Article Archive
September/October 2019

Clinical Matters: High-Plasmalogen Diets and Alzheimer’s
By Carissa Perez Olsen, PhD
Today’s Geriatric Medicine
Vol. 12 No. 5 P. 6

Supplements are commonly used to provide nutrients or vitamins that are not provided in the diet in sufficient quantities, such as the omega fatty acids found in fish oil. Although plasmalogens are not yet among the commonly known supplements, increasing plasmalogen levels may be important to preventing Alzheimer’s disease (AD). Plasmalogens are a specialized type of phospholipid—the molecules that build our cellular membranes. Until plasmalogens are available in pill form, foods that are high in plasmalogens, such as scallops, may help people with mild cases of Alzheimer’s disease improve their cognitive function.

Although more research needs to be done to determine the best way to increase plasmalogen levels, evidence is mounting about why and how this may work. In the meantime, adding more scallops, mussels, and other types of seafood to the diet of AD patients is a low-risk and relatively simple intervention with significant potential benefits.

Plasmalogens and Their Connection to AD
The advent of mass spectrometry-based measurements has allowed for the comparison of the molecules that are altered during AD. One of the changes that has emerged from these studies is a consistent depletion in plasmalogens. There’s tremendous diversity in the types of phospholipids found in membranes, and plasmalogens are a part of that diverse landscape. Plasmalogens make up more than 20% of phospholipids in humans and are particularly plentiful in the nervous system.1 In AD patients, plasmalogen levels decrease by up to 40%.2,3

The identification of this significant reduction in plasmalogens is important in two aspects of AD: early detection of the disease and therapeutic intervention.

First, these losses of plasmalogens may be useful biomarkers that signal the onset of AD. The advantage of identifying plasmalogens levels, as opposed to other detection methods, is that reduced plasmalogens can be seen in blood and do not require expensive and sometimes invasive alternatives.4 Importantly, the depletion of plasmalogens occurs before the onset of symptoms, and the decline in levels is correlated with the severity of disease.2 This presents an opportunity to develop these lipids as biomarkers for AD and other dementias.5

Second, restoring plasmalogen levels may be an important way to improve cognitive function in AD patients and potentially delay or prevent the onset of the disease. The role of plasmalogens in biology is not fully understood, but it’s clear that plasmalogens are important for the ability of cells to survive in stressful conditions, particularly when there are high levels of chemically reactive molecules that can damage cellular components. It’s not known how plasmalogens protect the cells in these conditions, but it’s clear that when plasmalogens are absent, the cells die more often.1,6 The role of plasmalogens in protecting cells from damage predicts that replenishing plasmalogens in patients would be beneficial.

In summary, a decrease in plasmalogens may be an effective way to identify AD before symptoms are noticeable in patients. We can measure plasmalogen depletion and intervene much earlier than otherwise would be possible. One of the ways to intervene and prevent disease progression is to replace the plasmalogens that are lost in these patients.

Dietary Supplements Improve Cognitive Function
Unlike other macromolecules such as protein and DNA, lipid composition can be altered through dietary changes, which presents a unique opportunity for intervention. Studies in mice and other models demonstrated a therapeutic benefit in providing plasmalogens to the diet to mitigating memory loss.7 Due to the ease and safety of the use of dietary supplements, a clinical study recently added plasmalogens to the diets of patients with early AD and showed cognitive improvement in mild cases.8

That clinical study tested 328 patients aged 60 to 85 with mild AD and mild cognitive impairment; these patients scored 20 to 27 points on the MiniMental State Examination in Japan, where the study was conducted. They received either 1 mg/day of plasmalogens purified from scallops or a placebo. In mild AD patients, measures of memory (WMS-R test) improved significantly in the treatment group among females and those younger than 77 years old. There was no statistically significant improvement in more advanced patients, suggesting that early intervention is critical.

Because beneficial effects of plasmalogen supplementation have been seen in AD, there have been efforts to identify sources of plasmalogens in food. In the 2016 study, the highest level of plasmalogens was found in ascidians (also called sea squirts), mussels, and scallops.9 There are also significant levels of plasmalogens in pork and beef. Plasmalogens are a group of lipids that can vary in the fatty acids and the headgroups that are components of lipids. Studies have not yet determined whether particular types of plasmalogens would have a greater benefit than others.

The Function of Plasmalogens
Plasmalogens were accidentally identified more than a hundred years ago. These lipids have a bond that’s sensitive to acid, and in early protocols to stain cells for imaging, the addition of acid reacted with these lipids, producing artifacts that looked like plasma.10 Despite their early identification, relatively little is known about their biological function. Their role is likely multifaceted, as people who lack the ability to produce plasmalogens have a peroxisomal biogenesis disorder and rarely survive past the age of 1. These patients have a suite of symptoms—including cognitive impairment, developmental delays, and a severely reduced lifespan.1

Along with studies from these patients, experiments with animals and model systems have suggested a number of potential functions of plasmalogens. One of the prominent features of plasmalogen deficiency is an intolerance to stress. This suggests that plasmalogens may play a role as sacrificial antioxidants, by which they are damaged in a way that mitigates the overall damage to the cell.1 An alternative model is that plasmalogens can function in signaling pathways to activate the appropriate response to elevated damage within the cells. Studies from Caenorhabditis elegans, a nematode system recently developed as a model for plasmalogen deficiency, are underway to determine the role of these plasmalogens in stress response as well as in other aspects of biology.11,12

Without plasmalogens, all cells are more likely to die. It’s not clear why that is, but it’s known that cells are better able to survive stresses with the appropriate amount of plasmalogens.

Membrane Changes in Natural Aging
Membrane changes are not specific to AD and have been observed in other neurodegenerative diseases as well as in various aging-related diseases.13 Membrane changes also occur over the course of natural aging, where the types of lipids that are found in our membranes change as we age. In comparison with young, healthy individuals, the membranes of older people have significantly more saturated fatty acids and more damaged fatty acids.14

There have been a number of interesting observations made about the connections between membrane composition and aging. For instance, the membranes of nonagenarians tend to have membranes that contain significantly fewer polyunsaturated fatty acids.15 Animal studies have also found correlations between longevity and healthy membrane composition.16 However, it’s yet to be established whether impacts on membrane composition can improve aging, and in particular, lead to heathy aging.

Future Studies
The clinical studies completed thus far have been limited to the use of general plasmalogen supplements purified from scallops.8 There’s significant potential to improve upon the supplementation protocol by testing more specific plasmalogen combinations. Because clinical studies are expensive and take significant amounts of time, model systems can be useful in determining the supplementation with the most potential before moving into clinical trials.

In addition to defining the most efficacious protocols, model systems are also being used to determine the genetic pathways that result in plasmalogen deficiencies. Knowing more about the genetic basis would generate potential targets; this, in turn, would identify pharmacological targets that may allow for even greater and rapid improvement in plasmalogen levels in patients where plasmalogen reduction has been observed.

Finally, more understanding about the role of plasmalogens in biology is needed to know how their depletion may cause the onset and progression of AD and other neurodegenerative diseases. Studies in model systems will help to clarify the role of plasmalogens in AD onset and progression. In addition to human cell culture, a nematode, C elegans, has been recently established as a model for plasmalogen deficiency.11,12 This model has several benefits. The nematodes allow for studies of how plasmalogens work, and they provide a platform for rapid screening of supplementation protocols to determine the most effective dietary options.

One of the advantages to studying membranes in C elegans is the ability to incorporate large amounts of tracers into the diet of the animal. These tracers can then be detected in the membranes of the animal by mass spectrometry. The ability to incorporate tracers into the membranes of C elegans allows us to measure the dynamics of membrane lipids.17 Using this system, we are providing individual and different combinations of plasmalogens to C elegans to determine which supplementation regime will have the best outcome on membrane health.

Summary
There’s significant potential to make dietary changes to help people with mild AD improve their cognitive functions. Increasing an AD patient’s intake of mussels, scallops, and other types of seafood is a relatively simple way to get started until further research clarifies more specific dietary interventions that will work for the majority of people.

— Carissa Perez Olsen, PhD, the Leonard P. Kinnicutt Assistant Professor of Chemistry and Biochemistry at Worcester Polytechnic Institute, is using a grant from the National Institutes of Health to gain a better understanding of the role lipids play in longevity and long-term health.

 

References
1. Braverman NE, Moser AB. Functions of plasmalogen lipids in health and disease. Biochim Biophys Acta. 2012;1822(9):1442-1452.

2. Han X, Holtzman DM, McKeel DW Jr. Plasmalogen deficiency in early Alzheimer’s disease subjects and in animal models: molecular characterization using electrospray ionization mass spectrometry. J Neurochem. 2001;77(4):1168-1180.

3. Marin R, Fabelo N, Martin V, et al. Anomalies occurring in lipid profiles and protein distribution in frontal cortex lipid rafts in dementia with Lewy bodies disclose neurochemical traits partially shared by Alzheimer’s and Parkinson’s diseases. Neurobiol Aging. 2017;49:52-59.

4. Jack CR Jr, Holtzman DM. Biomarker modeling of Alzheimer’s disease. Neuron. 2013;80(6):1347-1358.

5. Wood PL, Mankidy R, Ritchie S, et al. Circulating plasmalogen levels and Alzheimer Disease Assessment Scale-Cognitive scores in Alzheimer patients. J Psychiatry Neurosci. 2010;35(1):59-62.

6. Sindelar PJ, Guan Z, Dallner G, Ernster L. The protective role of plasmalogens in iron-induced lipid peroxidation. Free Radic Biol Med. 1999;26(3-4):318-324.

7. Hossain MS, Tajima A, Kotoura S, Katafuchi T. Oral ingestion of plasmalogens can attenuate the LPS-induced memory loss and microglial activation. Biochem Biophys Res Commun. 2018;496(4):1033-1039.

8. Fujino T, Yamada T, Asada T, et al. Efficacy and blood plasmalogen changes by oral administration of plasmalogen in patients with mild Alzheimer’s disease and mild cognitive impairment: a multicenter, randomized, double-blind, placebo-controlled trial. EBioMedicine. 2017;17:199-205.

9. Yamashita S, Kanno S, Honjo A, et al. Analysis of plasmalogen species in foodstuffs. Lipids. 2016;51(2):199-210.

10. Snyder F. The ether lipid trail: a historical perspective. Biochim Biophys Acta. 1999;1436(3):265-278.

11. Drechsler R, Chen SW, Dancy BC, Mehrabkhani L, Olsen CP. HPLC-based mass spectrometry characterizes the phospholipid alterations in ether-linked lipid deficiency models following oxidative stress. PLoS One. 2016;11(11):e0167229.

12. Shi X, Tarazona P, Brock TJ, Browse J, Feussner I, Watts JL. A Caenorhabditis elegans model for ether lipid biosynthesis and function. J Lipid Res. 2016;57(2):265-275.

13. Fabelo N, Martin V, Santpere G, et al. Severe alterations in lipid composition of frontal cortex lipid rafts from Parkinson’s disease and incidental Parkinson’s disease. Mol Med. 2011;17(9-10):1107-1118.

14. Maeba R, Maeda T, Kinoshita M, et al. Plasmalogens in human serum positively correlate with high-density lipoprotein and decrease with aging. J Atheroscler Thromb. 2007;14(1):12-18.

15. Puca AA, Andrew P, Novelli V, et al. Fatty acid profile of erythrocyte membranes as possible biomarker of longevity. Rejuvenation Res. 2008;11(1):63-72.

16. Shmookler Reis RJ, Xu L, Lee H, et al. Modulation of lipid biosynthesis contributes to stress resistance and longevity of C. elegans mutants. Aging (Albany NY). 2011;3(2):125-147.

17. Dancy BC, Chen SW, Drechsler R, Gafken PR, Olsen CP. 13C- and 15N-labeling strategies combined with mass spectrometry comprehensively quantify phospholipid dynamics in C. elegans. PLoS One. 2015;10(11):e0141850.