CHICAGO — New research reveals there may be a relationship between faulty lipid metabolism and Alzheimer’s disease (AD).
One such clue involves plasmalogens, a class of lipids containing long-chain fatty acids, such as the omega-3 docosahexaenoic acid (DHA) found in fish oil. These lipids are essential for proper membrane function.
A new study links reduced levels of plasmalogens to cognitive decline. The thinking is that faulty metabolism of these lipids in the liver results in less transport to the brain.
“The liver is a kind of factory for making plasmalogens that are packaged into lipoproteins and shipped to the brain, and we think that in Alzheimer’s disease, there is an insufficient amount of these plasmalogens to support normal brain function,” study author Mitchel A. Kling, MD, Veterans Affairs Medical Center and associate professor of psychiatry at Perelman School of Medicine, University of Pennsylvania, Philadelphia, told Medscape Medical News.
Finding an alternative way to get these lipids to the brain that bypasses the liver could offer a solution.
The study, and other related research, was presented here at the Alzheimer’s Association International Conference (AAIC) 2018.
Brain Function Regulation
During a press briefing, Kling noted that plasmalogens have unique properties, including the regulation of membrane functions in the brain and elsewhere. He noted that these lipids are important for synapse function, including the release of neurotransmitters, and that alteration of synaptic function is a hallmark of AD.
With age, levels of circulating plasmalogens drop off, which may reflect a decline in the function of peroxisomes, said Kling. Peroxisomes are necessary for the breakdown of long-chain fatty acids to be used to form membranes.
The liver is a key site for synthesis of plasmalogens, which are then exported in circulating lipoproteins for delivery to the central nervous system, said Kling.
For this new study, researchers collected serum samples from 1545 participants enrolled in the Alzheimer’s Disease Neuroimaging Initiative. Participants had AD, mild cognitive impairment (MCI), or normal cognition and were of similar age, sex, and education.
Researchers also had samples from 112 participants with AD, MCI or normal cognition from the Penn Alzheimer’s Disease Center.
The investigators used indices of different plasmalogens. Based on previous research, they examined plasmalogens containing DHA and eicosapentaenoic acid, another omega-3 fatty acid, and an omega-6 fatty acid.
They found that low levels of plasmalogen indices were significantly associated with increased likelihood of AD and MCI in both cohorts. As well, low levels were associated with cerebrospinal fluid (CSF) levels of total tau protein, a biomarker for AD, and with the ratio of tau to CSF amyloid β (Aβ), in both samples.
Biologically Meaningful
In general, the patterns showed that levels were lowest among patients with AD, followed by those with MCI and then health persons, Kling told Medscape Medical News.
Although the researchers didn’t compute the data to provide odds ratios, “if you lump all the values together, everyone who is below the highest 20% has a higher risk of developing Alzheimer’s disease. It’s at a level that seems biologically meaningful,” said Kling.
The investigators did not find an association between plasmalogen indices and Aβ alone in either cohort. Although researchers aren’t certain why this is, Kling has a theory that pertains to timing.
He explained that plasmalogen loss may occur closer to the time when people develop symptoms. By the time patients have cognitive impairment, amyloid has likely been accumulating in their brain for many years (although some patients with amyloid burden don’t develop symptoms), but tau changes closer to the time when cognitive impairment begins.
“It may be that when the plasmalogen levels fall to a certain level, that is followed soon afterwards by cognitive symptoms and by tau elevation.”
Interestingly, the APOE4 gene, which is linked to AD, does not seem to be associated with low plasmalogen levels, said Kling.
“There is even some data suggesting that a high plasmalogen level can offset the increased risk conferred by having the APOE4 variant,” he added.
In addition to AD, low levels of plasmalogens may be associated with other neurodegenerative diseases, such as Parkinson’s disease, said Kling.
Kling and his team are investigating an approach to correct the lipid transport problem that does not depend on the liver. They have received a grant to study an oral daily supplement containing a precursor of plasmalogen (so the process that the liver would carry out is already done).
The compound has been tested in animals. These studies suggest that the compound increases plasmalogen levels and “corrects some of the deficits in behavior and cognition associated with plasmalogen deficiency,” said Kling.
The aim of the upcoming 16-week study, which will use an ascending-dose approach, is to determine safety and tolerability of the compound in patients with AD and MCI and whether it boosts plasmalogen levels in the blood and spinal fluid.
Results should be available within the next 3 years.
While a diet rich in foods with omega-3 fatty acids — such as seafood — appears to protect against dementia, taking fish oil supplements doesn’t seem to have that effect. A possible explanation for this paradox, said Kling, is that these supplements don’t boost plasmalogens.
“That’s because you have this defect at the level of the peroxisome.”
Supplements No Help
Another study highlighted during the press briefing found that metabolism of certain unsaturated fatty acids is disturbed in people with AD, particularly among men and those who are obese. However, taking supplements with high levels of omega-3 fatty acids failed to bring lipid levels back to normal.
These and other studies discussed during the briefing are part of a growing body of work related to the “gut-liver-brain” axis.
The field of gut bacteria research has yielded new information on how some bacteria may lead to inflammation and disease. There’s evidence that some species in the microbiome can promote protein buildup in the brain.
Gut bacteria can be altered through diet, some studies show.
“As a nutritional scientist, I am really excited about these types of studies,” commented briefing chair, Martha Clare Morris, ScD, professor, Department of Internal Medicine, Division of Digestive Diseases and Nutrition, Rush Medical College, Chicago, Illinois.
Such research “provides clues to how eating patterns may be linked to brain health and dementia,” said Morris.
“These clues can hopefully lead to therapeutic interventions and better screening and diagnostic methods, and can advance knowledge around specific foods and diet patterns that will prevent dementia.”
Morris is co-principal investigator for the US POINTER study, which was announced at last year’s AAIC meeting. The study will test whether combining a healthy diet with exercise, cognitive and social stimulation, and management of cardiovascular conditions will prevent decline in cognitive ability and development of AD.
No relevant financial relationships have been disclosed.
Alzheimer’s Association International Conference (AAIC) 2018. Abstract 26446. Presented July 24, 2018.
