Globally, millions of people are affected by Alzheimer's disease, with around 120,000 individuals in Norway alone. Witnessing a loved one gradually decline because of this devastating condition can be heart-wrenching.
"Alzheimer's is a devastating disease, and we still don't have effective ways to stop or reverse it", says Beatriz Escobar-Doncel, a PhD student at the Fang-Stavem Lab at the University of Oslo and Akershus University Hospital.
Escobar-Doncel and her colleagues at the Fang-Stavem Lab are investigating what differentiates those individuals who develop Alzheimer's from those who remain unaffected.
People with Alzheimer's disease have low levels of REST protein
The researchers are studying a protective protein called REST, which is essential for maintaining the resilience and proper functioning of brain cells. They found that individuals with Alzheimer's have significantly lower levels of REST, compared to healthy older adults.
"In healthy seniors, REST levels are high. However, these levels drop considerably in Alzheimer's patients", Dr. Maria Jose Lagartos-Donate, a former postdoc fellow from the Fang-Stavem Lab, says.
As the disease progresses, REST levels fall even further.
The depletion of REST is linked to the accumulation of waste in the brain, and reduced energy supply to neurons, ultimately leading to memory loss and cognitive decline.
This may explain why some individuals experience memory loss while others remain healthy. However, this raises the question: can increasing REST levels improve brain function and protect against Alzheimer's disease?
Boosting REST levels in mice with NAD⁺
In previous studies, the researchers have found that a small molecule called NAD⁺ plays a crucial role in our aging process.
"We have reported multiple benefits on NAD⁺ on Alzheimer's disease. However, the underlying molecular mechanisms have not been entirely clear", Associate Professor Evandro Fei Fang-Stavem explains.
The researchers therefore wanted to test whether NAD⁺ supplements could increase the levels of the protective protein REST in mice with Alzheimer's disease.
The results were encouraging, administering NAD⁺ increased REST activity in the brain, slowed memory loss, and improved the brain's waste clearance capabilities.
These findings were published in the prestigious journal Brain.
What does this mean for Alzheimer's treatment?
The study provides new insight into how brain cells deteriorate over time in Alzheimer's, and the critical role REST plays in this. The findings raise hope for a new treatment approach.
"We show for the first time that NAD⁺ can induce the activity of the protective protein REST in the brain. This strengthens the scientific basis for conducting NAD⁺ related clinical trials with patients", Fang-Stavem says, and adds:
"By targeting the underlying mechanisms of the disease, we can aim to treat disease itself, rather than merely addressing its symptoms".
A potential biomarker for Alzheimer's disease
Understanding REST's role in Alzheimer's progression could lead to clinical advancements, including the development of a biomarker for the disease. Previous research at King's College London indicated that REST may serve as a novel biomarker for detecting Alzheimer's.
"Our research further strengthens this link between lower REST levels and the development of Alzheimer's disease", Escobar-Doncel notes.
The development of such a biomarker could lead to earlier diagnosis, potentially via blood tests in the future.
Could NAD⁺ treatment be useful for other neurodegenerative diseases?
The findings may also be relevant for other forms of dementia and other neurodegenerative diseases. Does REST play a similar protective role in these conditions?
"We know REST is vital for protecting our brain cells. Our findings open new opportunities to investigate its impact on similar conditions", Fang-Stavem explains.
He emphasizes the potential for forms of NAD⁺ as a therapeutic approach in these patient populations as well.
"This may slow cognitive decline and reduce memory loss in a larger group of patients, potentially improving the quality of life for millions worldwide", he says.
The aging brain's waste system
Fang-Stavem and his team have spent years researching Alzheimer's and aging in the laboratory. Their hypothesis is that, as we age, the brain's waste removal system, known as autophagy, becomes less efficient. The decline of this "engine" in the brain contributes to neurodegenerative diseases.
"Our aim is to develop pharmacological strategies to repair this 'cellular engine", Fang-Stavem says, highlighting several promising approaches under investigation in clinical trials.
From basic research to clinical application
Several laboratory breakthroughs have progressed to clinical trials involving patients, particularly involving NAD⁺ precursors, substances the body uses to produce NAD⁺.
Clinical trials have tested NAD⁺ precursors in conditions such as the rare Werner's syndrome, and in children with a rare genetic disorder, Ataxia Telangiectasia. Both studies reveal positive outcomes. (Links to previous articles here)
"These examples illustrate how basic science discoveries can lead directly to innovative treatments", Fang-Stavem says.
Understanding these treatments at a molecular level is crucial for refining and developing more effective medicines.
"These examples strengthen our belief that uncovering the underlying mechanisms of Alzheimer's and related diseases is key to finding meaningful treatments for patients", he concludes.
About the study
Beatriz Escobar-Doncel and Maria Jose Lagartos-Donate are both co-first authors of this study.
This project is in close collaboration with colleagues from Oslo University Hospital (Prof. Hilde Nilsen), NTNU (Dr. Rajeevkumar Raveendran Nair), Ji-Nan University in China (Profs. Guobing Chen and Oscar Junhong Luo), as well as University of Oxford in the UK (Dr. Shi Liu, Prof Alejo J Nevado-Holgado, and Prof. Noel Buckley).
The project was performed with generous funding from the Civitan Norway's Alzheimer's Disease Research Foundation, South-Eastern Norway Regional Health Authority and the Cure Alzheimer's Fund.
Reference
Maria J Lagartos-Donate, Beatriz Escobar-Doncel, Shi-qi Zhang, Jun-ping Pan, Noemí Villaseca González, Alexander Anisimov, Nicola P Montaldo, Vidar Jensen, Lipeng Mao, Bailei Li, Nuria Banzon-Pereira, Liu Shi, Shu-qin Cao, Domenica Caponio, Pingjie Wang, Rajeevkumar Raveendran Nair, Oscar Junhong Luo, Guobing Chen, Alejo J Nevado-Holgado, Noel Buckley, Hilde Loge Nilsen, Evandro Fei Fang, Loss of REST associated with Alzheimer's disease pathology is ameliorated by NAD+, Brain, 2026;, awaf261, https://doi.org/10.1093/brain/awaf261
