Alzheimer’s disease is one of the most common forms of dementia affecting millions of people worldwide. The failure rate of drugs against Alzheimer’s disease is incredibly high, and therefore new treatments targeting other pathways than previously addressed are needed.

During her PhD studies in Tinna Stevnsner’s laboratory at the Department of Molecular Biology and Genetics at Aarhus University in Denmark, Sofie Lautrup visited Vilhelm Bohr’s laboratory at the National Institute on Aging, NIH, USA. Here, she played a central role in the investigation of the effects of treatment with the NAD+ precursor Nicotinamide riboside (NR) on Alzheimer’s disease lead by Yujun Hou. The experiments conducted used a new and improved Alzheimer’s disease mouse model made by the Bohr laboratory. In this mouse model, the traditional triple-transgenic Alzheimer’s disease mouse has been crossed with a mouse expressing only 50% of the DNA repair protein DNA Polymerase Beta, resulting in reduced DNA repair capacity. These mice show an exacerbation of the Alzheimer’s disease phenotype, and additionally the phenotype is more comparable to human Alzheimer’s disease.

NAD+ is an important metabolite in the cell, being involved in the mitochondrial metabolism, and working as a coenzyme for several groups of proteins, including poly (ADP-ribose) polymerase and sirtuins. Previously, an age-dependent decrease of NAD+ in the brain has been shown, and in addition lower NAD+ levels are observed in neurodegenerative diseases.

The ability to remember and learn is increased with increasing NAD+ levels

The recently published study by Hou, Lautrup et al. in PNAS (Proceedings of the National Academy of Sciences in America) examines the level of NAD+ in the brain of Alzheimer’s disease mouse models, and investigates the effect of NAD+ precursor treatment on Alzheimer’s disease in these models. The research shows that NAD+ brain levels are reduced in two different Alzheimer’s disease models compared to healthy control mice. In addition, they show that three months treatment with the NAD+ precursor, NR, increases the NAD+ levels in the brain of the mice.

The study shows that by increasing NAD+ in the brain of Alzheimer’s disease mice, their ability to remember and learn, and the signaling between neurons, improve. Furthermore, the study demonstrates that the proliferation capacity of the neuronal stem cells increases, and the inflammation and level of phosphorylated Tau, a central protein in Alzheimer’s disease, decrease after treatment.

The proposed mechanism by which nicotinamide riboside works, is via two NAD+-dependent deacetylases, sirtuin 3 and 6. Both activity and level of the two sirtuins increase after NR treatment. Meanwhile the amount of DNA damage and oxidative stress in the mitochondria decrease. This results in an improved mitochondrial function, and hereby an improved neuronal function and reduced stress in the cells.

NR has already been tested on healthy individuals, and even at high dose, no toxic side effects have been observed. Hereby, this study demonstrates NAD+ supplementation as a possible treatment of Alzheimer’s disease.

Read the scientific article entitled "NAD+ supplementation normalizes key Alzheimer's features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency" published in  PNAS (Proceedings of the National Academy of Sciences in America). 

For further information, please contact

Sofie Hindkjær Lautrup
Department of Molecular Biology and Genetics, Aarhus University, Denmark
lautrup@au.dk - +45 5090 0938