Alzheimer Issues
'Good' Cholesterol – May Play a Role in Reducing the Risk of Alzheimer's Disease
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Apr 25, 2022 - 11:12:00 AM

(HealthNewsDigest.com) - A new USC study published this month in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association finds that small high-density lipoprotein (HDL) particles – also known as “good” cholesterol – may play a role in reducing the risk of Alzheimer's disease.

High circulating levels of these particles in cerebrospinal fluid was associated with better performance on cognitive tests. An abundance of “good” cholesterol was also linked with high levels of a particular protein called amyloid beta 42, which may lower risk for Alzheimer’s.

“This study represents the first time that small HDL particles in the brain have been counted,” said Hussein Yassine, an associate professor of medicine and neurology at the Keck School. “They may be involved with the clearance and excretion of the peptides that form the amyloid plaques we see in Alzheimer’s disease, so we speculate that there could be a role for these small HDL particles in prevention.”

Connections between HDL and brain health

The researchers recruited 180 healthy participants with an average age of nearly 77 and analyzed samples of their blood plasma and cerebrospinal fluid. Using a sensitive technique known as ion mobility, the investigators were able to identify, count and measure the size and amount of individual HDL particles. A subset of 141 participants also completed a battery of cognitive tests.

Of the participants who took the cognitive tests, the ones with higher levels of small HDL particles in their cerebrospinal fluid performed better, independent of their age, sex, education or whether they carried the APOE4 gene. The correlation was even stronger among those who had no cognitive impairment. The evidence suggests that these HDL particles may be key to finding treatments that would work early in the disease process, long before cognitive decline occurs.

“What we’re finding here is that before the onset of cognitive impairment, these oils — these small HDL particles — are lubricating the system and keeping it healthy,” he said. “You’ve got a time to intervene with exercise, drugs or whatever else to keep brain cells healthy. We still need to understand the mechanisms that promote the production of these particles, to make drugs that increase small HDL in the brain.”

Yassine and his team were led to study HDL particles in the brain by numerous links between good cholesterol and brain health.

Cholesterol itself is a fat necessary for the body to function, but at consistently high levels, excess cholesterol can build up in the walls of veins and arteries and poses the risk of eventual blockage that can cause a heart attack or stroke.

However, the same way oil and water don’t mix, cholesterol can’t travel solo to get where it needs to go via the bloodstream. Instead, it’s gathered, transported and released by balls of protein and fat called lipoproteins, including LDL and HDL. “Bad” LDL deposits cholesterol in the body, while “good” HDL collects cholesterol for breakdown, recycling and ejection by the liver.

A fresh direction and the potential for prevention

In the brain, HDL helps form the sheaths that insulate the brain and nerve cells so they can quickly communicate amongst themselves, and it plays a role in the growth and repair of neurons. It also appears to help prevent inflammation to the barrier between the brain and blood system, which can result in cognitive decline.

And it may be possible that, the same way HDL gets rid of excess cholesterol and fats in the body that lead to cardiovascular disease, it helps clear off clumps of misfolded peptides and proteins before they cause damage in the brain leading to Alzheimer’s disease.

But unlike most HDL in the blood, HDL particles in the brain are smaller and need a protein called apolipoprotein E, or ApoE, to do their work. The strongest risk factor for Alzheimer’s disease, the APOE4 gene, is a mutation or variant of the APOE gene that encodes that very same protein.

Yassine and his colleagues already have studies underway using electron microscopy — which can capture images down to the molecular level —to better understand the structure and function of ApoE HDL. They also hope to study ApoE HDL and Alzheimer’s risk over time in larger groups of participants, with an eye toward elucidating factors such as the effects of medications and diseases including diabetes.

“People are realizing that there is more to late-onset Alzheimer’s disease,” Yassine said. “Perhaps it’s equally interesting to see how lipids are interacting with amyloid or how newer treatments can be focused not just on amyloid or tau, but also on fats and ApoE.”

About this study

Co-first authors of the study are Ashley Martinez of the Keck School of Medicine of USC, Gali Weissberger of Bar Ilan University and Zsuzsanna Kuklenyik of the Centers for Disease Control and Prevention. Other authors are Xulei He, Cristiana Meuret, Trusha Parekh, Jon Rees, Bryan Parks, Michael Gardner, Melanie Sweeney, Michael Harrington, Xinhui Wang, Berislav Zlokovic, Elizabeth Joe, Lon Schneider, Helena Chui, John Barr and Duke Han, all of USC; Sarah King of UCSF; Timothy Collier of Quest Diagnostics in Cleveland; and Daniel Nation of the University of California, Irvine.

The study was supported by the National Institutes of Health, the L.K. Whittier Foundation, the Huntington Medical Research Institutes, the Dairy Research Institute, Quest Diagnostics, Saliogen, the Della Martin Foundation, the Cure Alzheimer’s Fund, the Foundation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease, the Centers for Disease Control and Prevention and Washington University. The Batey Foundation funded instrumentation used for ion mobility analysis.