Alzheimer’s disease is a chronic neurodegenerative disease affecting the brain and the leading cause of dementia. It starts with mild cognitive impairment and over time deteriorates into an ever-worsening loss of memory and other brain functions.
Melatonin, well known for regulating the body’s sleep-wake cycles, is a naturally occurring hormone and a robust antioxidant. Accumulating evidence suggests that melatonin shows promising neuroprotective activity against Alzheimer’s disease.
What is Alzheimer’s disease?
Alzheimer’s is not a single disease but results from a wide range of different biochemical processes that cause the loss of brain cells and synapses over time, resulting in cognitive decline and dementia.
The brain of an Alzheimer’s patient displays tangles (tau protein tangles) and plaques (amyloid-beta plaque) that affect the transfer of impulses between neurons. Tau is a normal protein that transports nutrients into brain cells and move waste products out of brain cells. Aging, or errant genes, can cause tau to become abnormal, resulting in pieces of the tau protein to tangle and clump together within the brain cells. In this event the nutrients and toxic waste products can no longer move freely in and out of brain cells, causing the cells to die.
Mitochondria are special compartments in our cells that act as the powerhouse of cells, as they break down nutrients (food molecules) and turn them into fuel to power the cells’ biochemical reactions. Mitochondrial dysfunction and the resulting impairment can occur early during Alzheimer’s disease, even before tangles and plaque.
What is melatonin?
Melatonin is a neurohormone that prepares the body for sleep, and it plays a crucial part in regulating the body’s circadian rhythm, a natural, biological timer present in each of our cells, which recognize sleepiness and wakefulness in a 24-hour sleep-wake cycle. Melatonin is produced by the tiny pineal gland near the center of the brain at night-time and results from signals from the retina of the eye. The production of melatonin is inhibited during the light of day and stimulated in the dark of night. While this hormone is mainly secreted into the bloodstream at night and affects both the central nervous system (brain and spinal cord) and peripheral organs (nerves and ganglia outside the central nervous system), the pineal gland can also release melatonin directly into the brain ventricles.
Melatonin also has antioxidant properties, and as it reaches every cell in the body, it can play a powerful role to protect the body against cell damage, particularly oxidative damage in brain cells. The antioxidant effects of melatonin also help to protect the mitochondria, as melatonin, working synergistically with vitamin D to optimize mitochondrial function, has the ability to enter the mitochondria and protect it from oxidative damage.
Melatonin’s potential therapeutic actions for Alzheimer’s disease:
As an antioxidant and scavenger of harmful oxygen radicals, melatonin is considered to be able to play an important role in protecting against cognitive impairment and neurodegenerative diseases such as Alzheimer’s.
Mitochondrial dysfunction contributes to neurodegeneration in Alzheimer’s disease and melatonin is a promising therapeutic candidate due to its ability to protect and enhance mitochondrial function. Studies have shown that melatonin levels are significantly lower in patients with Alzheimer’s disease than in age-matched healthy individuals.
The primary immune cells in the central nervous system are called microglia, which play an important role in maintaining brain homeostasis by clearing debris, pathogens, and dead cells in a healthy brain.
An inflammatory response in the brain is one of the hallmarks of Alzheimer’s disease. This occurs when the microglia are chronically activated and in a pro-inflammatory state, due to the immune system’s response to amyloid-beta plaque and other pathological changes in the Alzheimer’s brain.
Through melatonin’s role in immune regulation, it is known that melatonin interacts with and enhances the body’s immune system, as well as having an anti-inflammatory effect by facilitating a decrease in the immune system’s inflammatory response. Efficient clearance of amyloid-beta plaque and other toxic proteins by microglia, especially in the initial stages of Alzheimer’s disease, is essential to slow the progression of the disease.
Melatonin shows promise as a potential therapeutic agent to modulate a microglial inflammatory state, due to its dual action of improving mitochondrial function and reducing inflammation. While its merit in this regard has been shown in laboratory and animal studies, and several small-scale human trials suggest that melatonin supplementation can improve sleep and cognitive function in Alzheimer’s disease patients, more extensive research is needed.
Melatonin also shows potential to directly or indirectly impact on pathways that are implicated in Alzheimer’s disease, such as the potential to reduce the production of amyloid-beta plaque and counteracting its effects, as well as limiting the forming of tau protein tangles. Melatonin treatment has resulted in diminished amyloid-beta plaque levels in the brains in animal models. A bi-directional effect was also found, as amyloid-beta plaque has been shown to significantly decrease the production of melatonin by the pineal gland.
As melatonin production declines with aging, reduced melatonin levels and disrupted circadian rhythms are often seen in Alzheimer’s patients, as the pathways that governs melatonin production and regulation may be affected. Examples in this regard are a reduction in the number of photosensitive cells in the retina of the eye in Alzheimer’s patients, as well as the structural and functional loss of neurons in the suprachiasmatic nucleus, situated in the hypothalamus, which is the central pacemaker of the circadian timing system. Another possible contributing factor to diminishing melatonin levels is neurodegeneration and/or calcification of the pineal gland. It is quite common for the pineal gland to calcify with age, but excessive calcification can prevent the pineal gland from functioning properly.
Disrupted circadian rhythms can occur in brain cells, due to impaired functioning of the retina- suprachiasmatic nucleus-pineal gland axis, which may contribute to behavior in Alzheimer’s patients such as disturbances in sleep and wake cycles, sundowning (confusion or agitation in the late afternoon or early evening), and rest-activity patterns that are dramatically altered.
Conclusion:
Melatonin supplementation is a promising area of research and intervention for Alzheimer’s disease. Human trials have demonstrated that the administration of melatonin (3 mg per day) over a period of 6 to 12 months was associated with improved cognitive function.
The majority of studies on the impact of melatonin on Alzheimer’s mechanisms have been caried out in laboratory and animal studies, with only small-scale human observational studies and trials, and more extensive research is needed for conclusive findings. Another area of concern is a warning by the American Academy of Sleep Medicine that the use of melatonin and other sleep-promoting medications for demented elderly patients increase the risk for falls and other adverse events.
From emerging evidence, melatonin may be a potential candidate to address the underlying mechanisms of mitochondrial dysfunction and chronic inflammation in the Alzheimer’s brain, amongst other potential therapeutic actions such as the potential to mitigate the production of amyloid-beta plaque and the forming of tau protein tangles.
References:
Melatonin: A potential nighttime guardian against Alzheimer’s. Published 11August 2024 in the journal Molecular Psychiatry. Nature. (www.nature.com)
Melatonin – a possible therapeutic for Alzheimer’s disease. Blog published 21 August 2024 by Dr David Perlmutter. Neurologist and author. (www.drperlmutter.com)
Melatonin. Published online and updated 2 November 2023. Cognitive Vitality. A program of the Alzheimer’s Drug Discovery Foundation. (www.alzdiscovery.org)
Neurocognitive effects of melatonin treatment in healthy adults and individuals with Alzheimer’s disease and insomnia: A systematic review and meta-analysis of randomized controlled trials. Published August 2021 in Neuroscience Behavior Review. PubMed Central. National Centre for Biotechnology Information. US National Library for Medicine. National Institutes of Health. USA. (www.ncbi.nlm.nih.gov)
Role of melatonin in Alzheimer’s disease: From preclinical studies to novel melatonin-based therapies. Published April 2022 in Frontiers in Neuroendocrinology. Science Direct. (www.sciencedirect.com)
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