Scientists have uncovered an unexpected and potentially important link between a gene known as PHGDH and the development of Alzheimer’s disease, shedding new light on the molecular mechanisms behind this devastating neurological condition. For many years, PHGDH was considered merely a biological marker associated with Alzheimer’s, meaning its elevated presence was thought to reflect disease progression rather than contribute to it directly. However, new research suggests that PHGDH may play a far more active and influential role than previously believed.

Using advanced artificial intelligence techniques, researchers analyzed the three-dimensional structure of the PHGDH protein in unprecedented detail. To their surprise, the protein’s shape closely resembled that of transcription factors—specialized proteins responsible for controlling gene activity by binding directly to DNA. This discovery challenged long-standing assumptions about PHGDH’s function, revealing that it may act not only as a metabolic enzyme but also as a regulator of gene expression.

Further investigations showed that PHGDH can indeed bind to DNA and influence the activity of genes involved in critical cellular processes. By altering gene expression patterns in brain cells, abnormal PHGDH activity may disrupt normal neuronal function, promote inflammation, and accelerate the accumulation of toxic proteins commonly associated with Alzheimer’s disease. These disruptions are believed to contribute to memory loss, cognitive decline, and progressive brain degeneration—the hallmark symptoms of Alzheimer’s.

The research team conducted experiments using both genetically modified mice and lab-grown human brain organoids, which closely mimic key features of the human brain. When PHGDH activity was artificially increased, disease symptoms worsened significantly, including greater neuronal damage and faster cognitive decline. In contrast, reducing PHGDH activity slowed disease progression, preserved brain cell function, and improved neurological outcomes. These results strongly suggest that PHGDH is not simply a passive indicator of Alzheimer’s disease but an active participant in driving its progression.

The findings open the door to promising new therapeutic possibilities. If drugs can be developed to precisely regulate PHGDH’s activity—particularly its newly discovered gene-regulating function—it may be possible to slow or even partially prevent the progression of Alzheimer’s disease. Such treatments could complement existing approaches that target amyloid plaques and tau proteins, offering a broader and more effective strategy against the disease.

This research aligns with a growing body of evidence suggesting that Alzheimer’s is a complex, multi-factorial disorder involving metabolic dysfunction, gene regulation, and immune responses, rather than a single pathological pathway. The study’s insights contribute to a deeper understanding of how genetic and molecular changes interact over time to damage the brain.

The findings are supported by and consistent with broader Alzheimer’s research published in leading scientific journals such as Nature, Science Translational Medicine, and Neuron, as well as reports from organizations including the Alzheimer’s Association and the U.S. National Institute on Aging (NIA). Together, these sources emphasize the urgent need for innovative research approaches and novel drug targets to address the growing global burden of Alzheimer’s disease.

As scientists continue to explore PHGDH’s dual role in metabolism and gene regulation, this gene may emerge as a key target in the next generation of Alzheimer’s therapies—offering renewed hope for patients and families affected by the disease.