Combating Cognitive Decline With Quercetin: How This Antioxidant Protects the Aging Brain

Cognitive decline tops the list of conditions our society fears most as we age — with good reason, as the idea of losing our memories, thoughts, and personalities is a devastating scenario to consider. With one in 10 Americans over age 65 and almost one-third of those over age 85 afflicted by some form of cognitive decline, researchers and patients alike are searching for ways to combat this decline. While there is no known cure for cognitive disorders, many natural compounds show promise in their brain-protecting abilities. In a recent study, researchers out of Guangzhou, China, add to the evidence that the antioxidant quercetin may be one of these compounds. 

The cellular cascade of cognitive decline

Although cognitive decline and Alzheimer’s disease stem from a myriad of potential causes, many researchers believe that inflammation and oxidative stress in the brain are at the root of these disorders. Neuroinflammation is an immune response initiated primarily by two types of cells in the central nervous system: immune cells called microglia and support cells called astrocytes that constitute the majority of the brain. While these cells are essential for brain function, they also contribute to cognitive decline and impaired brain function when overly activated. 

Like in the rest of the body, acute inflammation in the brain is necessary to promote healing after injury. If left unattended, this neuroinflammation can become chronic, leading to damage and brain-related diseases. Overactivation of a complex of proteins called the NLRP3 inflammasome is also implicated in cognitive decline, as this complex triggers a cascade of pro-inflammatory cytokines and compounds that damage brain cells. 

The second key component contributing to cognitive decline is oxidative stress in the brain, characterized by an accumulation of reactive oxygen species (ROS) or free radicals. These unstable and inflammatory compounds build up when there are inadequate antioxidants to neutralize them, causing damage to cells, proteins, and DNA.

Quercetin’s quest to protect the aging brain

Quercetin is a compound in the flavonoid family, which is a group of antioxidant-rich molecules found in fruits, vegetables, and herbs. The greatest dietary sources of quercetin are apples, onions, peppers, leafy greens, berries, asparagus, and capers, allowing quercetin to be the most commonly consumed flavonoid in the American diet. However, many people opt for quercetin supplements — typical doses range from 500 mg to 2,000 mg  — as the estimated dietary intake of quercetin only amounts to approximately 15 to 50 mg per day. 

Previous research has shown that quercetin can cross the highly selective boundary between the circulating blood and the nervous system called the blood-brain barrier, linking the compound to improved brain health and cognition. Due to its antioxidant properties, quercetin reduces ROS levels, which contribute to inflammation and neuron dysfunction when accumulated in the brain. 

In addition to providing potent antioxidant activity, quercetin shows promise as an anti-aging compound, as it boosts levels of SIRT1, a protein in the sirtuin family that regulates longevity. Increased SIRT1 activity is thought to be protective in brain-related disorders, as the protein is highly active in neurons and plays a role in memory formation. Additionally, patients with Alzheimer’s disease or mild cognitive impairment exhibit significantly lower levels of SIRT1. 

With this knowledge, Li and colleagues authored a study published in Food and Function in December 2020 that aimed to discover if quercetin could combat cognitive decline by protecting the brain from inflammation, reducing oxidative stress, and increasing SIRT1 activity in aging mice. 

From boosting memory to battling inflammation, quercetin reigns queen

In addition to a control group of healthy mice, the research team used 7-month old mice who were genetic models of age-related cognitive impairment. The aging mice were then separated into three groups: aging without treatment, aging with low-dose of quercetin (QL; 35 mg/kg), and aging with high-dose of quercetin (QH; 70 mg/kg). Based on the average human body weight of 62 kg (136.4 pounds), the low- and high-doses of quercetin would translate to 2170 mg and 4340 mg, respectively.

After four weeks of treatment, mice who received supplemental quercetin exhibited improvements to several aspects of brain health. On tests of spatial learning and memory, both the QL and QH groups had improved scores, with QH improving slightly more. As a common early symptom of Alzheimer’s disease is memory impairment, especially with short-term memory and learning retention, these results indicate that quercetin may be able to mitigate this decline.

Quercetin also reduced oxidative stress and inflammation in the hippocampus — the area of the brain related to memory and learning — as seen by lower levels of ROS and the lipid oxidative marker malondialdehyde (MDA), as well as reduced activity of pro-inflammatory cytokines. 

Three other proteins were measured that are involved with brain health: brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and postsynaptic density protein 95 (PSD95). This trio of compounds is essential for the growth, survival, and maintenance of neurons and helps strengthen neuroplasticity — the brain’s ability to grow and adapt by forming new neural connections. Quercetin treatment reversed hippocampal neuron loss and ameliorated the decreases of BDNF, NGF, and PSD95 seen in the aging mice, especially in the high-dose group. 

Quercetin treatment also increased SIRT1 activity and prevented the rise of the NLRP3 inflammasome seen in the aging mice with cognitive impairment. As expected, the aging mice showed lower levels of SIRT1 than the healthy controls. Quercetin effectively reversed this decline; mice in both the QL and QH groups had hippocampal SIRT1 levels that were comparable to the control group after the 4-week supplement period. 

Lastly, the QH group exhibited reduced levels of a marker of astrocyte activity in the hippocampus, indicating that higher doses of quercetin may prevent the overactivation of astrocytes that triggers inflammation. As previous research has found that impaired astrocyte function accelerates aging in the brain, these results add to the mounting evidence of using quercetin to prevent cognitive decline. 

However, despite these promising results in animals, quercetin supplementation trials with humans have not always produced the same beneficial cognitive outcomes. This discrepancy could be because quercetin has low bioavailability in the human gut — meaning, it’s difficult for our bodies to effectively digest and absorb it. Additionally, although quercetin can pass through the blood-brain barrier, the penetrability of the compound reaching the brain may be too low to affect cognition. Future research will likely need to address these shortcomings before we see the same cognitive improvements in humans. As supplemental quercetin is safe and poses a low risk, there is likely no harm in taking it — but you could also try upping your apple and onion intake, too.

References: 

Costa LG, Garrick JM, Roquè PJ, Pellacani C. Mechanisms of Neuroprotection by Quercetin: Counteracting Oxidative Stress and More. Oxid Med Cell Longev. 2016;2016:2986796. doi:10.1155/2016/2986796

Kumar R, Chaterjee P, Sharma PK, et al. Sirtuin1: a promising serum protein marker for early detection of Alzheimer's disease. PLoS One. 2013;8(4):e61560. Published 2013 Apr 16. doi:10.1371/journal.pone.0061560

Li H, Chen FJ, Yang WL, Qiao HZ, Zhang SJ. Quercetin improves cognitive disorder in aging mice by inhibiting NLRP3 inflammasome activation [published online ahead of print, 2020 Dec 18]. Food Funct. 2020;10.1039/d0fo01900c. doi:10.1039/d0fo01900c