As the world population ages, more people than ever before are struggling with dementia or endeavoring to prevent it. Known as cognitive decline beyond that which is normal in the course of aging, the toll of dementia weighs heavily on patients and their loved ones; from its starting point as mild cognitive impairment (MCI), dementia slowly and unstoppably progresses until patients have minimal cognitive capability and, eventually, no ability to respond to external stimuli.
Dementia has been known to medical science for more than two thousand years, yet even with the advent of modern medicine, there is no cure. While there are several therapies intended to reduce the severity of mild dementia—like donepezil, an acetylcholinesterase inhibitor—these are of limited efficacy regardless of the dementia’s cause. While researchers try to develop new avenues of treatment, patients are often left to fend for themselves using questionably effective tools that can lead to transient improvements in neurocognitive symptoms like short-term memory, but not a slowing of the disease’s progression. For patients and caregivers who are not content to accept the ineffective standard of care, however, there are a number of natural compounds which may be helpful in addressing neurocognitive symptoms of dementia. Of these, the compounds known as quercetin, butyrate, and glutathione are especially promising.
Quercetin is a phenolic compound which is common to many vegetables and red wine. As with many other phenols, quercetin is an antioxidant, which gives it minor anti-inflammatory properties, though these properties are negligible at the quantities typically consumed in food. More significantly, scientists believe that quercetin could be helpful to treat dementia and other neurological conditions owing to its numerous interactions with critical proteins responsible for initiating cellular signaling pathways. Currently, the strongest evidence comes in the form of in vivo animal research.
In a particularly intriguing study published in 2009, researchers induced vascular dementia in rats, then treated some with quercetin while others received no treatment. All the rats were then introduced to the Morris water maze. The rats that were treated with quercetin exhibited the same ability to complete the maze task as healthy control rats, while the rats which weren’t treated with quercetin were incapable of completing the task, showing that they had unmitigated dementia.
There are reasons to believe that the effects of quercetin supplements wouldn’t be as night-and-day in humans as in the rats. First, while quercetin was shown to be effective at mitigating further neuronal death courtesy of vascular dementia in the rats, that dementia was caused by the researchers externally. Outside the laboratory, dementia occurs gradually and often can’t be measured consistently in the same person across short time periods. This means that quercetin might be much more effective at mitigating “acute” dementia as caused by the experimenters than it is at warding off the natural dementia experienced by human patients. Likewise, if the dementia is caused by a chronic condition like diabetes, quercetin might be able to offer more to patients than for those with dementia of another origin. The basis for this difference is that the dementia-inducing vascular damage to the brain caused by diabetes is easier to repair than chronic degeneration.
Furthermore, rats are not sound experimental models to derive magnitude of treatment efficacy; while rats are effective at modeling very basic indications of dementia like the ability to navigate through their environment, human behavior is substantially more complex. In other words, restoring the ability of a rat to navigate through a maze doesn’t necessarily translate to restoring the ability of a dementia-stricken patient to remember how to perform important daily tasks. However, the results of the in vivo study are promising and undoubtedly justify future research in humans.
Part of the reason quercetin is a compelling potential therapy for dementia is that it is proven to be bioactive via a handful of mechanisms. These mechanisms include binding to critical transcriptional regulators—the mediators of gene function—and other essential biological signaling molecules like phosphatidylinositol-3-kinase (PI-3K). The exact impact of these mechanisms on dementia symptoms is difficult to speculate on. Indeed, binding to a signaling molecule as fundamental as the PI-3 kinase would likely have systemic effects completely distinct from any of the other dementia therapies on the market. While the experimental PI-3 kinase pharmaceutical therapies are too toxic to be used in patients, quercetin is not similarly destructive. Because dementia entails a number of physiological deficits ranging from weaker axonal myelination to neuroinflammation and protein plaque formation, leveraging genetic and metabolic mechanisms increases the chances of beneficially affecting multiple pathologies. Reducing neuroinflammation via a genetic regulator, for example, could lead to improved short-term memory functionality while improved metabolic control of myelination could lead to improved motor control and arousal. As research in this area progresses, we will gain greater insight into how quercetin may affect these critical variables to support brain function.
While quercetin may be promising, it is not the only molecule capable of affecting multiple pathologies in dementia. Indeed, butyrate is widely regarded as an even more compelling approach to dementia therapy. Butyrate, also known as butyric acid, is an intracellular signaling chemical produced by the body which has anti-inflammatory and immunoregulatory effects that are highly likely to be beneficial to dementia patients. These beneficial effects are substantiated in the scientific literature, though, like with quercetin, large clinical trials are still forthcoming. Nonetheless, butyrate’s diverse physiological roles mean that it can potentially play a powerful role in the treatment of dementia.
Butyrate is naturally produced in the gut, where it is used to nourish beneficial gut microbiota and regulate the excitation of white blood cells. Increasing concentrations of butyrate lead to a suppression of inflammation as produced by these white blood cells. Because it’s common to the digestive system, butyrate is generally well-tolerated and produces few side effects. However, butyrate can cross the blood-brain-barrier and exhibit similar effects on white blood cells in the brain as well. This means that patients whose dementia symptoms are caused in part by neuroinflammation—likely a significant portion of all dementia patients—could stand to benefit from a well-formulated, highly bioavailable butyrate supplement that can act on brain tissue.
While trials in human dementia models are lacking, there are several studies in animal models that support the idea of using butyrate to ameliorate dementia via reducing neuroinflammation. In one study with rats, rats with artificial diabetically-induced vascular dementia experienced substantial improvement in a short-term memory consolidation task when treated with butyrate. This experiment was similar in setup to the earlier experiments investigating quercetin’s ability to rescue rats from induced dementia. The promising results of the butyrate study were later substantiated by a similar experiment examining vascular dementia in rats performed by a separate research group.
Unlike with quercetin, butyrate has been shown to be associated with faster learning of operant conditioning responses in rats. In one study, rats who received a butyrate supplement learned to associate a stimulus with an action that they could take to receive food as a reward with less than a third as many trials as the non-supplemented rats. This means that butyrate has the potential to improve the cognitive abilities which are affected negatively by dementia. Whether or not these results could carry over to human patients with dementia remains to be seen, but researchers are currently investigating if and how butyrate could be used in that role. With further research, physicians and patients will soon better understand the extent of butyrate’s benefits for dementia.
Butyrate, for all its potential benefits, hasn’t been studied in the brain as extensively as another physiological molecule: glutathione (GSH). Glutathione is a molecule produced by the body to use as an antioxidant, especially in the liver and the brain. While glutathione is found in many different organisms, dietary glutathione intake does little to improve health because it is readily destroyed by metabolism. This means that cells must synthesize their own glutathione supplies from precursor molecules, or, alternatively, receive glutathione which has been packaged such that it survives digestion and liver enzymes. Due to the difficulty with delivering glutathione to patients intact, research on glutathione has only recently taken off with the advent of sophisticated new drug delivery systems designed to optimize bioavailability. In light of these new advancements, researchers believe that boosting glutathione’s antioxidant activity can be a critical boon to brain health; unlike butyrate and quercetin, glutathione is a powerful antioxidant compound.
Under normal circumstances, people have high concentrations of glutathione in their bodies and in their brains. This glutathione protects cells from damage caused by oxidative stress. Oxidative stress occurs when molecular byproducts of metabolism—like reactive oxygen species—clutter cellular machinery and prevent it from performing its task. When cellular machinery can’t perform its purpose, the cell can’t perform basic self-maintenance, and gradually takes on more and more wear and tear. Eventually, this wear and tear can kill the cell. In most cases, however, the wear and tear is only sufficient to make the cell less efficient at its physiological purpose. In the case of a neuron, a cell suffering from a high amount of oxidative stress might be incapable of signaling other neurons with the same strength or frequency as is necessary to maintain normal cognition. This means that oxidative stress could potentially aggravate all of the symptoms of dementia if enough cells were affected with sufficient severity.
Glutathione has been studied in the context of dementia a number of times, with consistent results. One study, for example, linked the concentration of an enzyme responsible for trafficking glutathione to problem areas in cells with the risk of developing dementia. The researchers found that when levels of the trafficking enzyme glutathione s-transferase omega-1 were low, patients had 2.2 times the normal risk of developing dementia for any given age. Lower levels of the enzyme were also associated with a 2.1 times normal risk of having a stroke. Likewise, patients with high levels of the enzyme typically had low levels of biomarkers indicating oxidative stress, meaning that they were healthier than those with lower levels. Notably, the researchers didn’t explicitly examine glutathione, only the cellular machinery responsible for moving glutathione to problem areas. Nonetheless, the study was one out of many linking increased levels of glutathione to better patient outcomes in dementia.
Another study explicitly examined glutathione levels in relation to the dementia symptoms preceding Alzheimer’s disease. Healthy control patients had an average of 5.1 micromoles of glutathione per milliliter of blood. Patients of the same age with dementia had an average of 3.4 micromoles per milliliter of blood—only 66% as much. The authors of the study summarized the meaning of their findings succinctly: “Our results suggest that there is a defect in the antioxidant defense system [in patients with dementia] that is incapable of responding to increased free radical production, which may lead to oxidative damage and the development of the pathological alterations that characterize the neurodegenerative disorder of patients.” Interestingly, the researchers found that this effect varied depending on whether the patient was a man or a woman; men without dementia had higher glutathione levels than women without dementia, but this was reversed in the case of patients with dementia. The significance of this difference might indicate that men would benefit more from glutathione therapy than women, but further research is necessary. Glutathione therapy for dementia is under active investigation, and future findings will determine the precise symptoms of dementia that it could benefit the most.
Future Dementia Therapies
For patients seeking the next horizon of dementia therapies, quercetin, butyrate, and glutathione are exciting options which will soon be fleshed out further by researchers. Clinical trials with butyrate in a number of different neurocognitive applications are ongoing. Likewise, researchers are examining whether quercetin might be more useful in vascular dementia caused by diabetes than other forms of dementia with less certain causes. If patients wish to incorporate these compounds into their treatment plans now, there are already a number of state-of-the-art supplements on the market. While researchers endeavor to answer the many questions regarding the way that these supplements might be beneficial for dementia and other cognitive issues, patients who try them out early will have the advantage of heading off cognitive decline before those who wait for the final research verdict. Given that the current medical consensus is that dementia is irreversible once established, the potential benefits of acting early are difficult to overstate.
Carrasco MM, Agüera L, Gil P, Moríñigo A, Leon T, et al. 2011. Safety and effectiveness of donepezil on behavioral symptoms in patients with alzheimer disease. Alzheimer Disease & Associated Disorders. 25:333–340. https://journals.lww.com/alzheimerjournal/pages/articleviewer.aspx?year=2011&issue=10000&article=00007&type=abstract
Ji H-F, Li X-J, Zhang H-Y. 2009. Natural products and drug discovery. Can thousands of years of ancient medical knowledge lead us to new and powerful drug combinations in the fight against cancer and dementia? EMBO reports. 10:194–200. http://embor.embopress.org/content/10/3/194
Kolsch H, Linnebank M, Lutjohann D, Jessen F, Wullner U, et al. 2004. Polymorphisms in glutathione S-transferase omega-1 and AD, vascular dementia, and stroke. Neurology. 63:2255–2260. http://n.neurology.org/content/63/12/2255.short
Liu H, Zhang J-J, Li X, Yang Y, Xie X-F, et al. 2015. Post-occlusion administration of sodium butyrate attenuates cognitive impairment in a rat model of chronic cerebral hypoperfusion. Pharmacology Biochemistry and Behavior. 135:53–59. https://www.sciencedirect.com/science/article/pii/S0091305715001549
Ploense KL, Kerstetter KA, Wade MA, Woodward NC, Maliniak D, et al. 2014. Exposure to histone deacetylase inhibitors during Pavlovian conditioning enhances subsequent cue-induced reinstatement of operant behavior. Behavioural Pharmacology. 24:164–171. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4002259/
Puertas M, Martínez-Martos J, Cobo M, Carrera M, Mayas M, Ramírez-Expósito M, et al. 2012. Plasma oxidative stress parameters in men and women with early stage Alzheimer type dementia. Experimental Gerontology. 47:625–630. https://www.researchgate.net/publication/225184569_Plasma_oxidative_stress_parameters_in_men_and_women_with_early_stage_Alzheimer_type_dementia?_sg=uc8eam7bqQGQ2qlJaG7kXH-82N4BARCe4ox_38QkJ8_Rx74fZOb6gAcaNf5uoCjqBQ0LB8iL-w
Serban M, Sahebkar A, Zanchetti A, Mikhailidis DP, Howard G, et al. 2016. Effects of quercetin on blood pressure: a systematic review and meta‐analysis of randomized controlled trials. Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease. 5(7), e002713. http://doi.org/10.1161/JAHA.115.002713
Sharma B, Singh N. 2011. Attenuation of vascular dementia by sodium butyrate in streptozotocin diabetic rats. Psychopharmacology. 215:677–687. https://link.springer.com/article/10.1007/s00213-011-2164-0
Yao Y, Han DD, Zhang T, Yang Z. 2009. Quercetin improves cognitive deficits in rats with chronic cerebral ischemia and inhibits voltage-dependent sodium channels in hippocampal CA1 pyramidal neurons. Phytotherapy Research. 24:136–140. https://onlinelibrary.wiley.com/doi/full/10.1002/ptr.2902