Nicotinamide as potential biomarker for Alzheimer’s disease: A translational study based on metabolomics

Abstract

Introduction: The metabolic routes altered in Alzheimer's disease (AD) brain are poorly understood. As the metabolic pathways are evolutionarily conserved, the metabolic profiles carried out in animal models of AD could be directly translated into human studies.Methods: We performed untargeted Nuclear Magnetic Resonance metabolomics in hippocampus of McGill-R-Thy1-APP transgenic (Tg) rats, a model of AD-like cerebral amyloidosis and the translational potential of these findings was assessed by targeted Gas Chromatography-Electron Impact-Mass Spectrometry in plasma of participants in the German longitudinal cohort AgeCoDe.Results: In rat hippocampus 26 metabolites were identified. Of these 26 metabolites, nine showed differences between rat genotypes that were nominally significant. Two of them presented partial least square-discriminant analysis (PLS-DA) loadings with the larger absolute weights and the highest Variable Importance in Projection (VIP) scores and were specifically assigned to nicotinamide adenine dinucleotide (NAD) and nicotinamide (Nam). NAD levels were significantly decreased in Tg rat brains as compared to controls. In agreement with these results, plasma of AD patients showed significantly reduced levels of Nam in respect to cognitively normal participants. In addition, high plasma levels of Nam showed a 27% risk reduction of progressing to AD dementia within the following 2.5 years, this hazard ratio is lost afterwards.Discussion: To our knowledge, this is the first report showing that a decrease of Nam plasma levels is observed couple of years before conversion to AD, thereby suggesting its potential use as biomarker for AD progression.

Nurturing longevity through natural compounds: Where do we stand, and where do we go?

“…The preservation of NAD + levels along with the activation of SIRTs, PARPs, and FOXOs, all associated with improved DNA repair mechanisms, has become an extensively exploited strategy in healthspan improvement. Interventions elevating NAD + levels, including the administration of NAD precursors, such as nicotinamide riboside (NR), nicotinamide mononucleotide, and niacin, along with the development of NAD‐boosting therapies and molecules have been developed (Dalmasso et al., 2023; Mills et al., 2016; Phelan et al., 2017; Trammel et al., 2016; Yoshino et al., 2021). Indeed, multiple studies have proposed that NR supplementation extends the lifespan through DNA damage prevention in mice (Y. Hou et al., 2018; Trammell et al., 2016).…”

Metabolomic Footprint of Disrupted Energetics and Amino Acid Metabolism in Neurodegenerative Diseases: Perspectives for Early Diagnosis and Monitoring of Therapy

“…Interestingly, recently Dalmasso et al highlighted significantly reduced levels of nicotinamide, one of the NAD+ metabolites, in comparison to cognitively regular participants. In addition, high plasma levels of nicotinamide showed a 27% risk reduction of progressing to AD dementia within the following 2.5 years; this hazard ratio is lost afterward [ 108 ]. It suggested that not only the kynurenine pathway but also the investigation of NAD+ and nicotinamide metabolites might be interesting in investigating new AD biomarkers.…”