Dementia: Cholesterol breakdown in the brain plays key role

• There is a well-established connection between high cholesterol levels in the blood and dementia. However, cholesterol cannot cross the blood-brain barrier, so its link with dementia is hard to explain.
• A new study suggests that bile acids, the breakdown products of cholesterol, are detectable in the brain and play a vital role in healthy brain function.
• The research found that low levels of these molecules in the brain were associated with a more rapid progression of dementia in males.
• The study also found evidence that males who take drugs to lower the concentration of bile acids in their blood have a higher risk of dementia.

Raised serum cholesterol levels are known to increase a person’s risk of developing vascular dementia and Alzheimer’s disease, but researchers have been at a loss to explain why.

The problem with any explanation is that cholesterol is a large molecule that cannot cross the blood-brain barrier.

According to new research, the solution to the mystery may lie in the breakdown, or “catabolism,” of cholesterol into molecules called oxysterols.

These chemicals are small enough to enter the brain, where they break down further into other molecules called bile acids.

Researchers at the National Institute on Aging (NIA), part of the National Institutes of Health (NIH), in Bethesda, MD, found an association between low serum levels of oxysterols and the progression of dementia in males, though not in females.

Oxysterols are essential for the brain to synthesize bile acids, which in turn may be needed to maintain healthy nerves and brain function.

The researchers went on to find a link between drugs that lower the absorption of bile acids from the gut and a higher risk of vascular dementia, once again only in males.

Their study has been published in the journal PLOS Medicine.

The relationship between blood cholesterol, bile acids, and dementia is complex. First author Vijay Varma, Ph.D., a staff scientist at the NIA, told Medical News Today, “While our results suggest that dysregulation in cholesterol breakdown and bile acid synthesis may impact dementia pathogenesis, the conversion of cholesterol into bile acids is only one of several mechanisms that regulate blood cholesterol levels.”

“Other important mechanisms include intestinal cholesterol absorption, rates of cholesterol synthesis, [low-density lipoprotein] receptor activity, and secretion of cholesterol into bile.”

He added that the conversion of cholesterol into bile acids is only one of its possible “metabolic fates.” The others include its conversion into steroid hormones and vitamin D.

Toxic amyloid protein

The scientists investigated potential links between cholesterol catabolism and dementia in more than 1,600 participants of the Baltimore Longitudinal Study of Aging and the Alzheimer’s Disease Neuroimaging Initiative.

They found that lower serum concentrations of oxysterols and bile acids were associated with signs of the progression of dementia, as revealed by brain scans.

For example, the brains of participants with lower levels of these molecules in their blood contained more amyloid, which is the toxic protein that characterizes Alzheimer’s disease.

Next, the researchers turned to a large database of patient medical records in the United Kingdom, called the Clinical Practice Research Datalink.

In male but not female patients, the team found a significant association between the number of prescriptions for drugs called bile acid sequestrants and the risk of vascular dementia.

Physicians prescribe bile acid sequestrants to treat abnormally high levels of lipid in the blood, or hyperlipidemia.

The drugs bind to bile acids that are secreted in the gut, which prevents their absorption into the bloodstream.
Dr. Madhav Thambisetty, the study’s senior author and a senior investigator at the NIA, told MNT that further research will be needed to determine the precise roles of male and female sex hormones in the regulation of bile acid synthesis.

He explained:

“Such studies are needed to fully understand how sex differences may determine responses to drugs that lower cholesterol levels by targeting bile acid synthesis. A better understanding of the role of sex as a biological variable in bile acid metabolism will enable us to make informed decisions about relative risk versus benefit in patients prescribed these medications.”

Finally, when they compared brain autopsy samples from individuals who had been diagnosed with dementia and others who had not, the researchers discovered differences in the expression of genes for bile acid receptors.

Bile acid receptors

The authors note that there is growing evidence of the importance of receptors for bile acids in the brain.

The metabolic pathways that the receptors control may help regulate glucose, lipids, and energy levels. They may also influence the transmission of nerve signals.

The researchers speculate that drugs that promote bile acid signaling in the brain may be able to slow the progression of dementia and possibly even prevent it.

“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,” says Dr. Thambisetty, who heads the Unit of Clinical and Translational Neuroscience at the NIA’s Laboratory of Behavioral Neuroscience.

The authors caution that their study found associations rather than causal links. So there remains a possibility that the brain changes that they observed may alter cholesterol catabolism, rather than the other way around.

In addition, they note that the numbers of patients and autopsy samples involved in parts of their research were relatively small, which limited the reliability of some of their findings.

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