Updated on February 2, 2023
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 an effective therapy 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 regimens that support healthy cognition, and researchers are continuously investigating therapeutic combinations.
Although conventional pharmaceuticals have historically been the primary site of inquiry, advancements in alternative and complementary medicine along with the growing integration of such therapies in mainstream practice have led researchers to increasingly turn their attention to the potential benefits of these modalities when paired with conventional therapies. Of particular interest are dietary interventions and nutritional supplements, including brain health supplements that pair nutritional support 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 with positive outcomes, particularly when used alongside conventional therapies. 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 might provide benefit for patients when integrated with the current standard of care.
Conventional pharmacological therapy for 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 currently indicated for addressing Alzheimer’s are acetylcholinesterase inhibitors (AchE inhibitors) and NMDA receptor antagonists (NMDARAs). Although each of these drug classes can be used 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 individuals, leaving a deficit that compromises memory formation and produces a number of other cognitive impairments. AchE inhibitors seek to enhance cognitive functioning in Alzheimer’s patients by increasing the amount of acetylcholine at the synapses between neurons.
According to Dr. Giulietti and her peers, patients who take AchE inhibitors typically experience better visual memory and cognitive ability. However, these benefits are small. One study found that on a 70-point Alzheimer’s severity scale, introducing AchE inhibitors lowered patient scores by an average of only 2.4 points. Thus, while there is a beneficial effect, AchE inhibitors alone are insufficient for addressing Alzheimer’s symptomatology.
Research also indicates that not all patients experience similar outcomes, and efficacy is highly reliant on the patient’s genotype. If patients have a certain uncommon mutation, then their response to AchE inhibitors will be greater; if they have a different uncommon mutation, then their response will be weaker. Additionally, therapy adherence can be compromised by tolerability issues, because up to 10 percent of patients experience nausea and vomiting while on an AchE inhibitor.
NMDA is a neurotransmitter associated with synaptic plasticity, learning, and memory. In Alzheimer’s patients, NMDA activity is significantly higher than in healthy individuals, interfering with these functions and eventually causing higher concentrations of calcium inside of neurons, producing cellular damage. NMDARA class drugs, which are prescribed for moderate to severe Alzheimer’s, limit the ability of NMDA to cause physiological changes in the brain and avoid this damage. Giuletti et al observe 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 AchE inhibitors in terms of their ability to lower 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, the Giulietti et al review investigates studies that examined the use of supplemental metals, like calcium and magnesium, for addressing Alzheimer’s. Giulietti et al 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. Magnesium still has a role, however, because it can address malnutrition.
Giulietti et al find 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 forget to eat or are unable to feed themselves.
Despite the potential to compensate for malnutrition, Giulietti et al 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 that suggests supplementation with magnesium can limit the progression of Alzheimer’s and restore lost functionality, although this study has not yet been replicated. The takeaway message from the Giuletti et al 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 address cognitive symptoms.
Due to their role in limiting damage caused by oxidation of neuronal tissues, antioxidants are under active investigation for their potential ability to mitigate impairment in Alzheimer’s, possibly enhancing overall outcomes. As Giulietti et al write, “Since oxidative stress and inflammation appear to be involved in brain aging and in neurodegenerative diseases, it is theorized that higher intake of antioxidants could be effective in [...] ameliorating these changes.” Of these antioxidant compounds, the most studied is vitamin E.
Vitamin E is a controversial therapy for Alzheimer’s disease because its effects are proven in the laboratory but 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 is typically minor.
One study cited by the Giulietti et al review shows that long-term vitamin E supplementation lowers the chances of developing Alzheimer’s by 56 percent, but a significant number of research subjects who aggressively supplemented with vitamin E still developed Alzheimer’s, which then progressed at normal speed. Giulietti et al also point out that one study on vitamin E unintentionally caused the disease to progress faster in a cohort subset. This suggests that, as with metal supplements, insufficient vitamin E intake will make cognitive symptoms worse, but a glut of vitamin E won’t make symptoms better for individuals who are nourished and might even possibly exacerbate symptoms. This makes the regulatory environment for research into vitamin E difficult, despite the fact that many studies have documented no side effects whatsoever.
Antioxidants derived from fruit could potentially address 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 they have positive effects; in a mouse study examined by Giulietti et al, consuming this subset of antioxidants in fruits is associated with restricted cognitive impairment and higher 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 formulate supplements.
Fruit antioxidants aren’t the only ray of hope for Alzheimer’s patients who do not respond to conventional therapies. A number of multi-chemical nutritional supplement therapies have been developed that combine vitamins, fats, and minerals to provide a comprehensive supplement for Alzheimer’s patients that can be used to complement conventional therapies. Patients can take one dose of these compound nutritional supplements daily, which lowers the chance of non-adherence occasioned by multiple supplements. Of the nutritional supplements that claim to be helpful for Alzheimer’s disease, the Giulietti et al review only discusses the most popular one, called Souvenaid.
Souvenaid has been studied extensively in the context of Alzheimer’s therapies and comes in a drinkable formulation that patients take after a meal. Souvenaid contains fatty acids that behave as antioxidants, precursors to acetylcholine, and uridine. By providing the patient with more of the essential building blocks for neuronal repair, the expectation 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 et al, Souvenaid enhanced memory function in patients with mild Alzheimer’s by 21 percent based on neuropsychological test battery memory scores. However, these results were short-lived, because Souvenaid failed to slow the disease progression. Additionally, the behavioral symptoms and sleep difficulties associated with Alzheimer’s continued to worsen over time.
The conclusion of the Giulietti et al review crystallizes the multifactorial approach that doctors should take in addressing Alzheimer’s, because multiple therapies are currently necessary to address the multiple symptoms of the disease insufficiently resolved by conventional therapies. Giulietti et al identify a number of potentially promising complementary interventions that can be used to enhance outcomes while steering clinicians and patients away from therapies without empirical backing. However, with the advent of rapidly emerging research, the Giulietti et al 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 achieving cognitive benefits in Alzheimer’s patients.
Although butyric acid is a substance known for its many physiological roles in the gut, it might also offer an innovative approach to addressing 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 keeping 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 limit its interference with memory formation.
Much like other nutritional supplements indicated for Alzheimer’s disease, butyric acid 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 will likely have a place in the combination therapies that cutting-edge clinical practices are increasingly using. 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 enhance 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 therapies in their fight against the disease.
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