Depression, dementia, and Alzheimer’s disease are linked to oxidative stress in the brain

- and antioxidants like selenium, Q10, and melatonin play a role in prevention and treatment

There is a link between depression, dementia and Alzheimer’s disease. Also, it appears that chronic stress contributes to oxidative stress and brain cell damage. In a review article that is published in the science journal Antioxidants, researchers look closer at how oxidative stress affects the brain. They also study how antioxidants can be included in the prevention and treatment of Alzheimer’s disease, and why the most promising results are seen with selenium, Q10, melatonin, vitamin E, turmeric, and polyphenols. With regard to depression, selenium, zinc, vitamin E, turmeric, and saffron have demonstrated the greatest potential.

Depression is one of the most widespread mental disorders and affects more than 264 million people worldwide. Of these, nearly 800,000 people commit suicide every year.
Alzheimer’s disease, which is also very common, is an insidious disease and is the leading cause of dementia. As it progresses, plaque from a protein named beta-amyloid accumulates in the brain. As time passes, this destroys the brain cells that are also known as neurons. Scientists studying Alzheimer’s disease have observed insulin resistance in the brain which is why this ailment is also termed type 3 diabetes.
Epidemiological studies show that depression increases the risk of cognitive impairment and dementia. These symptoms typically occur in the final stage of Alzheimer’s disease. According to the new review article, both depression and Alzheimer’s disease are linked, more or less, to the following:

• Chronic stress, which leads to oxidative stress in the brain
• Strain on the hypothalamus-pituitary-thyroid-axis that increases the production of the stress hormone cortisol
• Atrophy of the hippocampus, the part of the brain that is responsible for memory and orientation
• Degeneration of the neuronal synapses, which impairs the communication of the nervous system
• Dysfunctions of neurotransmitters such as serotonin and dopamine that are important for our mood
• Disruptions of the BDNF protein (Brain Derived Neurotrophic Factor) that affects neurons and nerve cells throughout the body
• Activation of microglial cells (immune cells of the brain), resulting in local inflammation

Chronic stress and changes in the brain

Since the beginning of time, acute stress has been a useful tool that could help us humans mobilize our fight-or-flight response. The body’s reactions are primarily controlled through the hypothalamus-pituitary-thyroid axis to help us perform optimally, both physically and mentally. The fight-or-flight response is tremendously energy-consuming and is designed to last a split second only. However, modern life if often characterized by chronic stress response and there is an imbalance between the different physiological reactions, leaving us too little time to recover. It is sort of like constant overdraft abuse.
It seems that depression and Alzheimer’s disease are caused by stress-related dysfunctions in the hypothalamus-pituitary-thyroid axis. In connection with chronic stress, hormones from the hypothalamus trigger an increased release of ACTH (adrenocorticotropic hormone) from the pituitary gland, which stimulates the production of cortisol in the adrenal glands. The elevated cortisol levels cause dysfunctions in the hippocampus and other parts of the brain that control our mood, mental drive, and memory. Increased levels of cortisol can enhance the harmful effect of beta-amyloid plaque and destroy neurons in the hippocampus, causing it to shrink.
Stress leads to an activation of the immune system. In the brain, microglial cells release pro-inflammatory cytokines, chemokines, and nitrogen oxide. Over time, the chronic inflammation leads to various nervous system imbalances and destruction of neurons. Many studies have shown a direct link between brain inflammation and mental disorders like depression and Alzheimer’s disease.

Chronic stress and oxidative stress in the brain

Chronic stress leads to oxidative stress, which is an imbalance between free radicals and antioxidants. Free radicals are highly reactive molecules with a missing electron. They are both essential and life-threatening at the same time.
Free radicals are naturally involved in our oxygen metabolism, immune defense, and various other metabolic processes. Factors such as stress, chronic inflammation, smoke, ageing processes, and poisoning are known to increase the number of free radicals tremendously. It is vital to keep free radicals on a tight leash and make sure that they operate within narrow boundaries and only carry out their designated functions. In the case of oxidative stress, free radicals initiate chain reactions by attacking cells. The really dangerous part is when free radicals attack the unsaturated fatty acids in cell membranes. From here, the chain reactions can spread to the entire cell, its mitochondria, its DNA, and they can move to other cells.
The reason that our brain is so vulnerable to oxidative stress is that it has a very high content of unsaturated fatty acids. The enormous flow of iron-containing blood through the brain only adds to the risk. In this connection, ferroptosis is a type of iron-induced cell death caused by free radicals. Several studies have shown a link between ferroptosis, neuronal death, and various types of brain disturbances. As a consequence, things like Alzheimer’s disease, Parkinson’s disease, and stroke may occur.

Antioxidants that can prevent and treat depression and Alzheimer’s disease

Our only source of protection against free radicals and oxidative stress is different types of antioxidants that are able to donate the missing electron to the free radicals, thereby neutralizing them. Antioxidants are also able to counteract chain reactions and free radical damage.
Antioxidants have different mechanisms of action, which is why we need different types of antioxidants. Some antioxidants are produced by the body, while others are found in food. In fact, certain dietary antioxidants affect our endogenous production of antioxidants and also affect the way they work. This synergy is important for our redox balance – the balance between free radicals and antioxidants.

Important endogenously produced antioxidants

• Gluthatione peroxidase 1-8 (GPX). All types contain selenium
• Superoxide dismutase 1-3 (SOD). All types contain zinc, copper, and manganese
• Catalase (CAT)
• Glutathione (GSH)
• Q10 (also involved in our energy metabolism)
• Melatonin (also a sleep hormone)

Dietary antioxidants

• Vitamins A, C, and E, selenium, zinc, and manganese
• Various plant compounds such as carotenoids, indoles, phenols, polyphenols, flavonoids, phenolic acid, and anthocyanins
• Some of the good sources are turmeric and other herbs, nuts, berries, fruit (especially the peeling and seeds), broccoli, cabbage, garlic, onion, prunes, dark chocolate, and green tea or coffee (in moderation)

Effective treatments for diseases in the nervous system continue to be one of the greatest therapeutic challenges. This is why so much research has been done to uncover the therapeutic potential of antioxidants, especially in connection with depression and Alzheimer’s disease.
Studies of mice, for example have shown that a deficiency of the selenium-containing GPX antioxidant intensifies cell death caused by ferroptosis. It has also been seen that GPX-deficient mice suffer from cognitive impairment and neurodegenerative changes in the hippocampus. It also appears that supplementation with selenium and vitamin E, two nutrients that support one another, helps counteract cell death caused by ferroptosis.

Antioxidants and depression

According to WHO, depression is the most widespread mental disorder, and the rate is going up. To make matters worse, anti-depressive drugs often fail to work or have serious side effects. There are many factors involved in depression. Oxidative stress in the brain is one of them. The increased number of free radicals causes inflammation and destroys neurons and signal pathways. Oxidative stress in the brain, mainly in the hippocampus, can be crucial for the development of depression. Scientists have also observed that the size of the hippocampus is smaller in patients with depression. In the case of depression, the brain lacks antioxidants that are needed to protect cell membranes, the hippocampus, neurons, and other parts of the brain.
After thoroughly analyzing a large number of studies, the scientists behind the new review article conclude that selenium and vitamin E hold the most promise for preventing and treating depression. Turmeric and saffron contain other relevant antioxidants and biologically active compounds that can help boost our mood. The scientists also mention zinc and magnesium that are essential for a number of enzyme reactions and anti-inflammatory processes.
Just for the record, one should also consider taking vitamin D and fish oil with EPA and DHA, the two omega-3 fatty acids that support brain functions and counteract chronic inflammation by way of other processes. One should generally try to eat a healthy diet to stabilize blood sugar levels and to get as many antioxidants as possible. Proper sleep is also vital.

Antioxidants and Alzheimer’s disease

The number of seniors is on the rise and so is the number of people affected by Alzheimer’s disease. The ailment is multi-factorial and science is still trying to find better and more promising therapies. Within the last decade, several clinical studies have shown that antioxidants may have a certain effect by counteracting oxidative stress and cell damage caused by free radicals. According to the authors of the new review article, the best results have been obtained with selenium, vitamin E, Q10, melatonin, turmeric, and polyphenols. We get polyphenols from things like nuts, fruit (especially from the peeling and seeds), red wine, elderberries, vegetables, and cocoa beans.
According to another meta-analysis, supplementation with vitamin B12, folic acid, and vitamin B6 helps prevent or delay mild cognitive impairment in seniors, a potential sign of Alzheimer’s disease. This is because B vitamins lower blood levels of homocysteine, an amino acid that may cause accumulation of beta-amyloid plaques in the brain and brain atrophy.
It is always advisable when trying to treat Alzheimer’s disease to try to eat a healthy diet that stabilizes blood sugar levels and contains a variety of different antioxidants. It is also vital to get plenty of sleep.

Diet, supplements, and supplement quality.

First and foremost, make sure to get as many different antioxidants as possible by eating a varied diet consisting of pure raw materials. Also, make sure to get protein, healthy fats, and keep your blood sugar stable to ensure an even and constant supply of energy to the brain and nervous system. In Denmark, it is possible to buy melatonin with a prescription. However, it is perfectly legal to import melatonin from other EU countries (as a nutritional supplement or non-prescription drug), provided it is for your own personal use only.

References:

Gabriella Juszczyk et al. Chronic Stress and Oxidative Stress as Common factors of the Pathogenesis of depression and Alzheimer´s Disease: The Role of Antioxidants in Prevention and treatment. Antioxidants 1 September 2021

Dogan-Sander et al. Inflammation and the Association of Vitamin D and Depressive Symptomatology. Nutrients 2021

James J. Dicolantonio and James H. O´Keefe. The Importance of Marine Omega-3s for Brain Development and the Prevention and treatment of Behavior, Mood, and Other Brain Disorders. Nutrients. 2020

Rapaport MH et al. Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study. Molecular Psychiatry 2015

Shufeng Li et al. The preventive efficacy of vitamin B supplements on the cognitive decline of elderly adults: a systematic review and meta-analysis. BMC Geriatrics 16 June 2021

Underwood Emily. Sleep: The ultimate Brainwasher? Science/AAAS/News 2013