‘Good’ Cholesterol in Brain May Aid Cognition, Help Prevent Alzheimer’s

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by Steve Bryson, PhD |

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Higher levels of small high-density lipoprotein (HDL), known as “good cholesterol,” in the fluid surrounding the brain and spinal cord associated with a better performance on cognitive tests in older adults, a study reported.

Confirmation of a link between good cholesterol levels and cognitive outcomes in larger groups could lead to new biomarkers of Alzheimer’s disease and potential therapy targets for its prevention, its researchers noted.

“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,” Hussein Yassine, MD, a neurology professor with the Keck School of Medicine at the University of Southern California (USC), said in a university press release. “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, in order to make drugs that increase small HDL in the brain,” Yassine added.

The study “The small HDL particle hypothesis of Alzheimer’s disease,” was published as a feature article in the journal Alzheimer’s & Dementia.

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Multiple studies have suggested a link between brain health and cholesterol, a fat that is necessary for the body to work properly. Because of its fat-like nature, cholesterol is transported through the bloodstream by proteins called lipoproteins.

Low-density lipoprotein (LDL), or so-called “bad” cholesterol, deposits cholesterol that can build up and block blood vessels, increasing the risk of heart attack or stroke. In contrast, HDL or “good” cholesterol collects cholesterol to be broken down and cleared.

In the brain, HDL is known to play a role in the growth, protection, and repair of nerve cells and appears to prevent inflammation. Moreover, unlike most HDL in the bloodstream, HDL particles in the brain are smaller and associated with a lipoprotein called apolipoprotein E (ApoE), which is encoded by the APOE gene.

Mutations, or variants, in the APOE gene are a strong risk factor for Alzheimer’s.

In the same way that HDL clears excess cholesterol in the body, it has been suggested that HDL in the brain helps remove clumps of misfolded proteins, known as beta-amyloid plaques and tau tangles, before they cause brain damage that leads to Alzheimer’s disease.

But studies investigating a link between HDL and Alzheimer’s have been inconsistent, and the association between HDL and cognitive function is currently unknown.

USC researchers collected blood and cerebrospinal fluid (CSF) samples, the liquid that surrounds the brain and spinal cord, from 180 healthy older adults to measure HDL levels and compare them to cognitive measures and a biomarker of Alzheimer’s.

“This study represents the first time that small HDL particles in the brain have been counted,” said Yassine, who leads a lab that specializes in lipid metabolism and Alzheimer’s. “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.”

Participants had a mean age of 76.6, were mostly female (111 women, 69 men), and 53 (30%) carried an Alzheimer’s APOE risk variant called APOE-epsilon4. Cognitive tests given to 141 people found some level of cognitive impairment in 31 of them. HDL levels were measured using a sensitive technique called ion mobility, which can discriminate between large and small HDL particles.

The researchers found a significant positive link between higher levels of small HDL in the blood and CSF and a trend toward higher blood and CSF levels of HDL among adults without the APOE-epsilon4 mutation. No correlation was seen between large HDL in the blood or CSF.

To examine HDL and Alzheimer’s risk, CSF levels of a peptide called amyloid-beta 42 were measured. This peptide — peptides are similar to proteins, but smaller — is known to contribute to Alzheimer’s when it misfolds and clumps in nerve cells in the brain. But higher CSF levels of the normal peptide are linked to a lower disease risk.

In both the CSF and blood, levels of small HDLs were higher in those with lower CSF levels of the amyloid-beta 42 peptide. Surprisingly, APOE-epsilon4 carriers with low peptide CSF levels had greater levels of small HDLs in their CSF compared with non-carriers. This suggests that “conditions that promote greater levels of brain small HDLs in individuals carrying the [APOE-epsilon4 gene] may protect against the development of [Alzheimer’s],” the team wrote.

APOE-epsilon4 mutation carriers with higher CSF peptide levels also had higher concentrations of large HDL in the CSF but not in the blood. APOE-epsilon4 status did not linked with small or large HDL levels in blood or CSF.

Overall, higher CSF levels of small HDLs correlated with better scores on neuropsychological tests for memory, global cognition, and attention/executive functioning. However, after adjusting for age, sex, and APOE risk status, only the association between small HDLs in the CSF and memory remained significant.

Follow-up analyses showed a significant correlation between higher CSF levels of small HDLs and memory scores in adults with no cognitive impairment, but not in those with some impairment. This suggests “possible neuroprotective associations of small HDLs in persons without cognitive impairment,” the researchers wrote.

“Confirmation of the role of small HDLs in the early stages of AD has important implications for AD prevention and management,” the scientists concluded. “Measurements of neuroprotective small HDLs or its components in [blood] and CSF could serve as biomarkers for guiding future clinical trials of [Alzheimer’s disease] prevention, and determination of their exchange between plasma and CSF could aid in the development” of new treatments.

“People are realizing that there is more to late-onset Alzheimer’s disease,” Yassine added. “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.”