AI Uncovers New Cause and Potential Treatment for Alzheimer's Disease

AI Reveals PHGDH Gene's Hidden Role in Alzheimer's

Researchers at the University of California San Diego have made a groundbreaking discovery in Alzheimer's disease research, aided by artificial intelligence. The study, published in the journal Cell on April 23, 2025, reveals that the phosphoglycerate dehydrogenase (PHGDH) gene, previously identified as a biomarker for Alzheimer's, actually plays a causal role in the disease's development 1

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Uncovering the Mechanism

The research team, led by Professor Sheng Zhong, found that PHGDH has a previously unknown function beyond its known enzymatic role. Using AI to visualize the three-dimensional structure of the PHGDH protein, they discovered a substructure similar to a DNA-binding domain found in transcription factors 2

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This hidden function allows PHGDH to activate critical target genes, disrupting the delicate balance of gene regulation in brain cells. The imbalance leads to the early stages of Alzheimer's disease, independent of PHGDH's enzymatic activity 3

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Establishing Causality

To confirm PHGDH's causal role, the researchers conducted experiments using mice and human brain organoids. They found that altering PHGDH expression levels directly affected Alzheimer's disease progression:

1. Lower PHGDH levels corresponded to reduced disease progression
2. Higher PHGDH levels led to increased disease advancement

These findings establish PHGDH as a causal gene in spontaneous Alzheimer's disease, which accounts for the majority of cases 4

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Potential Treatment Option

The discovery of PHGDH's role opens up new possibilities for Alzheimer's treatment. The researchers identified a small molecule called NCT-503 as a potential therapeutic candidate. NCT-503 has several advantageous properties:

1. It can inhibit PHGDH's newly discovered regulatory function
2. It does not significantly impede PHGDH's essential enzymatic activity
3. It can penetrate the blood-brain barrier

Importantly, this approach targets an upstream pathway in Alzheimer's development, potentially reducing amyloid plaque formation before it becomes problematic 1

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Implications for Alzheimer's Research and Treatment

This study represents a significant advancement in understanding the mechanisms behind spontaneous Alzheimer's disease. By focusing on gene regulation imbalances rather than just amyloid plaques, it offers a new perspective on potential treatment strategies 2

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The use of AI in this research demonstrates its growing importance in scientific discovery, particularly in visualizing complex protein structures and identifying hidden functions 3

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As Alzheimer's affects about one in nine people aged 65 and older, this breakthrough could have far-reaching implications for millions of patients worldwide. However, further research is needed to translate these findings into effective treatments for human patients 4

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