what are plasmalogens?
Plasmalogens are critical membrane components involved with neurotransmitter release. They are found in high concentrations in the brain and heart. They are made mostly in the liver and there are no adequate food sources. Levels dramatically decrease after age 60. They are an important part of nerve cells and help cells communicate and function. Several scientific studies show plasmalogen levels are low in people with neurodegenerative diseases including dementia, Parkinson’s, and multiple sclerosis. Plasmalogen levels are also low in pancreatic cancer, diabetes, and heart and stroke.
Plasmalogens also have antioxidant properties – some plasmalogens contain oleic acid which is a mono-unsaturated fatty acid found in olive oil and some contain polyunsaturated fatty acids like docosahexaenoic acid (DHA) which is essential for health. DHA (an omega-3 found in fish oils) promotes cardiovascular health, is required for optimal brain function, is needed for cells to function, and is anti-inflammatory.
Plasmalogen Deficiency, Dementia, and Death
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Plasmalogens are a special type of phospholipid. They are found in high concentrations in the brain, heart, lungs, kidneys, and eyes. Plasmalogens are not some trace nutrient, they actually build a big part of the brain, as much as 20% of the dry weight.
Plasmalogens act as a reservoir for important fatty acids including oleic acid, arachidonic acid, and docosahexaenoic acid (DHA)[i]. Plasmalogens are anti-inflammatory, are powerful antioxidants, are a critical part of cell membranes, maintain optimal brain function, and are a major structural part of lipoproteins, myelin, and synaptic membranes[ii].
Plasmalogen levels in the brain increase up to 30 to 40 years of age and then significantly decrease by around 70 years of age[iii]. There are no adequate food sources. The body makes plasmalogens in the peroxisomes of cells; the majority are made in the liver. The body’s ability to make plasmalogens becomes impaired as peroxisome function is compromised with age and plasmalogens are degraded from inflammation and oxidative stress.
[i] Han X. Lipid alterations in the earliest clinically recognizable stage of Alzheimer's disease: implication of the role of lipids in the pathogenesis of Alzheimer's disease. Curr Alzheimer Res. 2005 Jan;2(1):65-77. Review. PubMed PMID: 15977990.
[ii] Senanayake V, Goodenowe DB. Plasmalogen deficiency and neuropathology in Alzheimer's disease: Causation or coincidence? Alzheimers Dement (N Y). 2019 Oct 4;5:524-532. doi: 10.1016/j.trci.2019.08.003. eCollection 2019.Review. PubMed: 31650009; PubMed Central PMCID: PMC6804645.
[iii] Rouser G, Yamamoto A. Curvilinear regression course of human brain lipid composition changes with age. Lipids. 1968 May;3(3):284-7. PubMed PMID: 17805871.
why are low levels of plasmalogens bad?
Data from the Rush University Memory and Aging Project showed that a 95-year-old with high plasmalogen levels had the same chance of dying in five years as a 65-year-old with low plasmalogen levels. A 95-year-old with high levels had an almost 70 percent chance of living to their 100th birthday whereas a person the same age with low plasmalogen levels had a less than 20 percent chance of living to their 100th birthday. These results were shocking.
Decades of data show that low plasmalogen levels have severe health effects and that plasmalogen supplementation has positive health effects.
Plasmalogens and Death
There is no question that plasmalogens are important for health. But what about having low levels of plasmalogens – just how bad can it be? I have made a lot of graphs in my career and only one graph has actually scared me: the relationship between blood plasmalogen levels and death.
Probability of dying in 5.3 years
Data from the Rush University Memory and Aging Project. Final dataset: 1262 participants, participants still living since last clinical visit = 896, participants deceased since last visit = 862. Average age at enrollment = 81. Low plasmalogens = 5th percentile +/- 95% CI. High plasmalogens = 95th percentile +/- 95% CI.
Plasmalogens and neurodegeneration
Plasmalogens are involved in several diseases. I have studied plasmalogens since 2006 when I first discovered and hypothesized about the role of plasmalogens in the cause of dementia[i]. Since then, research evidence has expanded to show that plasmalogens are part of the root cause of neurodegeneration that leads to Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis.
Most published data available is for plasmalogens and dementia. Plasmalogen deficiency is associated with cognitive impairment and Alzheimer’s disease[ii]. The severity of dementia correlates with the severity of plasmalogen deficiency, irrespective of APOE allele status which is the second biggest risk factor for Alzheimer’s disease after age 3.
People with dementia have low plasmalogen levels.
Levels are significantly lower in people with all stages of dementia.
The lower the plasmalogen levels, the more severe the disease.
Levels decrease years before any clinical symptoms.
Plasmalogens are a stronger risk factor for dementia than genetics.
The presence of an APOE e4 allele is a genetic risk factor for dementia/Alzheimer’s disease. This genetic risk is modified by the plasmalogen level of that person.
E4 carriers with high plasmalogen levels do not have an increased risk for dementia.
[i] Goodenowe DB, Cook LL, Liu J, Lu Y, Jayasinghe DA, Ahiahonu PW, Heath D, Yamazaki Y, Flax J, Krenitsky KF, Sparks DL, Lerner A, Friedland RP, Kudo T, Kamino K, Morihara T, Takeda M, Wood PL. Peripheral ethanolamine plasmalogen deficiency: a logical causative factor in Alzheimer's disease and dementia. J Lipid Res. 2007 Nov;48(11):2485-98. Epub 2007 Jul 30. PubMed PMID: 17664527.
[ii] Goodenowe DB, Senanayake V. Relation of Serum Plasmalogens and APOE Genotype to Cognition and Dementia in Older Persons in a Cross-Sectional Study. Brain Sci. 2019 Apr 24;9(4). pii: E92. doi: 10.3390/brainsci9040092. PubMed PMID: 31022959; PubMed Central PMCID: PMC6523320.
why do we get low levels of plasmalogens?
The body makes a lot of plasmalogens and consumes a lot. Plasmalogen deficiency occurs when the body can no longer make as much as it consumes. This can happen due to increased oxidative stress which degrades plasmalogens[i] or decreased biosynthesis caused by aging and chronic exposure to xenobiotics[ii].
[i] Jenkins CM, Yang K, Liu G, Moon SH, Dilthey BG, Gross RW. Cytochrome c is an oxidative stress-activated plasmalogenase that cleaves plasmenylcholine and plasmenylethanolamine at the sn-1 vinyl ether linkage. J Biol Chem. 2018 Jun1;293(22):8693-8709. doi: 10.1074/jbc.RA117.001629. Epub 2018 Mar 12. PubMed PMID: 29530984.
[ii] Terlecky SR, Koepke JI, Walton PA. Peroxisomes and aging. Biochim Biophys Acta. 2006 Dec;1763(12):1749-54. Epub 2006 Aug 23. Review. PubMed PMID: 17027095.
plasmalogens and the cause of diseases
What happens when there are not enough plasmalogens in the body? Plasmalogens have both structural and functional roles in the brain. Plasmalogen deficiency leads to cell membrane changes in structure, geometry, and function as the body is forced to substitute other molecules such as phosphatidylethanolamines in place of plasmalogens. This leads to cellular signaling abnormalities and neurotransmission deficits as well as lowered antioxidant defenses[i].
Inflammation can lead to a vicious cycle where oxidative stress degrades plasmalogens which further reduces the anti-inflammatory and antioxidative capacity of the tissues ultimately leading to clinical symptoms of disease[ii].
[i] Braverman NE, Moser AB. Functions of plasmalogen lipids in health and disease. Biochim Biophys Acta. 2012 Sep;1822(9):1442-52. doi: 10.1016/j.bbadis.2012.05.008. Epub 2012 May 22. Review. PubMed PMID: 22627108.
[ii] Su XQ, Wang J, Sinclair AJ. Plasmalogens and Alzheimer's disease: a review. Lipids Health Dis. 2019 Apr 16;18(1):100. doi: 10.1186/s12944-019-1044-1. Review. PubMed PMID: 30992016.
Alzheimer’s disease results from neurodegeneration of neurons responsible for cognition: cholinergic neurons. Cholinergic neurons are especially sensitive to decreased membrane fusion activity caused by plasmalogen deficiency because, unlike other neurons, membrane fusion is necessary for both neurotransmitter release and re-uptake. Reduced membrane fusion reduces neurotransmission which reduces cognition.
Parkinson’s disease results from neurodegeneration of neurons responsible for fine motor control: dopaminergic neurons. The direct cause of Parkinson’s is unknown, but some environmental neurotoxins selectively target dopaminergic neurons and cause Parkinson’s in animals. Plasmalogen deficiency increases susceptibility to neurotoxins.
Multiple sclerosis results from neurodegeneration of cells that insulate neurons: myelin or oligodendrocytes. Myelin has the highest concentration of plasmalogens in the whole body. When immune cells are activated to clean up a mess (inflammation), part of the myelin can be damaged and extra plasmalogens are needed to repair the cells before they die. If cells cannot be repaired before they die, the debris creates even more inflammation and degeneration. High levels of plasmalogens prevents demyelination by improving remyelination.
plasmalogens to prevent disease
Plasmalogens prevent neurodegeneration in animal models; the majority of the publications are for Parkinson’s disease. In a mouse model of Parkinson’s disease, an oral dose of plasmalogen at 50mg/kg was fully neuroprotective[i]. Several publications demonstrate the neuroprotective and anti-inflammatory properties in mouse and monkey models of Parkinson’s disease[ii],[iii],[iv],[v].
[i] Miville-Godbout E, Bourque M, Morissette M, Al-Sweidi S, Smith T, Mochizuki A, Senanayake V, Jayasinghe D, Wang L, Goodenowe D, Di Paolo T. Plasmalogen Augmentation Reverses Striatal Dopamine Loss in MPTP Mice. PLoS One. 2016 Mar 9;11(3):e0151020. doi: 10.1371/journal.pone.0151020. eCollection 2016. PubMed PMID: 26959819.
[ii] Nadeau J, Smith T, Lamontagne-Proulx J, Bourque M, Al Sweidi S, Jayasinghe D, Ritchie S, Di Paolo T, Soulet D. Neuroprotection and immunomodulation in the gut of parkinsonian mice with a plasmalogen precursor. Brain Res. 2019 Dec 15;1725:146460. doi: 10.1016/j.brainres.2019.146460. Epub 2019 Sep 13. PubMed PMID: 31525350.
[iii] Bourque M, Grégoire L, Di Paolo T. The plasmalogen precursor analog PPI-1011 reduces the development of L-DOPA-induced dyskinesias in de novo MPTP monkeys. Behav Brain Res. 2018 Jan 30;337:183-185. doi: 10.1016/j.bbr.2017.09.023. Epub 2017 Sep 14. PubMed PMID: 28917506.
[iv] Miville-Godbout E, Bourque M, Morissette M, Al-Sweidi S, Smith T, Jayasinghe D, Ritchie S, Di Paolo T. Plasmalogen precursor mitigates striatal dopamine loss in MPTP mice. Brain Res. 2017 Nov 1;1674:70-76. doi: 10.1016/j.brainres.2017.08.020. Epub 2017 Aug 19. PubMed PMID: 28830769.
[v] Grégoire L, Smith T, Senanayake V, Mochizuki A, Miville-Godbout E, Goodenowe D, Di Paolo T. Plasmalogen precursor analog treatment reduces levodopa-induced dyskinesias in parkinsonian monkeys. Behav Brain Res. 2015 Jun 1;286:328-37. doi: 10.1016/j.bbr.2015.03.012. Epub 2015 Mar 11. PubMed PMID: 25771209.
Scientifically designed plasmalogen supplement
After years of extensive research I designed plasmalogen supplements as a plasmalogen precursor that survives the gut and is then converted to the target plasmalogen molecule independent of peroxisomal function.
I first designed and invented a series of plasmalogen drugs because at the time there was a patent protecting the use of natural plasmalogens for dementia which just expired last year. I have since designed and developed natural plasmalogen supplements, the first being ProdromeNeuro developed by my company Prodrome Sciences, that has the same activity as my previously invented PPI-1011 plasmalogen drug.
While we continue to advance research on plasmalogens to answer important questions about the use in disease management, one thing is clear today: plasmalogens are an essential brain nutrient you do not want to be low on. Our scientifically designed, natural plasmalogen supplement ensures there is an adequate amount of plasmalogens in the blood supply for health.