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

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.