Choline is an essential nutrient produced in small amounts in the liver and found in foods including eggs, broccoli, beans, meat and poultry, and is vital to human health. A new study explores that a lack of dietary choline negatively affects the body and may be a missing piece in the puzzle of Alzheimer’s disease.
It is estimated that more than 90% of Americans do not meet the recommended daily amount of choline. Current research, which was conducted on rats, indicates that dietary choline deficiency can have profound negative effects on the heart, liver, and other organs.
A lack of adequate choline is also associated with profound changes in the brain associated with Alzheimer’s disease. These include pathologies implicated in the development of two hallmarks of the disease, amyloid plaques, which collect in the intercellular spaces between neurons, and tau tangles, which thicken within neuronal cell bodies.
The new research, led by scientists at Arizona State University, describes diseases in normal mice deprived of dietary choline as well as transgenic mice deficient in choline, which already show symptoms associated with the disease. Either way, dietary choline deficiency leads to liver damage, heart enlargement, and neurological changes in mice that are typically associated with Alzheimer’s disease, including increased levels of the plaque-forming protein amyloid-beta and disease-related changes in the tau protein.
Furthermore, the study shows that choline deficiency in mice causes significant weight gain, changes in glucose metabolism (which are associated with conditions such as diabetes), and decreases in motor skills.
In the case of humans, “it’s a twofold problem,” according to Ramon Velasquez, senior author of the study and assistant professor at the ASU-Banner Neurodegenerative Disease Research Center. “First, people do not reach the adequate daily intake of choline established by the Institute of Medicine in 1998. Second, there is ample literature showing that recommended daily intake amounts are not ideal for brain-related functions.”
Ramon Velasquez led the new study on the importance of dietary choline for the brain and other organs. He is a researcher at the ASU-Banner Neurodegenerative Diseases Research Center.
The research highlights a range of physical and neurological changes associated with choline deficiency. Adequate choline in the diet reduces levels of the amino acid homocysteine, which has been identified as a neurotoxin that contributes to neurodegeneration and is important for intermediate functions such as learning and memory, through the production of acetylcholine.
Increased awareness of the importance of choline should encourage all adults to ensure adequate choline intake. This is especially true for those who follow a vegan diet, which may be low in natural choline, since choline-rich foods are eggs, meat, and poultry.
Choline-rich plant foods, including soybeans, Brussels sprouts, and toast, can help boost choline in these cases. Moreover, inexpensive, over-the-counter choline supplements are encouraged to ensure systemic health and protect the brain from neurodegenerative effects.
Choline is necessary for the production of acetylcholine, a neurotransmitter that plays an essential role in memory, muscle control, and mood. Choline also builds cell membranes and helps regulate gene expression. The recommendations made by the Institute of Medicine were based on evidence to prevent fatty liver disease in men. New lines of evidence suggest that the recommended daily intake of dietary choline for adult women (425 mg/day) and adult men (550 mg/day) may not be optimal for brain health and proper cognition. Additionally, ~90% of Americans do not meet the recommendation levels and may not even be aware that dietary choline is required on a daily basis.
Despite decades of research and billions of dollars invested since the devastating disease was discovered more than a century ago, there is still no treatment that can slow the progression of the disease. However, new research findings suggest that environmental and lifestyle changes, including adequate choline, may help protect the brain against Alzheimer’s disease as well as improve overall health.
Velasquez is joined in the study by co-authors Nikhil Dave and Jessica Good. The work is very interdisciplinary, including researchers from ASU Biosciences Mass Spectrometry, and the Cardiovascular Research Center at the University of Arizona College of Medicine in Phoenix, Arizona.
“This collaborative work, which includes multiple institutions and surveys the molecular processes of aging at a systems level, adds to the body of evidence that has been produced on the importance of dietary choline in healthy aging,” said Nikhil Dev.
“What I found particularly compelling about this project was that many organs, whose dysfunction can have implications for brain health, were negatively affected by the choline-deficient diet,” said Jessica Good.
The research appears in the current issue of the journal Aging Cell.
A prolific and mysterious killer
Alzheimer’s disease is the leading cause of dementia and the fifth leading cause of death among Americans age 65 and older. Today, Alzheimer’s disease affects 6.5 million in the United States alone and is expected to strike nearly 14 million Americans by 2060. By this time, treatment costs for Alzheimer’s disease are expected to exceed $20 trillion, threatening healthcare infrastructure while causing in immense suffering.
The accumulation of sticky protein fragments outside neurons, (which form beta-amyloid plaques), and the accumulation of an abnormal form of the protein tau within the nerve cell bodies (tau tangles) have long been known signs of Alzheimer’s disease. These brain changes are usually followed by neurodegeneration, including damage and destruction of nerve cells. Plaques are thought to damage connections between cells in the brain while tangles prevent the transport of vital nutrients necessary for healthy cell function and survival.
In addition to amyloid-beta plaques and neurofibrillary tangles, the disease causes cell death in the brain and increased cognitive impairment. The current work also found dysregulation of proteins in the hippocampus, a major structure affected by Alzheimer’s disease, linked to learning and memory. Both normal mice and Alzheimer’s mice showed dysregulated proteins in the hippocampus with a choline-deficient diet, the Alzheimer’s model showing severe effects.
The recent dramatic increase in the incidence of Alzheimer’s disease is of grave concern. Although deaths from stroke, heart disease, and HIV decreased between 2000 and 2019, deaths from Alzheimer’s disease increased by more than 145%. In addition to the toll patients take on the disease, Alzheimer’s disease has placed an enormous burden on those who care for patients. In 2021 alone, 16 billion hours of care were provided by more than 11 million family members and other unpaid caregivers.
The first outward symptoms of the disease are usually associated with problems with language, memory, and thinking, as areas of the brain associated with these tasks tend to be among the first to be affected. However, researchers now know that by the time the disease causes noticeable symptoms, it has been quietly ravaging the brain for 20 years or more.
Many factors contribute to the development of Alzheimer’s disease, from genetic predisposition to age, lifestyle, and environmental influences. For reasons that remain obscure, females face an increased risk of contracting the disease.
Recent studies have identified diet as an important factor associated with preventing cognitive decline. In previous research, Velasquez and colleagues showed that when rats were fed a choline-rich diet, their offspring showed improved spatial memory, compared to a normal choline diet in the womb. Interestingly, the beneficial effects of choline supplementation are passed down through generations, protecting not only the mice receiving choline supplementation during pregnancy and lactation, but also the subsequent offspring of these mice, suggesting inherited modifications in their genes.
Subsequent studies in Velazquez’s lab showed that choline given to female rats throughout life led to improvements in spatial memory, compared to those receiving a normal choline regimen.
The new study examines mice at 3-12 months or early to late adulthood (roughly equivalent to 20-60 years in humans). In both normal and transgenic mice showing symptoms of Alzheimer’s disease, those exposed to the choline-deficient diet showed weight gain and adverse metabolic effects. Liver damage was noted by histological analysis, as was cardiac enlargement. Elevated soluble, oligomeric and insoluble amyloid-beta protein as well as alterations of tau protein properties to those that lead to neurofibrillary tangles have been detected in the brain.
Moreover, the choline-deficient mice performed poorly on a test of motor skills, compared to the mice that got adequate choline in their diet. These adverse effects were increased in transgenic mice. When translating these findings into humans, this means that people at risk of developing Alzheimer’s disease or experiencing the pain of the disease should ensure they get enough choline.
The study also included a detailed exploration of proteins in the hippocampus, a region of the brain severely affected by Alzheimer’s disease, as well as proteins detected in the blood. Dietary choline deficiency altered important hippocampal networks. These diseases involve disruption of pathways involved in microtubule function and postsynaptic membrane organization – both of which are essential for proper brain function. In the blood, proteins produced in the liver that play a role in metabolic function were particularly dysregulated with the choline-deficient diet.
“Our work provides further support that dietary choline should be consumed daily given the need throughout the body,” says Velasquez.
Ultimately, controlled human clinical trials will be necessary to determine the efficacy and appropriate doses of choline, before lifelong choline supplementation is encouraged. However, the powerful new findings offer hope that choline may be one tool in the arsenal needed to protect the brain from neurodegeneration and age-related cognitive decline.