Alzheimer’s disease affects approximately 50 million individuals worldwide and is a devastating disease with limited treatment options currently available. "Alzheimer's is a heartbreaking disease, and we continue to seek effective ways to stop or reverse its progression," Beatriz Escobar-Doncel, a researcher involved in the study, says.
This 5-year research project, led by Associate Professor Evandro Fang-Stavem, sheds light on why some elderly individuals may be protected from the onset of Alzheimer’s disease while others do not. The article, titled «Loss of REST associated with Alzheimer’s disease pathology is ameliorated by NAD⁺”, is published in the prestigious journal BRAIN.

Highlighting the protective role of the REST protein
Key to this understanding is the protective protein REST, which plays an essential role in brain health, and is naturally reduced during ageing. The study reveals that many 'lucky' older adults maintain higher levels of REST.
However, Alzheimer’s patients exhibit significantly reduced REST levels, suggesting a correlation between REST depletion and the cognitive decline associated with the disease. The depletion of REST contributes to waste accumulation in the brain, leading to a reduction in neuronal energy and overall memory loss.

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 ageing process. They reported multiple benefits on NAD⁺ in animal models of Alzheimer’s disease early in 2019, although the underlying molecular mechanisms have not been entirely clear.
Fang-Stavem and colleagues thus wanted to test whether administrating NAD⁺ precursors on animal models with Alzheimer’s disease could increase the levels of the protective protein REST. The results were encouraging, administering NAD⁺ increased REST activity in the brain, slowed memory loss, and improved the brain's waste clearance capabilities.

“We showed for the first time that NAD⁺ can induce the expression of the brain-protective protein REST. This discovery is important as it not only deepens our understanding of the fundamental molecule NAD⁺, consolidating the scientific foundation of the many NAD⁺ related clinical trials, but also provides new therapeutic and even diagnostic strategies for the hard-to-cure Alzheimer’s disease”, Fang-Stavem says.

Implications for Alzheimer’s treatment and diagnostics
This work not only pave the way for potential treatments but also points toward REST as a potential biomarker for Alzheimer’s disease. A previous study from King’s College London suggested that REST could serve as a novel candidate for Alzheimer’s detection.
Escobar-Doncel explains, “Strengthening the link between REST levels and Alzheimer’s progression could facilitate earlier diagnosis, potentially through blood tests in the future.”

Moreover, the research has wider implications beyond Alzheimer’s. Since REST plays a key role in protecting brain cells and maintaining their function, it may have protective roles in other neurodegenerative diseases as well. "This opens possibilities for NAD⁺ precursors to not only aid Alzheimer’s patients but potentially slow degeneration in a range of neurological disorders, providing hope for millions of patients worldwide," Fang-Stavem concludes.

A combined research effort
The collaborative efforts of the research team, including first authors Maria J. Lagartos-Donate and Beatriz Escobar-Doncel, Shi-qi Zhang, and main author Alexander (Sasha) Anisimov, also involved contributions from teams at Oslo University Hospital (Prof. Hilde L. Nilsen) and NTNU – Norwegian University of Science and Technology in Norway (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).

Funding
The study was generously funded by the Civitan Norway's Alzheimer's Disease Research Foundation, South-Eastern Norway Regional Health Authority, and the USA-based Cure Alzheimer’s Fund.