Effects of NAD+ supplementation with oral nicotinamide riboside on vascular health and cognitive function in older adults with peripheral artery disease: Results from a pilot 4-week open-label clinical trial.

Peripheral artery disease (PAD) significantly contributes to increased morbidity and mortality among older adults. Characterized by generalized endothelial dysfunction, PAD is associated with a heightened risk for cerebral small vessel disease and vascular cognitive impairment. Together, these conditions exemplify the phenomenon of accelerated systemic vascular aging, highlighting the interconnections between vascular health and cognitive functions in the elderly. This pilot trial investigated the potential of nicotinamide riboside (NR), a precursor of NAD⁺, to counteract age-related vascular and cognitive decline in individuals with PAD. Over 4 weeks, we administered NR to 8 participants and measured its effects on peripheral endothelial function, functional cerebrovascular responses, and cognitive performance (NCT06534944). Additionally, we assessed the effects of circulating factors present in patient sera on oxidative stress and mitochondrial function in cultured cerebromicrovascular endothelial cells. Preliminary results indicate a positive trend in peripheral endothelial function, significant improvements in cerebrovascular response in the left dorsolateral prefrontal cortex, and cognitive enhancement across multiple domains postsupplementation. NAD⁺ supplementation with NR was associated with reduced oxidative stress and increased nitric oxide production and mitochondrial efficiency in endothelial cells treated with patient sera. These findings suggest that NR supplementation could ameliorate cognitive outcomes in older adults with PAD, potentially through mechanisms linked to improved endothelial health and decreased oxidative stress. This study underscores the importance of future research using controlled designs in larger cohorts to verify these effects and elucidate the long-term benefits of NAD⁺ enhancement in the context of accelerated vascular aging and its cognitive consequences. SIGNIFICANCE STATEMENT: Despite growing interest in NAD⁺ enhancement for vascular and cognitive health, research on nicotinamide riboside (NR) in peripheral artery disease (PAD) is limited. One clinical trial to date has assessed NR in PAD, focusing mainly on walking capacity. This pilot study provides critical evidence by examining peripheral endothelial function, cerebrovascular responses, and cognitive performance. Its multifaceted approach lays the groundwork for future trials to refine effect sizes and validate NR's potential to counter vascular aging and cognitive decline in PAD.