When it comes to the treatment of Alzheimer’s disease, there’s no denying that the currently available treatments are suboptimal. So far, the FDA has only approved two classes of drugs for Alzheimer’s disease—cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists—and studies show that pharmacological treatment with these drugs only contributes “modest improvements” in efforts to relieve symptoms and slow the progress of the disease. As practitioners, patients, and families grow increasingly frustrated with the limited results of pharmacological, researchers have started exploring all-natural alternatives, including polyphenolic compounds derived from plant extracts.
For years, polyphenolic compounds have been recognized for their anti-inflammatory and antioxidant properties. They are also known to support cardiovascular function, which is relevant for Alzheimer’s disease patients because there is a growing body of evidence suggesting a link between cardiovascular health and the progression of the disease. In light of the literature on the bioactivity of polyphenols, researchers have begun to seriously consider supplementation as an alternative treatment for Alzheimer’s disease. In pre-clinical studies, two of the polyphenols that have shown particular promise are Epigallocatechin-3-gallate (ECGC) and quercetin.
Early Evidence of the Therapeutic Benefits of ECGC Supplementation
ECGC is a polyphenolic compound that is best known as the most abundant polyphenolic extract in green tea. So far, in vitro studies show that it can play a role in a variety of biological processes, but there are three ways in which it may particularly benefit patients with Alzheimer’s disease: reducing oxidative stress, attenuating neuroinflammation, and preventing the alteration of neurogenesis (that is, the creation of new brain cells in adults). According to a model developed based on the existing lab research, these activities should help prevent the enlargement of the ventricles and the atrophy of the cerebral cortex and the hippocampus, all of which are key structural changes that have been observed in the brains of patients with Alzheimer’s disease.
Indeed, a pre-clinical animal study from 2017 provided strong support for this proposed model. A group of researchers at Xi’an University in China were able to demonstrate that in a mouse model of Alzheimer’s disease, oral supplementation with ECGC could prevent structural changes in the brain. Without supplementation, this mouse model displays abnormalities in synaptic protein levels in both the frontal cortex and the hippocampus. However, the study showed that long-term ECGC therapy (15 mg/kg per day) could restore these levels, as measured by the reversal of the decreases in two different synaptic protein biomarkers. Moreover, these structural changes in the brain were coupled with notable behavioral effects; the mice that were treated with ECGC performed significantly better on maze tests that measured memory and spatial learning ability.
There is also pre-clinical evidence that ECGC supplementation can be even more effective when coupled with exercise, which is an exciting finding for patients who are interested in activity-based alternative treatments for Alzheimer’s disease. In 2015, a group of researchers from the University of Missouri conducted a study in which mouse models were subjected to four months of wheel-running exercise, combined with daily supplementation of ECGC (50 mg/kg per day). This led to significant decreases in the levels of amyloid beta plaque buildup (a hallmark of Alzheimer’s disease) in the cortex and hippocampus. The dual ECGC+exercise therapy also had key behavioral impacts: the mouse models that received the intervention did not demonstrate the same behavioral deficits as the untreated Alzheimer’s mouse models in maze tests (which measured memory) and nest-building tests (which measured anxiety levels).
Not only do these results suggest that ECGC can directly ameliorate the symptoms of Alzheimer’s disease, but it also supports the hypothesis that the cardiovascular effects of ECGC may further contribute to its impacts. Exercise is a known mediator of cardiac function, so its effectiveness for addressing Alzheimer’s disease symptoms suggests that the cardiovascular benefits of ECGC may be indirectly supporting reductions in Alzheimer’s disease progression. This would mean that ECGC and other polyphenolic compounds could help fight Alzheimer’s in two ways: through direct effects on the brain and through indirect effects on the cardiovascular system.
Quercetin: An Emerging Alternative Treatment for Alzheimer’s Disease
Like ECGC, quercetin is a polyphenolic compound that has shown considerable promise as an alternative treatment for Alzheimer’s disease in pre-clinical studies. Again, the potential of quercetin supplementation is underpinned by evidence of structural changes in mouse brains and by corresponding behavioral changes. In a study from 2015, researchers treated a mouse model of Alzheimer’s disease with quercetin (25 mg/kg per day for three months), and their extensive histological studies (that is, studies of the changes in mouse brain tissues) indicated that supplementation led to the attenuation of some of the hallmarks of Alzheimer’s disease, including the accumulation of beta-amyloid plaques, damage to astrocytes and microglia (two types of brain cells) in these brain structures in the amygdala and hippocampus, and declines in the presence of certain Alzheimer’s disease-associated proteins. These effects were observed alongside improvements on behavioral tests of both cognitive and emotional function, which would make quercetin an ideal treatment alternative for Alzheimer’s disease patients and practitioners who are looking for a comprehensive solution.
While there is broad speculation that the anti-inflammatory and antioxidant effects are at the core of quercetin’s effectiveness for treating Alzheimer’s disease as a polyphenolic compound, new research suggests that it may also be working through other molecular pathways. For instance, a 2016 study from Xiamen University in China suggests that quercetin supplementation may increase levels of Apolipoprotein E (ApoE) in a way that reduces amyloid plaque buildup. ApoE is a cholesterol carrier protein, and high cholesterol is a known risk factor for Alzheimer’s disease, so the researchers propose that improving cholesterol metabolism is a novel mechanism through which quercetin can address Alzheimer’s disease. Moreover, the findings provide further evidence of a link between polyphenol supplementation, cardiovascular health, and Alzheimer’s disease treatment. Because polyphenolic compounds like quercetin may indirectly slow Alzheimer’s disease progression by supporting heart health (in addition to their direct actions in the nervous system), these supplements may be more effective than treatment options that only target the brain.
From Pre-Clinical Studies to Rigorous Clinical Research: First Steps and Future Possibilities
So far, there have been no major clinical studies supporting the effectiveness of ECGC or quercetin in patients with Alzheimer’s disease. Although there was one double-blind, placebo-controlled study on resveratrol, a similar polyphenolic compound that has shown promise for treating Alzheimer’s disease in pre-clinical studies, the preliminary clinical results were inconclusive. The researchers found that the supplements were safe and well-tolerated (no surprise, given that polyphenolic supplements are derived from plant extracts), but more research is necessary before researchers can confidently confirm the efficacy of the supplements.
In the future, it will be important for researchers to conduct rigorous clinical trials on both ECGC and quercetin while continuing to probe the mechanisms through which they may be benefiting patients. At the same time, given the frustrating outcomes of conventional treatments and the promising laboratory evidence of polyphenolic supplements, patients and practitioners may also want to start trying these supplements out for themselves in order to see if they may support improvements in individual symptoms where other drugs have failed.
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