A lifelong dietary regimen of choline holds the potential to prevent Alzheimer’s disease, a new Arizona State University study suggests.
Choline is a safe and easy-to-administer nutrient that is naturally present in some foods and can be used as a dietary supplement. Lead author Ramon Velazquez and his colleagues at the ASU-Banner Neurodegenerative Disease Research Center (NDRC) looked into whether this nutrient could alleviate the effects of Alzheimer’s disease (AD).
Earlier this year, Velazquez and colleagues found transgenerational benefits of AD-like symptoms in mice whose mothers were supplemented with choline. The latest work expands this line of research by exploring the effects of choline administered in adulthood rather than in fetal mice.
Lifelong Choline Supplementation
The study focuses on female mice bred to develop AD-like symptoms. Given the higher prevalence of AD in human females, the study sought to establish the findings in female mice.
Results showed that when these mice are given high choline in their diet throughout life, they exhibit improvements in spatial memory, compared with those receiving a normal choline regimen.
Notably, findings published in July 2019 from a group in China found benefits of lifelong choline supplementation in male mice with AD-like symptoms.
“Our results nicely replicate findings by this group in females,"
Disease Related Microglia
Intriguingly, the beneficial effects of lifelong choline supplementation reduce the activation of microglia. Microglia are specialized cells that rid the brain of deleterious debris.
Although they naturally occur to keep the brain healthy, if they are overactivated, brain inflammation and neuronal death, common symptoms of AD, will occur.
[caption id=“attachment_100343” align=“aligncenter” width=“700”] Microglia
Credit: Arizona State University[/caption]
The observed reductions in disease-associated microglia, which are present in various neurodegenerative diseases, offer exciting new avenues of research and suggest ways of treating a broad range of disorders, including traumatic brain injuries, multiple sclerosis and Parkinson’s disease.
Choline acts to protect the brain from Alzheimer’s disease in at least two ways, both of which are explored in the new study.
First, choline blocks the production of amyloid-beta plaques. Amyloid-beta plaques are the hallmark pathology observed in Alzheimer’s disease.
Secondly, choline supplementation reduces the activation of microglia. Over-activation of microglia causes brain inflammation and can eventually lead to neuronal death, thereby compromising cognitive function.
[caption id=“attachment_100342” align=“aligncenter” width=“700”] Credit: Ramon Velazquez et al cc-BY[/caption]
Choline supplementation reduces the activation of microglia, offering further protection from the ravages of AD.
The reductions in microglia activation are driven by alteration of two key receptors, the alpha7 nicotinic acetylcholine and Sigma-1 receptor. A new report this year found that choline can act as an agonist for Sigma-1 receptors.
These results confirm that lifelong choline supplementation can alter the expression of the Sigma-1 receptor, which thereby attenuates microglia activation.
Prior research concerning Alzheimer’s has indicated that there is no one factor at play. Rather, a multitude of factors that are believed to contribute to the development of the disease, including genetics, age and lifestyle.
A recent report suggested that plant-based diets may be determinantal due to the lack of important nutrients, including choline. Another recent report found that the increase in cases of dementia in the United Kingdom may be associated with a lack of recommendations for choline in the diet throughout life.
In fact, as of August 2019, AD and other forms of dementia are now the leading cause of death in England and Wales.
The current established adequate intake level of choline for adult women (>19yrs of age) is 425mg/day, and 550mg/day for adult men. A converging line of evidence indicates that even the current recommended daily intake (RDI) may not be optimal for a proper aging process, especially in women.
This is relevant, given the higher incidence of AD seen in women. This suggests that additional choline in diet may be beneficial in preventing neuropathological changes associated with the aging brain.
The tolerable upper limit (TUL) of choline unlikely to cause side effects for adult females and males (>19yrs of age) is 3500mg/day, which is 8.24 times higher than the 425mg/day recommendation for females and 6.36 times higher than the 550mg/day recommendation for males.
“Our choline supplemented diet regimen was only 4.5 times the RDI, which is well below the TUL and makes this a safe strategy”,
Choline can be found in various foods. According to the United States Department of Agriculture (USDA), high levels of choline are found in:
chicken liver (3oz; 247mg)
eggs (1 large egg with yolk;147mg)
beef grass-fed steak (3oz; 55mg)
wheat germ (1oz toast; 51mg)
milk (8oz; 38mg)
Brussel sprouts (1/2 cup; 32mg)
Additionally, vitamin supplements containing choline, for example choline bitartrate and choline chloride, are widely available at affordable costs. The vitamin supplements containing choline are particularly relevant for those who are on plant-based diets.
All plant and animal cells require choline to maintain their structural integrity. It has long been recognized that choline is particularly important for brain function.
The human body uses choline to produce acetylcholine, a neurotransmitter responsible for functioning memory, muscle control and mood. Choline also is used to build cell membranes and plays a vital role in regulating gene expression.
Due to alterations of key microglia receptors induced by choline, the improvements in behavior may be attributed to reduced microglia activation.
“We found that lifelong choline supplementation altered the alpha7 nicotinic acetylcholine and Sigma-1 receptor, which may have resulted in the reduction of diseased associated activated microglia,"
Velazquez said. These receptors regulate CNS immune response and their dysregulation contributes to AD pathogenesis.
Although the results improve the understanding of the disease, the authors note that clinical trials will be necessary to confirm whether choline can be used as a viable treatment in the future.
Funding for the work came from the National Institute on Aging, and from the National Science Foundation.
 Velazquez, R, Ferreira, E, Knowles, S, et al. Lifelong choline supplementation ameliorates Alzheimer’s disease pathology and associated cognitive deficits by attenuating microglia activation. Aging Cell. 2019;e13037. https://doi.org/10.1111/acel.13037
 Ramon Velazquez, Eric Ferreira, Wendy Winslow, Nikhil Dave, Ignazio S Piras, Marcus Naymik, Matthew J Huentelman, An Tran, Antonella Caccamo, Salvatore Oddo. Maternal choline supplementation ameliorates Alzheimer’s disease pathology by reducing brain homocysteine levels across multiple generations. Molecular Psychiatry; https://doi.org/10.1038/s41380-018-0322-z
 Eugen Brailoiu, et al. Choline Is an Intracellular Messenger Linking Extracellular Stimuli to IP3-Evoked Ca2+ Signals through Sigma-1 Receptors. Cell Reports, Volume 26, Issue 2, 8 January 2019, Pages 330-337.e4
 Vennemann FB, et al. Dietary intake and food sources of choline in European populations. Br J Nutr. 2015 Dec 28;114(12):2046-55. doi: 10.1017/S0007114515003700.