Medical guidelines meant to reduce the risk for heart disease focus on levels of cholesterol in the blood, including low-density lipoproteins (LDL), labeled “bad cholesterol,” and high-density lipoproteins (HDL); labeled as “good.” Now, a new study suggests a meaningful connection between suitable cholesterol particles in cerebrospinal fluid and brain health as well.
Researchers at the Keck School of Medicine of USC took cerebrospinal fluid samples from people aged 60 and older and measured the number of small HDL particles in each piece. The team found that a higher number of these particles in the fluid is associated with two key indicators that the particles might have a protective effect against Alzheimer’s disease.
One indicator is better performance on cognitive tests. The other indicator is higher circulating levels in the cerebrospinal fluid of a particular peptide — like a protein, but smaller — called amyloid-beta 42. Although that peptide contributes to Alzheimer’s disease when it misfolds and clumps onto neurons, an increased concentration circulating around the brain and spine is actually linked to a lower risk of the illness.
“This study represents the first time that small HDL particles in the brain have been counted,” said Hussein Yassine, M.D., an associate professor of medicine and neurology at USC's Keck School of Medicine. “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 study has just been published in the journal Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. 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, initially developed by study co-author Ronald Krauss, M.D., at the University of California, San Francisco, the investigators were able to identify, count, and measure the size 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 or not they carried the APOE4 gene, which puts them at higher risk for Alzheimer’s disease. 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 a cognitive decline occurs.
“We’re finding here 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 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.”
A fresh Alzheimer’s research direction and the potential for prevention
Yassine and his team were led to study HDL particles in the brain by numerous links between good cholesterol and brain health. But first, it’s helpful to know a little more about what makes good cholesterol suitable.
Cholesterol itself is 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, in the same way, oil and water don’t mix; cholesterol can’t travel solo to get where it needs to go via the waterways of our blood. 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.
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 of the barrier between the brain and blood system, resulting in cognitive decline. And it may be possible that the same way HDL gets rid of excess cholesterol and fats in the body leads to cardiovascular disease. It helps clear off clumps of misfolded peptides and proteins before they cause damage in the brain 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 most potent 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 — in order better to 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 realize that there is more to late-onset Alzheimer’s disease,” Yassine said. “Perhaps it’s equally interesting to see how lipids interact with amyloid or how newer treatments can be focused on not just on amyloid or tau, but also on fats and ApoE.”
Source: USC