A groundbreaking study conducted by researchers at the University of California San Diego has unveiled a new dimension to Alzheimer's disease. The team discovered that PHGDH, previously identified as a biomarker for early detection of Alzheimer’s, is actually one of its causes due to an unknown secondary function. This revelation was made possible through the application of artificial intelligence, which not only unraveled the mystery behind Alzheimer's progression but also pointed towards a potential treatment option.

Alzheimer's disease affects approximately one in nine individuals aged 65 and above, making it the most prevalent form of dementia. While certain genetic mutations contribute to its development, these account for only a small fraction of cases. Most patients suffer from "spontaneous" Alzheimer's, where the underlying cause remains unclear. Identifying these causes could significantly enhance medical interventions. However, current treatments are limited and produce suboptimal results.

The research team focused on PHGDH, initially recognized for its role as a blood biomarker. Further investigation revealed a direct correlation between PHGDH gene expression levels and the severity of Alzheimer's symptoms in multiple patient cohorts. Intrigued by this consistent pattern, the scientists explored whether PHGDH might play a causal role in the disease. Using mice and human brain organoids, they confirmed that manipulating PHGDH expression levels influenced disease progression—reduced levels slowed advancement while increased levels exacerbated it.

In addition to confirming PHGDH's causative role, the study highlighted a previously unknown mechanism. AI-assisted analysis revealed that PHGDH disrupts cellular processes regulating gene activation and deactivation in the brain. Specifically, PHGDH possesses a unique substructure enabling it to bind DNA and regulate two critical target genes, thereby upsetting the delicate balance required for normal brain function and initiating Alzheimer's pathology.

To address this newly identified pathway, the researchers investigated therapeutic options. They found that NCT-503, a compound capable of penetrating the blood-brain barrier, effectively inhibits PHGDH's regulatory activity without affecting its primary enzymatic function. Testing NCT-503 in mouse models demonstrated significant improvements in memory and anxiety, key symptoms associated with Alzheimer's disease. Although limitations exist due to imperfect animal models, the findings offer hope for future clinical trials and the development of novel small molecule treatments.

This discovery marks a pivotal moment in Alzheimer's research. By targeting an upstream pathway, therapies like NCT-503 may prevent amyloid plaque formation altogether, offering a more effective approach than traditional methods focusing on late-stage accumulations. As the team moves forward with optimizing the compound for human use, the potential for oral administration adds another layer of convenience compared to current infusion-based treatments. These advancements bring us closer to understanding—and potentially overcoming—one of medicine's greatest challenges.