Scientists from the Keck School of Medicine of USC have discovered that HDL cholesterol – popularly known as ‘good’ cholesterol – may effectively stop the development of Alzheimer’s disease.
Medical guidelines aiming to reduce heart disease risk concentrate on levels of cholesterol in the blood, such as low-density lipoproteins (LDL cholesterol), labelled as ‘bad’ cholesterol, and high-density lipoproteins (HDL cholesterol). Now, researchers from the Keck School of Medicine of USC have identified an association between HDL cholesterol particles in cerebrospinal fluid and good cognitive health.
The team analysed cerebrospinal fluid samples from people aged 60 and older, assessing the amount of small HDL cholesterol particles in each sample, discovering that a higher number of these particles was associated with two essential indicators that the particles may protect from Alzheimer’s disease.
One of the indicators was a better performance on cognitive tests, and the other was higher circulating levels in the cerebrospinal fluid of a particular peptide called amyloid-beta 42, which is similar to a protein, but smaller. Although amyloid-beta 42 contributes to Alzheimer’s disease development when it misfolds and clumps onto neurons, higher concentrations of the peptide circulating in the brain and spine are linked to lower disease risk.
Hussein Yassine, MD, an associate professor of medicine and neurology at the Keck School of Medicine of USC, commented: “This study represents the first time that small HDL particles in the brain have been counted. 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.”
Relationship between cognitive health and HDL cholesterol
For their study, the team enrolled 180 participants with an average age of 77, examining samples of their blood plasma and cerebrospinal fluid using a sensitive method called ion mobility. This enabled the researchers to identify, count and measure the size of individual HDL cholesterol particles, with 141 of the participants also completed a range of cognitive tests.
Of the individuals who completed the cognitive tests, the participants with higher levels of small HDL particles in their cerebrospinal fluid achieved better performance, independent of their age, sex, education or whether or not they carried the APOE4 gene, which would give them a higher risk of Alzheimer’s disease.
Moreover, the association was stronger in those who had no cognitive impairment, with results suggesting that HDL cholesterol particles may be a crucial avenue for developing treatments that work early in the development of Alzheimer’s, long before cognitive decline starts.
Yassine said: “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. 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 in order to make drugs that increase small HDL in the brain.”
Preventing Alzheimer’s disease
The researchers were driven to analyse HDL cholesterol particles in the brain due to the plethora of ways they keep the brain healthy. HDL particles help form the sheaths that insulate the brain and nerve cells so that they can communicate together; they also help prevent inflammation of the barrier between the brain and blood system, which can cause cognitive decline.
In contrast to HDL cholesterol in the blood, HDL particles in the brain are smaller and require a protein called apolipoprotein E (ApoE) to perform. The APOE4 gene – the most significant risk factor for Alzheimer’s disease – is a mutation of the APOE gene that encodes that very same protein.
To comprehend the structure and mechanisms of ApoE HDL, the team is currently conducting studies using electron microscopy, which can obtain images down to the molecular level. They also aim to analyse ApoE HDL and Alzheimer’s risk over time in larger groups of participants, investigating factors such as the effects of medications and diseases, including diabetes.
Yassine concluded: “People realise that there is more to late-onset Alzheimer’s disease. 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.”
