As our population ages, Alzheimer’s disease is becoming increasingly prevalent in the United States and around the world. Unfortunately, the complexity of multifactorial symptoms means that effective treatment remains elusive; at present, there is no pharmacological therapy that is proven to halt the neurodegenerative effects of Alzheimer’s disease. Nonetheless, there are a number of treatment regimens that may provide some temporary improvements in cognitive abilities, and researchers are continuously investigating therapeutic combinations that may slow or stop the disease’s progression.
While conventional pharmaceuticals have historically been the primary site of inquiry, advancements in alternative and complementary medicine along with growing integration of such therapies in mainstream practice have led researchers to increasingly turn their attention to the potential benefits of these interventions when paired with conventional treatments. Of particular interest have been dietary interventions and nutraceutical therapies, including brain health supplements that pair nutritional supports with pharmaceutical-grade delivery mechanisms and encapsulants. Until recently, however, there were few investigations directly comparing the efficacy of these therapies. Now, that is changing.
In late 2015, Drs. Alessia Giulietti, Arianna Vignini, Laura Nanetti, and Mazzanti Laura of the Universita Politecnica delle Marche in Italy performed an extensive review of randomized controlled trials on nutritional supplements and dietary interventions for Alzheimer’s, seeking to identify those therapies which best improve outcomes, particularly when used alongside conventional treatment. Published in DNA Research, their report sifts through the vast amount of contradictory information within the field to identify a number of brain health supplements that may provide rays of hope for patients when integrated with the current standard of care.
The Shortcomings of Pharmaceutical Treatment Options for Alzheimer’s
Conventional pharmacological treatment of Alzheimer’s disease focuses on either increasing or decreasing the concentration of certain key neurotransmitters in the brain to compensate for the neurotransmitter abnormalities associated with the condition. The pharmaceuticals that are currently indicated for treating Alzheimer’s are acetylcholinesterase inhibitors (AchE inhibitors) and NMDA receptor antagonists (NMDARAs). While each of these drug classes may be used in alone, Giulietti’s group notes that the best outcomes are achieved when they are used in combination:
Within the healthy brain, acetylcholine is a neurotransmitter responsible for triggering neurons to consolidate memories, among many other functions. In patients with Alzheimer’s, however, acetylcholine is either produced in a lower quantity or cleared more rapidly than in healthy people, leaving a deficit that compromises memory formation and produces a number of other cognitive impairments. AchE inhibitors seek to enhance cognitive functioning in patients with Alzheimer’s by increasing the amount of the acetylcholine at the synapses between neurons.
According to Dr. Giulietti and her peers, patients who take AchE inhibitors typically experience improvements in visual memory and cognitive ability. However, these improvements are small. One study found that on a 70-point Alzheimer’s severity scale, treatment with AchE inhibitors reduced patient scores by an average of only 2.4 points. Thus, while there is an effect, AchE inhibitors alone are direly insufficient for addressing Alzheimer’s symptomatology.
Research also indicates that not all patients experience improvement of symptoms and efficacy is highly reliant on the patient’s genotype. If patients have a certain uncommon mutation, their response to AchE inhibitor treatment will be greater; if they have a different uncommon mutation, their response will be weaker. Additionally, treatment adherence may be compromised by tolerability issues, as up to 10% of patients experience nausea and vomiting while on AchE inhibitors.
NMDA Receptor Antagonists
NMDA is a neurotransmitter associated with synaptic plasticity, learning, and memory. In patients with Alzheimer’s, NMDA activity is significantly higher than in healthy people, interfering with these functions and eventually causing increased concentrations of calcium inside of neurons, producing cellular damage. NMDARA class drugs, which are prescribed for moderate to severe Alzheimer’s, reduce the ability of NMDA to cause physiological changes in the brain and prevent this damage. Giuletti observes that these drugs likely also have a second mechanism of action affecting neurons’ phosphate metabolism. However, this mechanism is mostly undescribed.
Unfortunately, the efficacy of NMDARAs is comparable to the AchE inhibitors in terms of their ability to reduce patient Alzheimer’s severity scale scores—which is to say, they are not very effective. They also don’t slow the progression of the disease.
In addition to prescription pharmaceuticals, Giulietti’s review investigates studies that examined the use of supplemental metals like calcium and magnesium in the course of treating Alzheimer’s to overcoming some of the shortcomings of conventional treatment. Giulietti finds magnesium supplements to be potentially useful for improving the quality of life of patients as a result of magnesium’s calming effect. However, magnesium is insufficient to reverse the disease’s progression in humans. The reason magnesium still has a role is that it can address malnutrition.
Giulietti finds that the conditions of malnutrition result in critical shortages of magnesium and calcium, both of which have significantly detrimental effects on the brain’s ability to function in the context of Alzheimer’s. When these minerals are depleted, neurons become incapable of transmitting action potentials to other neurons, and the brain’s activity drops precipitously as a result. In effect, malnutrition multiplies the severity of the symptoms of Alzheimer’s. Malnutrition is more common in mid to late-stage Alzheimer’s, when patients may forget to eat or be unable to feed themselves.
Despite the potential to compensate for malnutrition, Giulietti finds the research supporting the use of mineral supplementation beyond that required to maintain health scant. Of the studies examined in the review, none could show efficacy alone or in conjunction with other supplements and pharmaceuticals. Nonetheless, there is a study performed in mice which suggests supplementation with magnesium can prevent the progression of Alzheimer’s and restore lost functionality, though this study has not yet been replicated. The takeaway message from Giuletti’s review is that magnesium and calcium supplementation will stave off the detrimental effects of malnutrition, but will do little to slow the progression of Alzheimer’s or improve cognitive symptoms.
Due to their role in preventing damage caused by oxidation of neuronal tissues, antioxidants are under active investigation for their potential ability to reverse impairment in Alzheimer’s, possibly enhancing overall outcomes. As Dr. Giulietti writes, “Since oxidative stress and inflammation appear to be involved in brain aging and in neurodegenerative diseases, it is theorized that an increased intake of antioxidants could be effective in preventing or ameliorating these changes.” Of these antioxidant compounds, the most studied is vitamin E.
Vitamin E is a controversial supplement for Alzheimer’s disease because its effects are proven in the laboratory but utterly inconsistent when used in a clinic with patients. For every methodologically sound study that found a beneficial effect of vitamin E, there is another study that contradicts it. Even in studies with positive results, the effect of vitamin E was typically minor.
One study cited by Giulietti’s review shows that long-term vitamin E supplementation reduced the chances of developing Alzheimer’s by 56%, but a significant number of research subjects who aggressively supplemented with vitamin E still developed Alzheimer’s which then progressed at normal speed. Giulietti’s group also points out that one study on vitamin E unintentionally caused the disease to progress faster in a subset of their cohort. This suggests that, as with metal supplements, insufficient vitamin E intake will make cognitive symptoms much worse, but a glut of vitamin E won’t make symptoms any better for those who are nourished and may even possibly exacerbate symptoms. This makes the regulatory environment for research into vitamin E very difficult, despite the fact that many studies document no side effects whatsoever.
Antioxidants derived from fruit could potentially instigate improvement of Alzheimer’s symptoms based on the amount consumed. Figs, blackberries, blueberries, red wines, and black currants have each respectively been studied for their high antioxidant content and there is some evidence that they may have positive effects; in a mouse study examined by Giulietti, consuming this subset of antioxidants in fruits was associated with decreased cognitive impairment and increased life expectancy. However, correlating the results to human patients is difficult for a disease as complex as Alzheimer’s.
While it isn’t possible to stop the progression of Alzheimer’s disease by eating fruit, dietary supplementation with the antioxidants derived from these fruits is an area of active investigation based on the promise of animal studies. Further experimentation will be necessary to identify the exact compounds responsible for the most effective symptom remission and isolate those compounds to form supplements.
Fruit antioxidants aren’t the only ray of hope for Alzheimer’s patients who do not respond to conventional treatment. A number of multi-chemical nutraceutical therapies have been developed that combine vitamins, fats, and minerals in an attempt to provide a comprehensive supplement for Alzheimer’s that may be used to complement conventional treatment. Patients can take one dose of these compound nutraceuticals each day, which reduces the chance of non-adherence brought on by multiple supplements. Of the nutraceuticals that claim to be helpful for Alzheimer’s disease, Giulietti’s review only discusses the most popular one, called Souvenaid.
Souvenaid has been studied extensively in the context of Alzheimer’s treatment and comes in a drinkable formulation that patients take after a meal. Souvenaid contains fatty acids which behave as antioxidants, precursors to acetylcholine, and uridine. By providing the patient with more of the essential building blocks for neuronal repair, the hope is that the neurons make use of the glut of resources and evidence of efficacy exists in both animal and human studies. According to one study cited by Giulietti, Souvenaid enhanced memory function in patients with mild Alzheimer’s by 21% based on neuropsychological test battery memory scores. However, these improvements were short-lived, as Souvenaid failed to slow the progression of the disease. Additionally, the behavioral symptoms and sleep difficulties associated with Alzheimer’s continued to worsen over time.
Emerging Brain Health Supplements for Alzheimer’s
The conclusion of Giulietti’s review crystallizes the multifactorial approach that doctors will need to take in addressing Alzheimer’s, as multiple treatments are currently necessary to address the many symptoms of the disease insufficiently resolved by conventional therapies. Giulietti’s group identifies a number of potentially promising complementary interventions that may be used to enhance treatment outcomes while steering clinicians and patients away from treatments without empirical backing. However, with the advent of rapidly emerging research, Giulietti’s review is already incomplete. Supplements like butyric acid, for example, are currently being investigated by a growing number of researchers for their unique approach to potentially restoring memory functionality in Alzheimer’s patients.
While butyric acid is a chemical known for its many physiological roles in the gut, it may also offer an innovative approach to treating Alzheimer’s. This approach is grounded in the ability of butyric acid to inhibit the action of the histone deacetylase enzyme, regardless of where it is in the body. Histone deacetylase blocks memory formation by preventing the DNA responsible for memory formation from being used by neurons, giving it a potentially critical role in the development and progression of Alzheimer’s; a forensic study revealed highly elevated concentrations of neural histone deacetylase in Alzheimer’s patients. By disrupting histone deacetylase activity, butyric acid could thus prevent its interference with memory formation, alleviating Alzheimer’s symptoms and possibly slowing disease progression.
Much like other nutraceuticals indicated for Alzheimer’s disease, butyric acid treatment needs significant future investigation before researchers can develop exhaustive guidelines for use; in many ways, experimentation with brain health supplements for Alzheimer’s is just beginning. However, due to its potential to enhance memory function, butyric acid may have a place in the combination therapies that cutting-edge clinical practices are increasingly using to treat patients. While butyric acid supplementation is still new, researchers find it promising and are investigating it further, particularly as more advanced delivery systems are developed to improve bioavailability and augment therapeutic benefit. Thanks to its solid theoretical basis and high tolerability, some patients are already using butyric acid alongside conventional Alzheimer’s treatment as they seek to minimize the impact of the disease and enjoy a better quality of life.
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