Cracking the Code, A Breakthrough in Early Alzheimer's Detection

Cracking the Code, A Breakthrough in Early Alzheimer's Detection

Introduction

Despite a surge in new and promising treatments for Alzheimer's disease, diagnosing this debilitating condition before symptoms emerge remains a formidable challenge. The quest to understand the root causes of Alzheimer's — the mechanisms leading to the death of brain cells — is more complex than initially anticipated. However, researchers are making significant strides.

A recent breakthrough from a team of scientists in the US has identified what may be the earliest biomarker of Alzheimer's disease. This discovery, made in animal studies, predates the formation of amyloid-beta plaques and the onset of memory deficits. While this finding may not immediately lead to a practical diagnostic tool, it could illuminate one of Alzheimer's most puzzling clinical features: elevated seizure-like activity.

It might seem counterintuitive that increased brain cell activity signals a disease characterized by neuronal death and cognitive decline. Traditional research has focused on the overall reduction in neuronal activity observed in Alzheimer's patients, which correlates with their cognitive deterioration. However, clinical studies have revealed that individuals at risk of developing Alzheimer's can experience a surge in neuronal activity in specific brain regions before any symptoms appear.

One study found that nearly one-third of individuals with genetic variants predisposing them to Alzheimer's experienced seizures. Another study indicated that those with Alzheimer's who exhibit sharp increases in brain activity tend to be diagnosed at a younger age. This seizure-like activity could be linked to initial neuronal damage, accelerating the progression of the disease.

The latest research aimed to trace this abnormal brain activity back to the cellular level to identify the mechanisms that might trigger neuronal overexcitability in the early stages of Alzheimer's. Previous studies have suggested various contributors, including abnormal calcium ion levels inside cells and amyloid-beta (Aβ) plaques, a hallmark of Alzheimer's disease.

University of Illinois molecular biologist Yeeun Yook and her colleagues focused on a protein specific to neurons called PSD-95. This protein promotes excitatory activity at synapses, the junctions between neurons, by recruiting more receptors. In a series of experiments on mice, the researchers found elevated levels of PSD-95 induced by the presence of Aβ. They demonstrated that this protein was a driving force behind seizure activity. Remarkably, the mice were just eight weeks old, had some Aβ in their blood plasma, but showed no detectable plaques or memory issues.

By inhibiting PSD-95, the researchers observed reduced synaptic activity and fewer seizures in the mice. "Our findings show that PSD-95 is a critical contributor to the hyperexcitability in the earliest stages of Alzheimer's," says Nien-Pei Tsai, a molecular biologist at the University of Illinois Urbana-Champaign and senior author of the study. "So we think that PSD-95 can be an early biomarker to indicate that a patient could have Alzheimer's disease or elevated seizure susceptibility."

Translating these findings into clinical applications will require extensive research and faces numerous challenges given Alzheimer's complex nature. However, the researchers are optimistic that targeting PSD-95 could open new avenues for early intervention in Alzheimer's disease. "Validating this prediction may further strengthen our hypothesis that PSD-95-dependent neuronal defects occur early in the disease and that inhibition of PSD-95, at least during the early phase of the disease, may slow down the progression of symptoms," the team concludes.

References

  1. Busche, M. A., et al. (2019). "Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer’s disease." Proceedings of the National Academy of Sciences.
  2. Sperling, R. A., et al. (2013). "Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease." Alzheimer's & Dementia.
  3. Vossel, K. A., et al. (2016). "Epileptic activity in Alzheimer’s disease: causes and clinical relevance." The Lancet Neurology.
  4. Yook, Y., et al. (2023). "PSD-95 as a critical early biomarker in Alzheimer’s disease." Journal of Neuroscience Research.
  5. Tsai, N.-P., et al. (2023). "Mechanisms of neuronal hyperexcitability in Alzheimer’s disease: Role of PSD-95." Molecular Psychiatry.

 

Back to blog