Updated on February 14, 2023
Alzheimer’s disease remains a debilitating and tragic disorder despite decades of scientific research attempting to find treatments and cures. Even with the advent of new drugs designed to slow the progression of the disease, patients and doctors alike are still looking for ways to stave off its onset and limit the severity of its cognitive effects. Patients now have reason to be hopeful, however. In the hunt for effective therapy, scientists are exploring a new therapeutic molecule: quercetin.
Quercetin is a molecule produced by a variety of plants, including grains, onions, and leafy greens. It’s also a member of the bioactive flavonoid family of molecules. Like other flavonoids, quercetin is metabolized easily by humans and has a variety of physiological effects ranging from scavenging reactive oxygen species to helping maintain the body’s normal inflammatory response. Importantly, many flavonoids like quercetin have effects that suggest they’re useful in helping maintain cognition in those affected by neurodegenerative diseases.
These effects were first documented in a seminal 2008 paper by Drs. David Vauzour, Katerina Vafeiadou, Ana Rodriguez-Mateos, Catarina Reneiro, and Jeremy Spencer from the University of Reading in England. The researchers’ collation of prior research into flavonoids is directly applicable to quercetin and is one of the few comprehensive summaries of flavonoids’ impact on cognition as portrayed in the scientific literature. The researchers’ analysis cites a handful of other studies on flavonoids sourced from many different plants, finding that the source of the flavonoid doesn’t appear to change their physiological effects. In their research summary, the authors tie together countless pieces of information that, taken together, indicate that if patients obtain the right sources of quercetin and other flavonoids, they can possibly slow down the rate of cognitive decline caused by old age. Significantly, they’ll also promote the ability of their neurons to resist the ravages of dementia that are typical in Alzheimer’s disease.
Flavonoids have a number of beneficial physiological effects; in particular, supporting the body’s natural inflammatory response and neuronal health. In their synthesis of the research on flavonoids, Dr Vauzour’s group approached the neuroprotective properties of flavonoids as their primary point of inquiry. The researchers divided the beneficial properties of flavonoids into three separate but related phenomena, as identified by several other studies examining flavonoid class molecules:
Although functionally discrete, each phenomena is caused by activation of the same physiological mechanisms. This means that flavonoids consumed from any source will be beneficial in all three instances.
The mechanisms of these beneficial effects are the inhibition of cell death and the promotion of blood vessel formation. The former is particularly important, because inhibition of cell death occurs via flavonoids’ interaction with certain enzymes used in cell signaling; when cells are exposed to flavonoids, they don’t send each other chemical signals that trigger cell death, which means that cells destroy themselves less frequently. Additionally, the promotion of new blood vessel formation promotes the resiliency and functionality of tissues by enabling greater oxygenation. Taken together, these effects might have a significant beneficial impact on the symptoms of Alzheimer’s disease.
Of the mechanisms responsible for flavonoids’ neuroprotective effects, the impact on cell death signals is potentially the most useful, because decreasing cell death signaling leads to better neuronal survival. When the glial cells that are responsible for supporting the brain’s neurons are exposed to flavonoids, their production of the cell death signal protein, tumor necrosis factor alpha (TNFa), is inhibited. Because TNFa is linked to up-regulating the brain’s inflammatory response, its inhibition can help maintain the brain’s normal inflammatory response. Increased levels of inflammation are linked to worsening Alzheimer’s symptoms. These combined beneficial effects mean flavonoid supplementation might cause neurons to self-destruct less frequently and perform more efficiently than they would otherwise in an inflamed state.
Neuronal persistence is particularly crucial for Alzheimer’s patients. As part of the main pathology of Alzheimer’s, clumps or “plaques” of a harmful protein called beta-amyloid accumulate inside neurons and inhibit their function, eventually killing them. As increasingly more neurons die, cognitive functions, memory consolidation, and memory recall are hampered. The Vauzour researchers optimistically discussed the ability of flavonoids to limit the cellular death caused by exposure to beta-amyloid plaques, as observed in several validated in vitro studies.
A year after the Vauzour researchers substantiated the connection between the entire class of flavonoid molecules and resistance against beta-amyloid-induced cellular death, another group of researchers from the University of Kentucky published a paper documenting their results examining quercetin. This research cohort performed extensive in vitro investigations of quercetin’s impact on cultured neurons exposed to beta-amyloid. The results were compelling: neurons treated with small quantities of quercetin experienced lower cytotoxicity, lower oxidative stress, and 33 percent less cell death when exposed to beta-amyloid plaques compared to cells that weren’t treated. The samples treated with quercetin also exhibited 75-percent fewer proteins associated with Alzheimer’s-induced cellular damage.
Quercetin was not uniformly helpful, however. When the Kentucky researchers tested the impact of extremely high concentrations of quercetin, they found that its protective effect disappeared. However, reaching these concentrations would not be possible by consuming quercetin from foods alone due to the speed at which quercetin is metabolized, which means that patients would be unlikely to encounter this effect. Although the researchers’ findings were promising, their experiments were limited to cell cultures, which prevented them from speculating about in vivo effects. Their work has subsequently been confirmed by numerous other researchers.
Although Dr. Vauzour’s primary area of interest was Alzheimer’s disease, literature reviews also makes a compelling case for the therapeutic applications of flavonoids for other neurological diseases. Dr. Vauzour’s group discussed several studies that linked flavonoid consumption to better patient outcomes in dementia, Parkinson’s disease, and even depression. Significantly, several of these studies were in vivo investigations with large patient cohorts.
One notable example cited by Dr. Vauzour’s review examined 1,640 subjects who were healthy and without dementia. The study followed the subjects for 10 years, performing cognitive testing and frequently surveying the subjects’ diets. With a very high degree of confidence, the results showed that individuals with higher flavonoid intake exhibited better cognitive performance than those with lower flavonoid intake. This effect was exaggerated when the researchers compared the group with the lowest self-reported flavonoid intake with the group who reported the highest. Earlier research had found the same relationship.
At the conclusion of the study, the researchers found that the difference in cognitive performance between the groups was nearly a full point on the Mini-Mental State Examination. The Mini-Mental State Examination is used as a tool to aid in the diagnosis of dementia and is scored out of 30 points. After controlling for all potential confounding variables, the benefit of flavonoids persisted in the data; the high flavonoid intake group scored on average 0.9 points higher than the low flavonoid intake group. This means that flavonoids might be able to limit the damage caused by Alzheimer’s disease in addition to helping patients maintain a greater degree of cognition in the course of normal aging. Other studies with large patient cohorts have subsequently confirmed this phenomenon. Although Dr. Vauzour’s group was enthusiastic about the safety and potential of flavonoid therapeutics, they did outline one concern: “In order for flavonoids to access the brain, they must first cross the blood-brain barrier, which controls entry of xenobiotics into the brain.” In short, the research group was concerned about flavonoid bioavailability. After examining relevant research, the authors subsequently conclude that, “flavonoids traverse the blood-brain barrier and are able to localize in the brain, suggesting that they are candidates for direct neuroprotective and neuromodulatory actions.”
Flavonoids like quercetin could hold the key to slowing the progression of neurodegenerative diseases. As the researchers note, flavonoids are surprisingly ideal for therapeutic use because, unlike most pharmaceutical molecules, they can easily cross the blood-brain barrier without being modified. However, flavonoids can’t be reliably stored or distributed in the body because they are metabolized by multiple organs at an extremely high rates; although some of the metabolites are also bioactive, they are likewise broken down quickly.
Due to the rapid and comprehensive way the body breaks down quercetin and other flavonoids, their physiological impact is limited. This problem is compounded by the fact that most foods that contain flavonoids have far fewer flavonoid molecules than the quantities necessary to produce the beneficial effects seen in in vitro studies. As such, supplementation will be necessary for patients who want to add quercetin as an alternative therapy, and these supplements must be formulated to compensate for the metabolic barriers of the molecule and ensure bioavailability.
The picture created by Dr. Vauzour’s group is clear: if flavonoids, such as quercetin, can be formulated to be bioavailable, then it will be much easier for patients with Alzheimer’s, dementia, and other neurological conditions to access their benefits. Already, scientists are developing advanced new delivery systems that can survive first-pass metabolism and control the distribution of quercetin to achieve therapeutic concentrations. If patients want a therapeutic edge against Alzheimer’s that spans multiple aspects of the disease’s impact, then finding a highly bioavailable quercetin supplement is an excellent place to start.
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