NR Supplementation Improves Brain Blood Flow and Cognition in PAD Patients

Peripheral artery disease affects millions of older adults and is far more than a limb-circulation problem. PAD is a marker of systemic vascular aging characterized by generalized endothelial dysfunction, and it is strongly associated with cerebral small vessel disease and vascular cognitive impairment. Despite growing interest in NAD+ precursors as anti-aging interventions, only one prior clinical trial had examined nicotinamide riboside in PAD, and that study focused narrowly on walking capacity. This pilot trial (NCT06534944) was designed to fill that gap by simultaneously assessing peripheral vascular, cerebrovascular, and cognitive outcomes after 4 weeks of oral NR supplementation in 8 older adults with confirmed PAD.

Participants received NR supplementation over 4 weeks. Peripheral endothelial function was assessed using flow-mediated dilation (FMD) of the brachial artery. Cerebrovascular reactivity was measured with functional near-infrared spectroscopy (fNIRS) during cognitive tasks, focusing on hemodynamic responses in the left dorsolateral prefrontal cortex (LDLPFC) — a region critical for executive function and working memory. Cognitive performance was evaluated across multiple domains using standardized neuropsychological assessments. Blood was drawn before and after supplementation, and patient sera were applied to cultured human cerebral microvascular endothelial cells (hCMEC/D3) to assess cellular mechanisms including mitochondrial reactive oxygen species (mtROS), nitric oxide (NO) production, and mitochondrial efficiency.

On the vascular side, FMD showed a positive trend toward improvement after NR supplementation, though the small sample limited statistical power for this endpoint. More striking were the cerebrovascular findings: fNIRS revealed significant improvements in neurovascular coupling responses in the LDLPFC post-supplementation, indicating that the brain's ability to match blood flow to neural activity improved meaningfully after just 4 weeks. Cognitive assessments corroborated these vascular changes, with participants demonstrating enhancements across multiple cognitive domains following NR treatment.

The cellular experiments provided mechanistic insight. Endothelial cells treated with post-supplementation patient sera showed reduced oxidative stress (lower mtROS), increased nitric oxide production, and improved mitochondrial efficiency compared to cells treated with pre-supplementation sera. These findings suggest that NR supplementation alters the circulating milieu in ways that directly benefit cerebrovascular endothelial health — potentially through NAD+-dependent activation of sirtuins and PARP pathways that regulate mitochondrial function and endothelial NO synthase activity.

The authors acknowledge that this is a small, open-label pilot without a placebo control, making it impossible to rule out placebo effects or regression to the mean. The 8-participant sample provides insufficient power for definitive conclusions on most endpoints. Nevertheless, the multi-modal approach — combining peripheral vascular, cerebrovascular, cognitive, and cellular readouts — provides a rich framework for designing adequately powered future trials. The study underscores that PAD patients represent a compelling target population for NAD+ enhancement strategies, given their accelerated vascular aging phenotype and elevated risk for cognitive decline.