Nicotinamide riboside and caffeine partially restore diminished NAD availability but not altered energy metabolism in Alzheimer's disease

Abstract

The redox co‐factor nicotinamide adenine dinucleotide (NAD) declines with age, and NAD deficits are specifically associated with dysfunctional energy metabolism in late‐onset Alzheimer's disease (LOAD). Nicotinamide riboside (NR), a dietary NAD precursor, has been suggested to ameliorate the aging process or neurodegeneration. We assessed whether NR with or without caffeine, which increases nicotinamide mononucleotide transferase subtype 2 (NMNAT2), an essential enzyme in NAD production, modulates bioenergetic functions in LOAD. In LOAD patients—and young or old control individuals—derived dermal fibroblasts as well as in induced pluripotent stem cell‐differentiated neural progenitors and astrocytes, NR and caffeine cell type‐specifically increased the NAD pool, transiently enhanced mitochondrial respiration or glycolysis and altered the expression of genes in the NAD synthesis or consumption pathways. However, continued treatment led to reversed bioenergetic effects. Importantly, NR and caffeine did not alter the characteristics of a previously documented inherent LOAD‐associated bioenergetic phenotype. Thus, although NR and caffeine can partially restore diminished NAD availability, increasing NAD alone may not be sufficient to boost or restore energy metabolism in brain aging or alter aberrant energy management in LOAD. Nicotinamide riboside might still be of value in combination with other agents in preventive or therapeutic intervention strategies to address the aging process or age‐associated dementia.

Effect of Exercise and Oral Niacinamide Mononucleotide on Improving Mitochondrial Autophagy in Alzheimer’s Disease

“…These results suggest that NR and caffeine may alter the metabolism of NAD + and bioenergy in the aging body in nature. It may be necessary to improve the degraded NAD + metabolism in the aging body through long-term stimulation, such as periodic regular exercise, so as to improve the spatial memory, cognitive memory, and prevent the loss of neurons in AD [113]. Whether or not SLC12A8, which acts as a Na + -dependent transporter protein, and exercise can regulate the Na + concentrations inside and outside myocytes via the sodiumpotassium pump, which would promote the turning on of SLC12A8, is unknown, but in cellular experiments, the removal of Na + resulted in a significant decrease in SLC12A8 expression, leading to a decrease in intracellular NAD + content [19,114].…”

Nicotinamide Riboside, a Promising Vitamin B3 Derivative for Healthy Aging and Longevity: Current Research and Perspectives

“…In APP/PS1 transgenic (AD) mice, NRS for eight weeks normalized gut dysbiosis for Adlercreutzia , Akkermansia , Bacteroides , Bifidobacterium , Butyricicoccus , Desulfovibrio , Lactobacillus , Olsenella , and Oscillospira microbiota species [ 208 ]. In late-onset AD patients, NR and caffeine co-administration partially restores diminished NAD + availability but does not alter bioenergetic metabolism [ 209 ]. In a randomized, double-blinded, PLA-controlled, phase II clinical trial, combined metabolic activators (CMAs) administered in a single dose during the first 28 days and twice daily between days 28 and 84 significantly increased the cognitive capacity and alleviated NAD + plasma levels and GSH metabolism of AD patients.…”

The complex determinants of Alzheimer’s-type dementias

“…The supplement most often studied is nicotinamide riboside (NR). We assessed whether supplementation with NR, along with caffeine, which has also been observed to enhance NAD production, would normalize bioenergetic anomalies associated with LOAD [ 8 ].…”

“…Dermal fibroblasts obtained from individuals with LOAD, and from young and age-matched healthy subjects, were reprogrammed to induced pluripotent stem cells (iPSCs) used to produce neural precursor (NPC)- and astrocyte-like cells in culture [ 4 , 8 ]. This is the model in which we observed inherent LOAD-associated bioenergetic abnormalities.…”