhood mortality. Likewise, better neonatal care of infants and their mothers have allowed higher survival rates, raising the average age of mortality. Better care and better access to medical care both contribute to reduced mortality in all groups. With a notable exception: our poor diet and sedentary lifestyle may be increasing mortality of older people from diabetes, heart disease, and cancer, which is the opposite of what you suggest.
Propaganda?
I have followed the crumbs of this discovery and it is legitimate and dates back to an initial discovery by Shen Zhong archived on the NIH website.
Interesting
Rebuttal to UC San Diego Study on PHGDH and Alzheimer’s: Surface Mechanism or Downstream Catastrophe?
By S. J. Bloom
May 2025
The recent UC San Diego study published in Cell (April 23, 2025) claims a major breakthrough in Alzheimer’s disease research by identifying a “hidden function” of the PHGDH gene. The authors assert that this gene, long regarded as a biomarker, is in fact a causative agent of Alzheimer’s through its non-enzymatic disruption of gene regulation.
This is a commendable step toward understanding spontaneous (non-familial) Alzheimer’s, but the conclusion is premature and fundamentally incomplete.
PHGDH’s aberrant role as a rogue transcriptional activator is not the endpoint of Alzheimer’s pathology. It is the opening move in a cascade of molecular damage. By describing PHGDH-induced transcriptional imbalance as a “cause” of Alzheimer’s, the researchers fail to account for the structural consequences of sustained dysregulation, including:
Somatic insertions and deletions (indels) in gene regulatory regions;
Epigenetic destabilization and loss of methylation fidelity;
R-loop accumulation and replication-transcription collisions;
Persistent splicing errors and loss of transcript integrity;
Chromatin remodeling errors leading to cell cycle arrest or apoptosis.
These are not speculative. These are documented results of long-term transcriptional chaos in neural tissue. In non-dividing neurons — which cannot dilute or repair damage through mitosis — such structural decay becomes permanent and compounding.
To say PHGDH is causal without addressing these downstream genomic disruptions is to mistake the match for the wildfire.
Furthermore, while NCT-503 is a promising inhibitor of PHGDH’s moonlighting function, targeting regulatory imbalance without addressing the cumulative indel burden may be palliative at best. We cannot reverse neurodegeneration by turning off the faucet once the room is already flooded.
If Alzheimer’s is to be understood — and treated — we must look beyond transient expression levels and into the deep architecture of somatic genome damage, driven by the very instability PHGDH initiates.
The real cause isn’t PHGDH’s transcriptional role. It’s the structural rot that follows.
Respectfully,
S. J. Bloom
Independent Investigator
Well stated and probably absolutely applicable, S. J. Bloom. However, with a family history of dementia and two separate temporary incidents of short-term memory problems of my own, my own independent lay investigations have informed me of potentially multiple non-genetic origins of dementia, which I continue to share at-large: https://odysee.com/@charlesgshaver:d?view=about
You indirectly raise an important point. So many articles here, and in the general press, present their findings as a breakthrough in science that suggests that we will now make rapid progress in curing or eliminating a disease (or other social problem). In reality, it is suggestive of good news, but needs replication and further study. It is not the end of the problem. Instead, it is the beginning of another path that may or may not lead to where we want to go. Those anxious to get renewed research funding commonly overstate the significance of their results. Long term, such optimism may do more harm than good if the funding organization(s) are disappointed in the results because it was oversold.
Charles, I appreciate your response and the years of work you’ve dedicated to documenting overlooked factors in chronic disease. Your personal history and persistence in exposing non-IgE food reactions and the regulatory failures around MSG reflect a crucial insight: the body does not forget.
Where our paths intersect is in identifying slow, cumulative damage as the real driver of modern pathology. You trace that damage to hidden dietary allergens and toxic additives; I trace it downstream into the genetic wreckage left behind — somatic indels, splice failures, transcriptional pileups, and the architectural collapse of the genome itself. We’re describing different layers of the same catastrophe.
But here’s the distinction: your model is exposure-based — mine is structural. I’m not looking at the triggers. I’m documenting the internal unraveling. PHGDH, MSG, processed soy — if these are matches, I’m analyzing the ash patterns left behind. What I’m saying is that Alzheimer’s is not caused by one compound or gene, but by the cumulative failure of transcriptional fidelity and repair inside non-dividing neurons.
You rightly expose negligence in regulation. I’m exposing the consequence: irreversible, compounding genomic rot in post-mitotic tissue.
This isn’t just about avoiding exposure. It’s about rebuilding the architecture — or watching it collapse.
Respectfully,
S. J. Bloom
Thank you for your time and kindness, S. J. Never eligible for any research grants I ever investigated and ill equipped to do more on my own, I heartily agree with you. And, I already emailed something similar but less explanatory to the corresponding author, Sheng Zhong. While still believing prevention is superior to cure and/or perpetual treatments, I still wonder if interrupting the process early-on in some cellular or molecular level would work? I’ve been welcoming of your kind of input for nearly twenty years but with no such luck. Two factors I suspect would likely continue-on into full-blown dementia are an undiagnosed calcium deficiency and an acidic metabolism/high serum level of uric acid. If I might be of any real help, I’m available through the email address on my about page.
I bet I have signs of losing my brain. I have had them since a young adult. It would be interesting to get it varified.