Why Choline Is the Missing Link in Preventing Dementia

Analysis by Dr. Joseph Mercola Fact Checked

• May 25, 2020

Story at-a-glance

• Proton pump inhibitors selectively inhibit the production of acetylcholine necessary for long-term cognitive function
• A mounting body of evidence points to cholinergic dysfunction associated with the development of dementia; choline is key to the system
• Choline may play a central role in the development of nonalcoholic liver disease (NAFLD), one of the most common forms of liver disease in the U.S.
• Choline is required for optimal health, yet up to 90% of the population is deficient; at high risk are pregnant women, vegans, endurance athletes and those who consume high amounts of alcohol
• Seek out natural sources first: Choline is found in eggs, grass fed beef liver, organic pastured chicken and krill oil

Dementia is a growing problem worldwide and the numbers are overwhelming. Alzheimer's Disease International estimates the global number with dementia reached 46.8 million in 2015 and is predicted to grow to 75 million by 2030, and 131.5 million by 2050.¹
In the U.S. there are more than 5 million people with Alzheimer’s, one form of dementia.² This number is estimated to nearly triple to 14 million by 2050. One in 3 of older adults dies every year with some form of dementia, which is more than the numbers with breast cancer and prostate cancer combined.
To put it another way, from 2000 to 2018, the number who died from heart disease dropped 7.8%, while the number who died from Alzheimer's rose 146%.
The economic costs have reached $305 billion and could rise to $1.1 trillion by 2050. Primary care doctors are overwhelmed by the number of patients in their practices and half believe the profession isn't ready for the growing number.
The development of dementia and Alzheimer's disease is likely due to a number of reasons. Researchers have identified several factors that impact cognitive impairment, including insulin resistance,³ certain drugs,⁴ lack of sleep⁵ and low levels of some vitamins.⁶

Cholinergic Dysfunction May Drive Dementia

As explained in a recently published paper, scientists analyzed the effect proton pump inhibitors have on the development of dementia. They recognized indicators pointing to cholinergic dysfunction in the development of dementia. In a review article from 1999,⁷ other scholars outlined data to support the hypothesis that cholinergic dysfunction contributes to Alzheimer's.
By 2008,⁸ the research community had identified areas of the brain where cholinergic dysfunction may influence dementia. Subsequently, acetylcholine was recognized for the central role it plays in the nervous system.⁹ It requires an enzyme to synthesize from acetyl-COA and choline. That enzyme is choline acetyltransferase.
Cholinergic synapses are found throughout the brain, including the basal forebrain, which is severely damaged in those who have the disease. With further research,¹⁰ scientists found using cholinesterase inhibitors could increase acetylcholine in the brain, which has proven to be clinically useful in the treatment of Alzheimer's dementia.
The use of anticholinergic drugs has a known side effect, though, of causing short-term cognitive impairment in the elderly.¹¹ These medications act on the neurotransmitter acetylcholine, which is involved in sending messages that affect muscle contraction. They also act on parts of the brain that handle memory and learning.
Anticholinergic drugs have been used for decades to treat diarrhea, asthma, insomnia, motion sickness and even some psychiatric disorders. Some of the more common side effects include blurry vision, dizziness, confusion, hallucination and drowsiness.¹²
As described in study published in JAMA,¹³ scientists looked at whether exposure could increase the risk of dementia in people 55 years and older. The data revealed that those taking strong anticholinergic drugs, which affect acetylcholine, was associated with a greater risk of dementia.
Gastric acid secretion is regulated in part by acetylcholine. The development of proton pump inhibitors for chronic heartburn became a mainstay of treatment. This resulted in people taking the medication for long periods of time. The intended use of the drug was to inhibit the cellular proton pump that produces acid.
However, proton pump inhibitors are not specific to stomach cells and will inhibit any cell with a proton pump. This may be the trigger for the long list of side effects associated with the drugs, including kidney disease, dementia and liver disease.¹⁴ While researchers found an association between proton pump inhibitors and dementia, the mechanism had yet to be discovered.

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One Drug Selectively Inhibits Synthesis of Acetylcholine

One team of researchers¹⁵ looked at all proton pump inhibitors approved by the FDA and found that the drugs negatively affected the production of acetylcholine in the body.
Using computer simulations, they evaluated how different substances in six proton pump inhibitors interacted with choline acetyltransferase.¹⁶ While the drug was designed to limit cellular proton pumps and reduce acid production, the simulations showed they could bind with the enzyme that synthesizes acetylcholine.
The effect of this was to reduce production of acetylcholine. The researchers believe new studies are needed to determine if the effects in the lab also happen in the body. One of the team members commented:¹⁷

"Special care should be taken with the more elderly patients and those already diagnosed with dementia. The same also applies to patients with muscle weakness diseases such as ALS, as acetylcholine is an essential motor neurotransmitter. In such cases, doctors should use the drugs that have the weakest effect and prescribe them at lowest dose and for as short a time as possible.”

Choline: Key Factor in Nonalcoholic Fatty Liver Disease?

Nonalcoholic liver disease (NAFLD) is one of the most common forms of liver disease in the U.S.¹⁸ It is initiated in part by obesity and insulin resistance. Scientists have found it may lead to fibrosis of the liver and then to cirrhosis or liver cancer.
There are two forms of NAFLD which are not associated with alcohol consumption. The first is simple fatty liver or nonalcoholic fatty liver (NAFL) in which there are fatty deposits in the liver but very little, if any, inflammation or cellular damage.
The second is called nonalcoholic steatohepatitis (NASH). This is a form of NAFLD in which you have fatty deposits in the liver and hepatitis, or inflammation of the liver. This results in liver cell damage that can lead to fibrosis, cirrhosis or liver cancer. Most people with the condition have simple fatty liver while only a small number have NASH.
The National Institute of Diabetes and Digestive and Kidney Diseases reports that between 30% and 40% of all adults in America have NAFLD. Those who have a higher risk are obese and have Type 2 diabetes. The condition can affect people of any age, race or ethnicity.
In one animal study, researchers found that by supplementing with choline they could normalize cholesterol metabolism, which appeared to help prevent NASH and improve liver function.¹⁹ As described in one paper, choline is necessary for liver health:²⁰

“Humans must eat diets containing choline because its metabolite phosphatidylcholine constitutes 40–50% of cellular membranes and 70–95% of phospholipids in lipoproteins, bile and surfactants; it is needed to form acetylcholine, an important neurotransmitter; its metabolite betaine is needed for normal kidney glomerular function, and perhaps for mitochondrial function; and it provides one-carbon units, via oxidation to betaine, to the methionine cycle for methylation reactions.

When humans eat diets low in choline, fatty liver is one of the earliest adverse events, and in some people significant hepatic damage occurs (as assessed by release of hepatic enzymes into blood).”

According to Chris Masterjohn, Ph.D., choline deficiency may be a more significant in development of the condition than taking in too much fructose. His degree is in nutritional science and he believes the rise in fatty liver conditions is largely due to more and more people avoiding egg yolks and liver.
In his review of the medical literature, Masterjohn found a link between choline and fatty liver, which was initially discovered in research into Type 1 diabetes. He describes the relationship:²¹

"Physicians and researchers had started pinning the blame on alcohol abuse for fatty liver back in the 1800s, so while research was first highlighting the role of sucrose in fatty liver, other research was doing the same for alcohol.

In 1949, however, researchers showed that sucrose and ethanol had equal potential to cause fatty liver and the resulting inflammatory damage, and that increases in dietary protein, extra methionine, and extra choline could all completely protect against this effect.

Conversely, much more recent research has shown that sucrose is a requirement for the development of fatty liver disease in a methionine- and choline-deficient (MCD) model. The MCD model of fatty liver disease is the oldest and most widely used dietary model.

The MCD model produces not only the accumulation of liver fat, but massive inflammation similar to the worst forms of fatty liver disease seen in humans. What no one ever mentions about this diet is that it is primarily composed of sucrose and its fat is composed entirely of corn oil!

The picture that is clearly emerging from all of these studies is that fat, or anything from which fat is made in the liver, such as fructose and ethanol, are required for the development of fatty liver. But in addition to this [same] factor — overwhelmingly, it appears to be choline deficiency — must deprive the liver of its ability to export that fat."

Choline Needed for Optimal Health

Your liver produces a small amount of choline,²² but the rest must be supplied through your diet. Unfortunately, nearly 90% of people living in the U.S. have a deficiency,²³ which increases the risk of babies being born with neural tube defects.²⁴
As I’ve written before, groups at particularly high risk for choline deficiency include pregnant mothers, endurance athletes, postmenopausal women, vegans, and those who consume high amounts of alcohol.
Choline serves several vital functions in the body.²⁵ It's used in the manufacture of some phospholipids essential to the development of your cell membranes. Choline is also a precursor for intracellular molecules used in cell signaling.
The neurotransmitter acetylcholine is synthesized from choline and involved in memory, circadian rhythm and muscle control. Each of these specific functions contribute to the impact it has on cardiovascular health, liver diseases, neural tube defects and cognitive health.

Seek Best Natural Sources of Choline First

The National Institutes of Health²⁶ lists the adequate intake for choline provided in the Dietary Reference Intakes developed by the Institute of Medicine (IOM). At the time these were developed, there was not sufficient data to establish an estimated average requirement.
This is a number that's usually used to determine the amount of nutrients needed to adequately supply diets for 50% of healthy individuals. Instead, the Food and Nutrition Board of the IOM established adequate intakes for all ages they believe would prevent the development of liver damage.
To date, men 19 years and older who get 550 mg per day and women who take in 425 mg per day have an adequate intake. This rises to 450 mg per day during pregnancy and 550 mg per day while breastfeeding. These are suggested values and may vary depending on your diet, age, ethnicity and genetic makeup.
It is best to first seek healthy natural sources for your nutrients. For instance, a single hardboiled egg weighing approximately 50 grams may contain from 113 mg²⁷ to 147 mg²⁸ of choline. This is 25% to 30% of your daily requirement. Only grass fed beef liver has more, with per 50 grams per serving.²⁹ As noted in the Fatty Liver Diet Guide:³⁰

"Eggs rank very high on the list of foods that are high in either lecithin, which converts to choline, or in choline itself. Note that this is the egg yolks only, not egg whites, which only have traces of this micronutrient.

Choline is essential in the production of phosphatidylcholine, a fat molecule called a phospholipid. But wait! Isn't all fat bad? No — especially if it is essential to overall health and in particular, liver health. Simply put — if you don't have enough choline, your liver can't move out fat. It instead begins to collect within your liver, creating fatty liver."

Other healthy choices can include wild-caught Alaskan salmon, organic pastured chicken, and krill oil. In 2011, the authors of one study³¹ found 69 choline-containing phospholipids in krill oil.
That said, supplementation is a potential option if you don’t eat eggs, salmon or other foods with ample amounts of the nutrient. The tolerable upper intake for an adult is 3.5 grams per day.³² Be careful not to take too much, as side effects of excessive choline include low blood pressure, sweating, diarrhea and a fishy body odor.

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