Disease: Dementia
Type of study: Interventional trial
Coordinating investigators: Ragnhild Eide Skogseth & Kristoffer Haugarvoll
Study director: Kristoffer Haugarvoll
Background: Alzheimer’s disease (AD) is the most common progressive neurodegenerative dementia and predominantly affects older women. The prevalence of AD in Norway in 2020 was estimated to be 8.4% in individuals aged 70 years or older the prevalence was 9,3% in women and 7.3% in men, respectively, with no disease-modifying treatment available.
It is paramount to target novel biological mechanisms therapeutically. Increasing evidence supports that boosting cellular levels of nicotinamide adenine dinucleotide (NAD) confers neuroprotective effects in both healthy aging and neurodegeneration. NAD is an essential cofactor for several metabolic reactions. Boosting NAD levels could potentially help ameliorate several major processes implicated in the pathogenesis of Alzheimer disease, including mitochondrial respiratory dysfunction, neuroinflammation, epigenomic dysregulation and increased neuronal DNA damage. NAD can be replenished via supplementation of nicotinamide riboside (NR), a vitamin B3 molecule and biosynthetic precursor of NAD.
The primary objective of the N-DOSE AD study is to determine the Optimal Biological Dose (OBD) for NR, defined as the dose required to achieve maximal cerebral NAD increase (measured by 31P-MRS or CSF metabolomics), or maximal alteration in cerebral metabolism patterns (measured by FDG-PET), or maximal proportion of MRS-responders, in the absence of unacceptable toxicity.
Design: N-DOSE AD is a randomised double-blinded placebo-controlled trial (RCT) to assess the optimal biological dose for nicotinamide riboside (NR) in Alzheimer’s dementia. Individuals with probable mild or moderate AD (n=80) will be randomised to receive placebo (n=20), 1000 mg of NR (n=20) or increasing doses (1000 mg, 2000 mg, 3000 mg) of NR (n=40) over 12 weeks. The selected dose range is within the safety limits for healthy humans.
Primary endpoint: The between-visit change in the following parameters: 1) Cerebral NAD levels (measured by 31P-MRS). 2) Proportion of MRS responders 3) CSF NAD and related metabolite levels (measured by HPLC-MS metabolomics, or the NADmed method) 4) Brain metabolic expression (measured by FDG-PET).
The between-visit difference in the placebo group will be assessed to determine the specificity of the findings to the NR-therapy. The between-visit difference in the 1000 mg NR group will be assessed to identify any time effects and differentiate those from dose-effects.
Status: The study was initiated in 2022. Sixty-nine out of a total of 80 study participants will be included by the end of 2024.
Participating centres
- Haraldsplass Deaconess Hospital, Bergen
- Haukeland University Hospital, Bergen
Funding
- The Research Council of Norway, Neuro-SysMed
- The Regional Health Authority of Western Norway
- Haraldsplass Deaconess Hospital
- Haukeland University Hospital
- The University of Bergen