Cholesterol Abnormalities Can Crash Cognition, Study Linking Bile Acid Production to Brain Health Finds
High cholesterol levels are linked to an increased risk of Alzheimer’s disease and vascular dementia. Yet, cholesterol is impermeable to the blood-brain barrier (BBB), which protects against circulating toxins or pathogens that could cause brain damage or infection, and is also virtually insoluble in liquids.
But cholesterol is a precursor to bile acids, which are soluble. So, can cholesterol influence brain health as a precursor to bile acids?
Researchers from the National Institute of Aging (NIA) followed this clue, leading them to find that lower blood levels of bile acids and cholesterol precursors were associated with higher brain amyloid deposition and faster brain atrophy and accumulation of lesions. Bile acids were also detectable in the brain, and levels of receptors for bile acids were altered in Alzheimer's disease. These results set the stage for experimental studies to test whether bile acid signaling in the brain may be a novel therapeutic target in dementia.
Meals, Metabolism, and the Mind
The two most common forms of dementia are vascular dementia and Alzheimer’s disease. Vascular dementia is caused when blood flow to the brain is impaired because of structural damage to the brain vasculature, and abnormal protein build-up in the brain that interrupts communication between neurons drives Alzheimer’s disease. Both conditions lead to the death of neural tissue.
Recent research has placed a spotlight on the cardiovascular origins of these diseases. Scientists believe that if the risk factors for cardiovascular disease can be reduced, or even eliminated, it might be possible to keep the risk of developing this type of dementia to a minimum.
To understand how these changes happen in the brain, it’s necessary to understand the metabolic changes that start the process that results in dementia. One of the key drivers of cardiovascular disease is high levels of cholesterol. Having high levels of cholesterol also increases the risk of developing Alzheimer’s disease (1).
Even though this relationship to high cholesterol is well documented, scientists do not understand how this leads to the development of dementia. The process is not well understood, because the brain has a specialized barrier known as the BBB that prevents substances such as cholesterol from reaching the blood vessels in the brain.
Cholesterol break-down might hold clues to dementia
Researchers believe that dementia’s relationship with cholesterol might have to do with the way the body gets rid of excessive amounts of cholesterol. Under normal circumstances, cholesterol provides the building blocks for the production of bile acids, which help in the digestive process. The liver produces these acids to help break down fatty foods. The cholesterol by-products are then expelled into the stool.
This process is closely related to the production of amyloid, a type of harmful protein that builds up in the brain and leads to Alzheimer’s disease. Scientists don’t clearly understand how exactly amyloid and bile acid production are related, but they know that there is some kind of connection between these two processes.
Cholesterol plays a role in the development of vascular dementia because of the way it affects blood vessels. From genetics or an excessive intake of cholesterol-rich foods in the diet, extra cholesterol may build up and damage the lining of blood vessels throughout the body. Cardiovascular events like strokes and heart attacks occur when blood vessels either rupture or become obstructed because of this process.
These effects may damage blood vessels, but the brain has built-in safeguards to counter such events. The brain depends on the BBB to protect the blood vessels that feed the brain from the damaging effects of cholesterol. However, certain by-products from bile acid production can cross this barrier and end up damaging important structures through other pathways such as the build-up of amyloid.
Linking cholesterol to dementia may propel Alzheimer’s treatment
Researchers from the National Institutes of Health and the National Institute on Aging inspected the relationship between cholesterol and dementia. Their findings were recently published in the journal PLoS Medicine (2,3). This study analyzed data from two long-term research studies from the US and UK with participant data that, in some cases, dates back all the way to 1958. Participants from the studies have provided information from their medical histories, lab tests, and brain imaging scans for over 20 years.
The authors first checked participant’s brain images to see if their scans were related to blood levels of biomarkers for bile acid production. They also took a look at the information on medications for treating bile acid-related conditions to see if these affected the lesions typical of vascular dementia and Alzheimer’s disease.
The next step was to examine genetic expression for bile acid production in the brain, to see if any of the examined mechanisms changed throughout the lifespan. Finally, researchers checked brain samples from participants looking for changes typical of vascular dementia or Alzheimer’s disease.
The results showed that lower biomarkers of bile acid production were associated with higher levels of amyloid deposition, degenerative lesions, and shrinking of the brain. These findings were more frequent in males. Participants that used bile-acid medication had a higher risk of developing dementia. Bile acids and their by-products were detected in the brain, and researchers found that gene activity for bile acid was altered in participants with dementia.
"To further extend these findings, we are now testing whether approved drugs for other diseases that may correct bile acid signaling abnormalities in the brain could be novel treatments for Alzheimer's disease and related dementias," said senior author Madhav Thambisetty, M.D., Ph.D., investigator and chief of the Unit of Clinical and Translational Neuroscience in the NIA's Laboratory of Behavioral Neuroscience. "These analyses are being pursued in the Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study."
These results help researchers better understand the association between cholesterol, bile acid production, and dementia. This sets the stage for research into developing a treatment for cholesterol-related dementias.
- Appleton JP, Scutt P, Sprigg N, Bath PM. Hypercholesterolaemia and vascular dementia. Clin Sci (Lond). 2017;131(14):1561-1578. Published 2017 Jun 30. doi:10.1042/CS20160382
- Varma VR, Wang Y, An Y, et al. Bile acid synthesis, modulation, and dementia: A metabolomic, transcriptomic, and pharmacoepidemiologic study. PLoS Med. 2021;18(5):e1003615. Published 2021 May 27. doi:10.1371/journal.pmed.1003615