Key Points:
- NAD+ (nicotinamide adenine dinucleotide) levels decline with age in human tissues, including the brain.
- Restoring brain NAD+ levels may be a viable treatment for Alzheimer’s disease, but scientists need to figure out how to target brain cells other than neurons.
In 2024, 3.8 billion US tax dollars went towards researching Alzheimer’s disease (AD) via the National Institute of Health (NIH). However, there are still no adequate treatments for AD, and scientists have yet to agree upon its root cause.
In a recent publication, Harvard Medical School researchers Kai-Christian Sonntag, MD, PhD, and Bruce M. Cohen, MD, PhD, proclaimed that NAD+ deficiency is an “inherent and targetable risk factor for late-onset AD.” This means readily available compounds, such as NAD+ precursors, may treat AD by restoring NAD+ levels in brain cells such as neurons. However, considering their findings, the Harvard researchers say that it may be necessary to combine interventions targeting NAD+ with other compounds.
Restoring NAD+: A Promising Alzheimer’s Intervention
Late-onset AD (LOAD), which occurs in 1 of 10 people over the age of 65, accounts for 95% of AD cases. LOAD is also called sporadic AD because its causes are unknown. Nevertheless, most scientists agree that one of the underlying drivers of AD is a disruption in how brain cells produce energy. The reduced production of stored cellular energy, called ATP (adenosine triphosphate), helps to fundamentally explain the progression of AD pathology.
NAD+, a vital mediator of ATP production, is in constant flux, always being synthesized, degraded, and recycled. With age, studies show that NAD+ synthesis decreases while its degradation increases, leading to a reduction in NAD+ levels. For this reason, NAD+ precursors like niacin, nicotinamide, NMN (nicotinamide mononucleotide), and NR (nicotinamide riboside), which elevate NAD+ levels, have been used to counteract its age-related decline.
Several studies have shown that NAD+ levels decline with age in the human brain, including a pioneering 2015 study done by the University of Minnesota, which was replicated in a 2024 study with higher resolution. Moreover, Sonntag and Cohen’s team have observed low NAD+ levels in brain cells derived from AD patients. Studying single cells allows scientists to examine the intricacies of diseases more closely. As such, disruptions in cellular energy metabolism in AD cells have been linked to reduced utilization of glucose, the brain’s primary fuel source.
Additionally, a literature review showed that NMN and NR can treat AD models, while human studies have shown that NR is beneficial. Studies testing the effect of NMN on AD are in the works, including one by Metro Biotech, but have not yet been completed. However, Sonntag and Cohen say,
“Although there has been some evidence that boosting NAD+ can improve cognitive function and alter AD pathological markers, the available data are too limited to conclude that this approach is an effective pharmacological intervention for LOAD.”
How Low NAD+ Poses a Risk for Neurodegeneration
LOAD is caused by neurodegeneration —the progressive loss of neuronal function leading to neuron death— but what causes neurodegeneration?
Oxidative Stress.
Many chronic diseases, including neurodegenerative disorders like LOAD, have a common denominator — oxidative stress. Oxidative stress involves the excessive buildup of reactive oxygen species (ROS), which are highly reactive molecules containing oxygen. Low levels of ROS are essential, but their buildup can be triggered by external factors like ultraviolet radiation, pollution, smoking, lack of exercise, and diets high in fat and carbohydrates.
ROS buildup can also occur due to internal factors, such as dysfunctional mitochondria. When mitochondria produce ATP, they inevitably generate ROS, and dysfunctional mitochondria generate abnormally high levels. Importantly, low NAD+ levels can lead to mitochondrial dysfunction, in turn promoting the excess generation of ROS. Moreover, specialized enzymes that reduce the buildup of ROS, called antioxidants, depend on NAD+ to function.
Thus, low NAD+ levels promote oxidative stress both by stimulating the generation of excess ROS and decreasing cellular antioxidant defenses. In turn, oxidative stress causes damage to important cellular components such as mitochondria, enzymes, and DNA, leading to the neuronal dysfunction and eventual neuron death that defines neurodegeneration.
Astrocyte Dysfunction
Sonntag and Cohen propose that the missing element in treating LOAD with NAD+ restoration is the ability to target specific types of brain cells, namely astrocytes. Astrocytes are the most abundant type of cell in the brain, accounting for 50% of the brain’s volume, and consuming about 80% of the brain’s glucose. Sonntag and Cohen’s research has shown that while NAD+ can be restored in LOAD neurons, the same does not occur in LOAD astrocytes. This poses a critical problem, particularly considering the role astrocytes play in keeping up with the energy demands of neurons.
Glucose is the primary fuel source for astrocytes, neurons, and almost all human cells. Its complete breakdown ultimately leads to the production of ATP through a series of cellular processes (glycolysis, Krebs cycle, and mitochondrial respiration). These cellular processes also produce molecules like NAD+ (NADH), as well as lactate, which was once thought of as a potentially harmful waste product. However, it is becoming more widely accepted that lactate is an important secondary fuel source for neurons, especially during times of high-energy demand, such as with LOAD.
Lactate can be utilized by our cells to make ATP, and studies have shown that astrocytes can transfer lactate to neurons. Studies also show that, under conditions of high metabolic stress, neurons become increasingly dependent on astrocyte-derived lactate to produce ATP. Thus, the inability to restore LOAD astrocyte NAD+ levels may exacerbate the metabolic dysfunction of LOAD neurons. Sonntag and Cohen say,
“Bioenergetically inefficient or stressed astrocytes may play a central role in dysfunctional brain metabolism and cell death associated with LOAD pathology. And, as suggested by our data, attempts to boost NAD+ may not be successful in these cells, which could be one of the reasons why NAD+ supplementation has not produced substantial improvement in cognitive brain functions in patients with LOAD. There may be other ways to target and support NAD+ levels and use them in astrocytes and other brain cells.”
Reducing the Risk of Developing Alzheimer’s Disease.
Sonntag and Cohen emphasize that LOAD is a complex disease with many interacting factors contributing to its progression. They list known risk factors for LOAD, including those associated with diseases such as cardiovascular disease and diabetes, and lifestyle factors such as diet, exercise, and psychosocial stimulation. They go on to say,
“NAD+ substrate deficiency and associated bioenergetic dysfunctions are inherent risk factors of LOAD, which are amplified by age-acquired NAD+ reductions, changes in NAD+ redox, and compromised energy metabolism. While young, these bioenergetic deficiencies can be compensated for, but in middle to old age, the amount of NAD+ substrate may become quantitatively insufficient to maintain metabolic needs or provide sufficient compensatory reserve in situations of cell stress. Thus, with inherently low and age-related further reductions of NAD+, there is a gradual acceleration of cellular bioenergetic decompensation that eventually leads to disintegration and cell death, and untimely onset of dementia.”
Thus, reducing the risk of LOAD encompasses factors like eating a healthy diet and exercising consistently, while maintaining social relationships. Sonntag and Cohen do not say that supplementing with NAD+ precursors can reduce the risk of LOAD, and more studies will be needed to determine how to boost astrocyte NAD+ levels, which may require additional compounds.
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