Nicotinamide riboside benefits older adults with MCI

In older adults with mild cognitive impairment (MCI), daily supplementation with oral nicotinamide riboside (NR) at a dose of 1 g for 10 weeks appears to show a favourable safety profile and increases blood levels of NAD+* and associated metabolites, a phase II study suggests.

“We observed an average 139-percent increase in NAD+ (mean change, 30.63 pmol/μL blood). NR supplementation also significantly increased NAAD, NMN, and Me-4-Py** (6, 1.2, and more than tenfold increases, respectively),” said the researchers.

Despite the increase in NAD+, the researchers noted that there was no evidence of haemolysis with NR. “These findings suggest that indirectly increasing NAD+ through its precursor molecules may be a safer approach than directly infusing it. Alternatively, the magnitude of increase may be an important consideration to control and monitor when using NAD+ boosting therapies.”

Furthermore, flushing – the most common complaint from niacin intake (a historically used strategy to increase NAD+) – was not reported in this trial. This, according to the investigators, implies that NR provides a safe and tolerable alternative to increasing NAD+.

Cognitive function

From screening to end of study, MoCA*** – the primary cognitive outcome measure – dropped in both treatment (from 23.1 to 22.8; μ, -0.3; p=0.730) and placebo arms (from 24 to 23.11; μ, -0.89; p=0.154). [GeroScience 2024;46:665-682]

There were no appreciable differences in CLOX, CLOX2, or EXIT^# in either arm, and all participants scored normal on the GAS/GDS^## at both pre- and post-study visits.

“Collectively, these results indicate that depression, anxiety, and cognitive performance in short-term memory; visuospatial abilities; executive functions; attention, concentration, and working memory; language; and orientation to time and place remained stable during the 10-week study,” the researchers explained.

“[However,] we are cautious to not overinterpret these results due to the small sample size,” they pointed out. The study was also primarily designed to assess safety and tolerability and was not powered to evaluate outcomes associated with cognition or disease modification.

Moreover, almost all participants were Hispanic. Hispanics reportedly have a higher risk of developing dementia than other ethnic groups due to risk factors such as lower educational level, hypertension, diabetes, and vascular disease. [Neurology 2002;59:378–383; J Am Geriatr Soc 2003;51:169–177]

“The subtle between-group differences … are encouraging – NR did not worsen cognition in a primarily Hispanic population. However, a larger study with a longer trial duration is needed to confidently infer treatment effects,” the researchers said.

MRI assessment

NR recipients had decreased cerebral blood flow (CBF) in the nine default mode network (DMN) nodes collectively post-treatment (μ, 0.92; p=0.013), with the greatest differences seen in the left IPL^### (μ, 1.66; p=0.009) and the PCC^### (μ, 1.54; p=0.033). The right IPL and precuneus showed similar patterns (μ, 1.36; p=0.066 and μ, 1.4; p=0.069, respectively).

“Specifically, the nodal stress hypothesis proposes that decreases in blood flow in high metabolically active brain regions such as the DMN would decrease oxidative stress. Therefore, the NR-associated decrease in blood flow may prevent these regions from experiencing degradation from high metabolic cost,” the researchers explained.

“However, it is important to note that other studies have found reduced CBF in MCI, suggesting that a further reduction with NR may be detrimental,” they added.

Larger, longer trials warranted

Twenty participants were randomized 1:1 to receive placebo or NR. The daily dosing strategy for NR was 250 mg for week 1, 500 mg for week 2, and 750 mg for week 3. By week 4, all were on 1 g daily, which was maintained throughout the 10-week study duration.

NR was well tolerated at the dose assessed. A total of 18 adverse events (AEs) were reported by seven NR recipients, but none were serious. Apart from one case of severe nausea and heartburn, most AEs were mild to moderate. The severe symptoms resolved by reducing the NR dose from 1 g to 750 mg for a week and then reverting to 1 g for the rest of the study period.

Given the small sample size, the investigators called for larger, longer trials to ascertain the potential of NR as a strategy to modulate the progression of MCI to AD.

They also recommended incorporating neuropsychiatric measures for social cognition and other more subtle paradigms relevant to the DMN and IPL in future trials, as “instruments of social cognition may be more sensitive at detecting effects from NR.”