Al Uncovers a Possible Trigger for Alzheimer’s and Points to a Promising New Treatment

6 August 2024
by: Juice Juice
in Health

Last updated on

Scientists have wrestled with a puzzling question for decades: why do most people develop Alzheimer’s disease without carrying any known genetic mutations? Nearly every person over 65 shows early signs of brain changes linked to Alzheimer’s, yet the vast majority lack the genetic alterations that researchers traditionally blame for the disease. Recent breakthrough research may have finally cracked this mystery. Using advanced AI-powered analysis and cutting-edge brain organoid technology, researchers have discovered a hidden trigger that has been operating right under their noses. What they found challenges everything we thought we knew about how Alzheimer’s starts and spreads through the brain. Even more exciting: their discovery led directly to the identification of a potential treatment that shows remarkable promise in early testing. Animals given the experimental drug showed dramatic improvements in memory and significant reductions in the toxic brain plaques that define Alzheimer’s disease.

The Protein That Predicts Alzheimer’s

At the center of this breakthrough sits an enzyme called phosphoglycerate dehydrogenase, or PHGDH. Unlike the famous Alzheimer’s biomarkers, such as amyloid plaques and tau tangles, PHGDH doesn’t require complex processing or protein clumping to signal trouble. Both the protein itself and its genetic instructions increase directly in step with disease progression. PHGDH stands out among Alzheimer’s biomarkers for another crucial reason: it appears in blood samples before patients show any cognitive symptoms. “PHGDH exRNA levels in blood serum increase in patients prior to clinical diagnosis, suggesting plausible early diagnosis with this biomarker,” the research reveals. This early detection capability could revolutionize how doctors identify and potentially prevent Alzheimer’s before irreversible damage occurs. Studies across multiple patient groups confirmed that PHGDH levels correlate with both brain degeneration stages and individual cognitive decline. Higher PHGDH levels indicate worse outcomes, establishing a direct relationship that researchers can track and potentially target for treatment.

When Scientists Looked Closer, Everything Changed

Researchers expected PHGDH’s role in Alzheimer’s would relate to its regular job: producing serine, an amino acid essential for brain function. When they tested this theory using brain organoids grown from human stem cells, they got a shocking result. Even when they created mutated versions of PHGDH that couldn’t produce serine at all, the protein still triggered Alzheimer ‘s-like changes in brain tissue. Brain organoids provided the perfect testing ground for these experiments. Scientists can grow miniature brain-like structures in laboratory dishes, complete with neurons and support cells that closely resemble the architecture of a real human brain. When exposed to conditions that simulate aging brain environments, these organoids develop the same toxic protein clumps and cell death patterns seen in Alzheimer’s patients. Experiments with normal mice told the same story. Increasing PHGDH levels in healthy animals caused amyloid protein accumulation even without any genetic predisposition to Alzheimer’s. Something beyond enzyme activity was driving these changes, leading researchers to investigate what they call “moonlighting” functions—secondary jobs that proteins perform beyond their primary roles.

How PHGDH Hijacks Brain Cells to Trigger Disease

The breakthrough came when researchers discovered PHGDH doesn’t just work in the cell’s main compartment, where it typically produces serine. In brain support cells called astrocytes, some PHGDH migrates into the cell nucleus—the control center where genes get activated or silenced. Once inside the nucleus, PHGDH acts like a rogue genetic switch, activating harmful genes that are typically dormant. Specifically, it activates two troublemaker genes called IKKa and HMGB1. These genes produce proteins that trigger inflammation and disrupt the cell’s natural mechanisms for cleaning up cellular debris. PHGDH accomplishes this genetic manipulation through a DNA-binding region that resembles structures found in other gene-regulating proteins. Researchers identified specific DNA sequences that PHGDH recognizes and binds to, allowing it to increase or decrease gene activity with surgical precision. When PHGDH activates IKKα and HMGB1 production, it triggers a destructive cascade of events. These proteins activate inflammatory pathways while simultaneously shutting down autophagy—the cellular garbage disposal system that usually clears out damaged proteins and toxic debris.

Brain Support Cells Gone Wrong

Astrocytes serve as the brain’s maintenance crew, providing nutrients to neurons, cleaning up waste products, and maintaining the proper environment for nerve cell communication. When PHGDH hijacks these cells, it turns them from helpers into harmful contributors to disease progression. The research showed that astrocyte changes often precede other Alzheimer’s pathology, suggesting these support cells play crucial early roles in disease development. When astrocytes are unable to perform their cleanup duties due to PHGDH interference, toxic amyloid proteins accumulate more rapidly and cause greater damage to surrounding brain tissue. Brain organoid experiments demonstrated this connection. Reducing PHGDH levels in astrocytes decreased amyloid accumulation, preserved connections between nerve cells, and reduced cell death—essentially reversing multiple aspects of Alzheimer ‘s-like damage.

From Lab Discovery to Potential Treatment

Armed with knowledge about PHGDH’s hidden function, researchers set out to find drugs that could block its gene-regulating activity without interfering with its regular enzyme duties. They identified a compound called NCT-503 that specifically targets PHGDH’s DNA-binding abilities. NCT-503 offers several advantages as a potential treatment for Alzheimer’s disease. It crosses the blood-brain barrier efficiently, allowing it to reach brain tissue when given as a simple injection. The drug interferes explicitly with PHGDH’s transcriptional activities while leaving its serine-producing function intact, thereby avoiding potential side effects from disrupting normal metabolism. Laboratory testing confirmed that NCT-503 reduces the expression of the harmful IKKa and HMGB1 genes that PHGDH typically activates. Cell culture experiments showed the drug could reverse multiple aspects of Alzheimer ‘s-like damage in brain organoids, including reducing amyloid accumulation and preserving nerve cell connections.

Remarkable Results: Memory and Brain Plaques Improve

Mouse studies produced dramatic results that exceeded researchers’ expectations. Animals treated with NCT-503 showed substantial reductions in brain amyloid plaques compared to untreated controls. In different brain regions, plaque numbers dropped by 44% to 62%, while the areas covered by toxic protein deposits decreased by 54% to 63%. Beyond reducing brain pathology, NCT-503 improved actual behavior and cognitive function. Treated mice showed less anxiety-like behavior and performed better on spatial memory tasks. In maze tests, treated animals maintained efficient search strategies while untreated mice with Alzheimer ‘s-like changes showed deteriorating performance. “A blood-brain-barrier-permeable small-molecule inhibitor targeting PHGDH’s transcriptional function reduces amyloid pathology and improves AD-related behavioral deficits,” the study reports. These improvements were observed across multiple mouse models, indicating that the treatment approach has broad applicability. The behavioral improvements aligned closely with brain changes, indicating that reducing PHGDH activity produces meaningful functional benefits rather than just laboratory measurements that don’t translate to real-world outcomes.

Why Changes Everything We Know About Alzheimer’s

Before these discoveries, Alzheimer’s research focused heavily on genetic mutations found in families with early-onset disease. However, these mutations account for only a small fraction of Alzheimer’s cases. “Virtually all individuals aged 65 or older develop at least early pathology of Alzheimer’s disease (AD), yet most lack disease-causing mutations in APP, PSEN, or MAPT, and many do not carry the APOE4 risk allele,” the research explains. PHGDH explains how Alzheimer’s develops in people with seemingly normal genetics. Rather than requiring inherited mutations, the disease can arise when normal proteins, such as PHGDH, begin to perform abnormal functions due to aging, environmental factors, or other influences that accumulate over time. Blood-based PHGDH testing could enable much earlier detection than current methods allow. Since PHGDH levels rise before symptoms appear, doctors might identify at-risk individuals years before memory problems begin, opening windows for preventive interventions.

Why You Can’t Get This Drug Tomorrow

NCT-503 and similar compounds represent a new class of potential Alzheimer’s treatments that target transcriptional regulation rather than trying to clear existing protein clumps or replace damaged brain tissue. By addressing disease processes at their source, these approaches might prevent damage rather than attempting to reverse it after it occurs. However, significant work remains to be done before these discoveries benefit patients. NCT-503 requires extensive safety testing and clinical trials to determine appropriate human dosing and identify potential side effects. The transition from promising mouse studies to proven human treatments typically takes years or decades. Researchers also need to determine optimal timing for treatment. Early intervention might prevent disease progression most effectively, but identifying the right patients and treatment windows requires additional study. Current Alzheimer’s patients shouldn’t alter their treatment plans based on these early findings. Established treatments and participation in clinical trials remain the best options for managing disease progression while awaiting the complete development of new approaches.

Hope on the Horizon

The discovery of PHGDH represents a fundamental shift in understanding how Alzheimer’s disease develops in most people. By identifying transcriptional regulation as a key disease mechanism, researchers have opened entirely new avenues for drug development and early detection strategies. Multiple research teams are now working to develop additional compounds that target PHGDH and related transcriptional regulators. The field has moved from having few viable targets to exploring numerous possibilities for intervention. While today’s breakthrough may not immediately benefit current patients, it offers genuine hope for future generations. Early detection through blood testing combined with preventive treatments could potentially eliminate Alzheimer’s as a significant public health threat. For families affected by Alzheimer’s, these discoveries offer both scientific validation and realistic optimism. The disease isn’t an inevitable consequence of aging or entirely dependent on genetic luck. Instead, it results from specific biological processes that researchers can understand, predict, and potentially control. The journey from laboratory discovery to patient benefit remains long, but the destination finally appears within reach. After decades of failed approaches, scientists have found a promising new path forward in the fight against Alzheimer’s disease.

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