Managing cholesterol may help lower the risk of Alzheimer's, Parkinson's disease

• Cholesterol is a fat-like substance that is an essential part of the membranes of all cells.
• It is produced by the body, primarily in the liver, but people also consume it in their diet.
• A new review has found four molecular mechanisms by which cholesterol imbalances, particularly in the brain, may lead to neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease.
• The review suggests that managing cholesterol could help reduce the risk of these diseases.

Cholesterol is a fatty or waxy molecule that has several functions in the human body. It is essential in the structure of cell membranes, and for making steroid hormones, bile acids and vitamin D.

Cholesterol is particularly important in the brain for the formation and functioning of nerve cells.

The two main types of cholesterol are low-density lipoproteins (LDLs, or “bad cholesterol”), which collect in the walls of blood vessels, and high-density lipoproteins (HDLs, or “good cholesterol”), which move LDLs out of the bloodstream.

Studies suggest that a higher level of HDL may be associated with a reduced risk of cardiovascular disease , while high LDL increases the risk of heart disease and stroke.

Now, a new review of the existing research has laid out the molecular mechanisms that may link cholesterol imbalances with neurodegenerative diseases . The researchers suggest that by managing cholesterol levels, people could potentially reduce their risk of developing diseases such as Alzheimer’s and Parkinson’s disease .

The review appears in Experimental and Molecular Medicine .

David Gill, MD , an associate professor of neurology at the University of Rochester Medical Center and of the Division of Cognitive and Behavioral Neurology, who was not involved in this research, commented on the review for Medical News Today , commenting that:

“The article describes a number of ways that cholesterol is involved in how the brain functions, including helping brain cells communicate […], stabilizing the membrane of the brain cell, regulating production of a protein called beta Amyloid, and playing a role in how a protein called Tau clumps together.”

Cholesterol: A key risk factor in neurodegeneration

A recent Lancet commission review listed high LDL cholesterol after the age of 40 as one of 14 modifiable factors that increase the risk of dementia , the most common neurodegenerative disease.

This latest review adds to this by identifying four molecular mechanisms of neurodegeneration that are linked to cholesterol imbalances.

The first is synaptic dysfunction. Synapses are the connections between nerve cells, and their function relies on cholesterol in the plasma membrane.

Lack of cholesterol in the plasma membrane can interrupt the passage of impulses between nerve cells, leading to the declines in cognitive and motor function seen in neurodegenerative diseases.

The second mechanism is linked to cell membrane structure and protein clustering. Cholesterol deficiency in nerve cells causes defects in the cell membranes which can lead to neurodegeneration.

The third is related to oligomers of beta-amyloid protein. Imbalance of cholesterol influences the clumping and misfolding of proteins, such as amyloid precursor protein (APP). High cholesterol levels speed up the formation of beta-amyloid from APP, making beta-amyloid plaques that are characteristic of Alzheimer’s disease.

Finally, there is, alpha-synuclein aggregation: Cholesterol accelerates the aggregation of alpha-synuclein and formation of Lewy bodies , the main causes of neurodegeneration in Parkinson’s disease.

How exactly does cholesterol lead to neurodegeneration?

Yongsoo Park, PhD , one of the authors of the recent Experimental and Molecular Medicine review, from the Neurological Disorders Research Center at the Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), explained for MNT that:

“Cholesterol cannot directly cross the blood-brain barrier (BBB), and most brain cholesterol is synthesized locally within the brain. However, there is a complex relationship between peripheral cholesterol (cholesterol in the bloodstream) and brain cholesterol that can influence neurodegeneration.”

“First, high levels of cholesterol in the bloodstream can contribute to the formation of atherosclerotic plaques in blood vessels, including those supplying the brain. This can impair blood flow and reduce the delivery of oxygen and nutrients to brain tissues, potentially leading to neurodegeneration,” Park told us.

“Second,” he added, “elevated cholesterol levels in the bloodstream can also compromise the integrity of the BBB. A compromised BBB might allow peripheral molecules, which would normally be excluded, to enter the brain, potentially contributing to neuroinflammation and neurodegeneration.”

However, he also suggested that these molecular mechanisms were “mainly due to problems with de novo synthesis of cholesterol in the brain and cholesterol dysregulation in neurons.”

Can managing blood cholesterol make a difference?

General advice to help maintain health is to try and minimize LDL and increase levels of HDL in the blood, and this review suggests that doing this may also help to preserve the health of nerve cells in the brain.

“There are a number of tenets to a healthy brain lifestyle that include not smoking, controlling blood pressure, and maintaining a healthy weight as well as increasing mental, physical and social activity and following a heart healthy diet,” Gill told us.

People can manage their cholesterol levels by taking medications, such as statins , and by modifying their diet and lifestyle.

The Centers for Disease Control and Prevention (CDC) recommend the following to help reduce high LDL cholesterol:

• make healthy eating choices, such as limiting the intake of saturated fats, trans fats, salt and added sugars, and choosing foods that are naturally high in fiber and unsaturated fats
• maintain a healthy weight
• get regular physical activity
• do not smoke/ give up smoking
• limit your alcohol consumption, as too much alcohol can raise cholesterol levels.

Park explained that “lowering blood cholesterol levels can reduce the risk of atherosclerosis, thereby maintaining better blood flow to the brain and preserving BBB integrity [and] decrease chronic inflammation, as high cholesterol is associated with the release of inflammatory cytokines.”

People with Alzheimer’s risk gene should watch their cholesterol

“We also know that a gene that plays a role in cholesterol in the brain, APOE , also plays a role in the risk of Alzheimer’s disease,“ said Gill.

“Given that cholesterol plays a role in the build up of these proteins as well as the structure of the membrane of the brain cell as well as how well brain cells communicate, it makes sense that cholesterol may play a role in the Alzheimer’s disease process,” he noted.

Thus, controlling blood cholesterol could be particularly important for people who have the APOEε4 allele (gene variant) that increases their risk of developing Alzheimer’s disease, as Park told us:

“ APOEε4 is a lipoprotein [that is] the most critical risk factor for Alzheimer’s disease, and high cholesterol levels in the bloodstream might lead to translocation and accumulation of APOEε4 in the brain, thus probably inducing neurodegeneration.”