National Institute on Aging Finds NAD+ Booster Lowers Neurodegenerative Markers 

NAD+ precursor nicotinamide riboside (NR) raises NAD+ in neuron-originated vesicles (membrane-bound sacs) and lowers Alzheimer’s biomarker, Aβ42 in older adults.

By Daniel R. Miranda, Ph.D.

Key Points:

  • 1000 mg of NR increases the NAD+ content of vesicles from neurons in older adults. 
  • NR lowers vesicle Aβ42 — a protein associated with neurodegeneration and cognitive decline. 
  • Proteins associated with insulin resistance and brain inflammation are altered by NR. 

Our brain uses more energy than any other organ in the body. As such, brain cells are especially vulnerable to age-related depletion of nicotinamide adenine dinucleotide (NAD+), a central mediator of cellular energy production. It is, therefore, possible that NAD+ depletion contributes to neurodegeneration. Furthermore, replenishing NAD+ could potentially contribute to slowing or preventing neurodegeneration. 

Now, researchers from the National Institute on Aging (NIA) present data in Aging Cell showing that boosting NAD+ with NR could protect against neurodegeneration. As a surrogate for measuring NAD+ from the brain, Vreones measured the NAD+ contained within vesicles from the brain. They found that NR increased vesicle NAD+ levels, which correlated with changes in insulin signaling. Additionally, NR decreased vesicle Aβ42 levels, suggesting that NR could guard against Alzheimer’s disease. 

Boosting NAD+ with NR Reduces Neurodegenerative Marker 

Twenty-two healthy older adults were given an oral dose of 500 mg of NR twice daily for six weeks. As it is difficult to measure NAD+ from the brains of living humans, Vreones and colleagues isolated vesicles from blood samples taken from the participants. Vesicles are released by all cells, but the researchers were able to pinpoint neuronal vesicles using protein markers. 

Using a less sensitive method, the researchers were able to detect but not quantify NAD+ levels. They, therefore, used a more sensitive measurement in 10 of the 22 participants. The results showed that the vesicles of older adults supplemented with NR had a higher concentration of NAD+ compared to older adults who took a placebo. However, only nine out of ten participants displayed this increase. 

(Vreones et al., 2022 | Aging Cell) NR Raises NAD+ in Vesicles of Neuronal Origin. Vesicles released from neurons have a higher concentration of NAD+ (nM) when older adults are supplemented with NR compared to placebo.

Aβ42 is a protein associated with the onset and progression of Alzheimer’s disease and other cognitive disorders. In the participants who responded to the NAD+-boosting effects of NR, called responders, Vreones and colleagues found reduced vesicle concentrations of Aβ42. These data suggest that NR could potentially mitigate the progression of cognitive impairment and neurodegeneration in older adults with low NAD+ levels.

(Vreones et al., 2022 | Aging Cell) NR Reduces Marker for Neurodegenerative Disease. In older adults who display increased vesicle NAD+ levels in response to NR (Responders), NR lowers vesicle concentrations of the neurodegenerative biomarker Aβ42 (pg/mL) compared to placebo.

Insulin resistance — when cells stop intaking glucose in response to insulin — is a major contributor to neurodegeneration that promotes neuroinflammation. Vreones and colleagues found that the vesicle concentration of two activated (phosphorylated) proteins involved in insulin signaling called ERK and JNK were reduced in responders — participants who had increased NAD+ levels in response to NR. 

The NIA scientist hypothesized that these two proteins would be increased by NR to improve insulin signaling, but this was not the case. However, increased NAD+ was correlated with increases in other insulin signaling proteins, suggesting that NR engages the insulin signaling pathway. Notably, increased ERK and JNK are associated with Alzheimer’s, suggesting that NR reduces proteins involved in Alzheimer’s pathology. 

NR Clinical Trials and Brain Aging 

The vesicles analyzed by Vreones and colleagues were from participants of a clinical trial showing that NR increases NAD+ in immune cells and tends to improve blood pressure, which may affect brain aging. In another clinical study, 1000 mg of NR improved clinical symptoms of Parkinson’s disease only in responders. Additionally, Combining 1000 mg of NR with L-carnitine, N-acetylcysteine, and serine improved the cognition and brain structure of Alzheimer’s patients, especially in more severe cases of cognitive decline. Based on these studies, it could be that NR has a neuroprotective effect on individuals who are particularly susceptible to the consequences of brain aging. Determining who is more susceptible will require more research. 

Model & Dosage

Model: Older adults (65 ± 7 years old)

Dosage (oral): 1000 mg nicotinamide riboside (500 mg twice a day for 6 weeks)


Vreones M, Mustapic M, Moaddel R, Pucha KA, Lovett J, Seals DR, Kapogiannis D, Martens CR. Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin. Aging Cell. 2022 Dec 14:e13754. doi: 10.1111/acel.13754. Epub ahead of print. PMID: 36515353.

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