Supplementation with NAD+ and Its Precursors to Prevent Cognitive Decline across Disease Contexts

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Abstract

The preservation of cognitive ability by increasing nicotinamide adenine dinucleotide (NAD+) levels through supplementation with NAD+ precursors has been identified as a promising treatment strategy for a number of conditions; principally, age-related cognitive decline (including Alzheimer’s disease and vascular dementia), but also diabetes, stroke, and traumatic brain injury. Candidate factors have included NAD+ itself, its reduced form NADH, nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), and niacin (or nicotinic acid). This review summarises the research findings for each source of cognitive impairment for which NAD+ precursor supplementation has been investigated as a therapy. The findings are mostly positive but have been made primarily in animal models, with some reports of null or adverse effects. Given the increasing popularity and availability of these factors as nutritional supplements, further properly controlled clinical research is needed to provide definitive answers regarding this strategy’s likely impact on human cognitive health when used to address different sources of impairment.

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George Bloom (2014)

The defining features of Alzheimer disease (AD) include conspicuous changes in both brain histology and behavior. The AD brain is characterized microscopically by the combined presence of 2 classes of abnormal structures, extracellular amyloid plaques and intraneuronal neurofibrillary tangles, both of which comprise highly insoluble, densely packed filaments. The soluble building blocks of these structures are amyloid-β (Aβ) peptides for plaques and tau for tangles. Amyloid-β peptides are proteolytic fragments of the transmembrane amyloid precursor protein, whereas tau is a brain-specific, axon-enriched microtubule-associated protein. The behavioral symptoms of AD correlate with the accumulation of plaques and tangles, and they are a direct consequence of the damage and destruction of synapses that mediate memory and cognition. Synapse loss can be caused by the failure of live neurons to maintain functional axons and dendrites or by neuron death. During the past dozen years, a steadily accumulating body of evidence has indicated that soluble forms of Aβ and tau work together, independently of their accumulation into plaques and tangles, to drive healthy neurons into the diseased state and that hallmark toxic properties of Aβ require tau. For instance, acute neuron death, delayed neuron death following ectopic cell cycle reentry, and synaptic dysfunction are triggered by soluble, extracellular Aβ species and depend on soluble, cytoplasmic tau. Therefore, Aβ is upstream of tau in AD pathogenesis and triggers the conversion of tau from a normal to a toxic state, but there is also evidence that toxic tau enhances Aβ toxicity via a feedback loop. Because soluble toxic aggregates of both Aβ and tau can self-propagate and spread throughout the brain by prionlike mechanisms, successful therapeutic intervention for AD would benefit from detecting these species before plaques, tangles, and cognitive impairment become evident and from interfering with the destructive biochemical pathways that they initiate.

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NAD+ metabolism and its roles in cellular processes during ageing

Anthony J Covarrubias, Rosalba Perrone, Alessia Grozio … (2020)

Nicotinamide adenine dinucleotide (NAD+) is a coenzyme for redox reactions, making it central to energy metabolism. NAD+ is also an essential cofactor for non-redox NAD+-dependent enzymes, including sirtuins, CD38 and poly(ADP-ribose) polymerases. NAD+ can directly and indirectly influence many key cellular functions, including metabolic pathways, DNA repair, chromatin remodelling, cellular senescence and immune cell function. These cellular processes and functions are critical for maintaining tissue and metabolic homeostasis and for healthy ageing. Remarkably, ageing is accompanied by a gradual decline in tissue and cellular NAD+ levels in multiple model organisms, including rodents and humans. This decline in NAD+ levels is linked causally to numerous ageing-associated diseases, including cognitive decline, cancer, metabolic disease, sarcopenia and frailty. Many of these ageing-associated diseases can be slowed down and even reversed by restoring NAD+ levels. Therefore, targeting NAD+ metabolism has emerged as a potential therapeutic approach to ameliorate ageing-related disease, and extend the human healthspan and lifespan. However, much remains to be learnt about how NAD+ influences human health and ageing biology. This includes a deeper understanding of the molecular mechanisms that regulate NAD+ levels, how to effectively restore NAD+ levels during ageing, whether doing so is safe and whether NAD+ repletion will have beneficial effects in ageing humans.

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Vascular dementia is one of the most common causes of dementia after Alzheimer's disease, causing around 15% of cases. However, unlike Alzheimer's disease, there are no licensed treatments for vascular dementia. Progress in the specialty has been difficult because of uncertainties over disease classification and diagnostic criteria, controversy over the exact nature of the relation between cerebrovascular pathology and cognitive impairment, and the paucity of identifiable tractable treatment targets. Although there is an established relation between vascular and degenerative Alzheimer's pathology, the mechanistic link between the two has not yet been identified. This Series paper critiques some of the key areas and controversies, summarises treatment trials so far, and makes suggestions for what progress is needed to advance our understanding of pathogenesis and thus maximise opportunities for the search for new and effective management approaches.