Plasmalogens and Alzheimer's Prevention
Let's be honest, no one wants to increase their longevity just to have years of Alzheimer's or dementia.
When reading through studies on Alzheimer's, a picture emerges showing the following:
Melatonin (higher without light at night) is important as an antioxidant in the brain[ref]
Circadian rhythm dysregulation is part of Alzheimer’s pathology[ref]
Viral or bacterial pathogens in the brain can cause insult, cell damage, and oxidative stress[ref]
Heavy metals (iron, aluminum, lead, cadmium) cause oxidative stress in the brain[ref][ref]
Toxicants, bad food, air pollution, stress, lack of exercise -- all add to the picture.
The Bredesen protocol for reversing mild cognitive impairment with a good diet, supplements, and exercise shows that the dial can be moved a little bit in Alzheimer's pathology with easy-to-implement changes.[ref]
While a lot of research has focused on amyloid-beta plaque in the brain, targeting amyloid-beta with expensive drugs doesn't seem to cure Alzheimer's.
Instead, a picture emerges of oxidative stress - due to mitochondrial dysfunction, or pathogens, or toxins, or circadian disruption - that overwhelms the cellular antioxidant defense in the brain. For example, high levels of inflammatory cytokines and reactive oxygen species (ROS) are produced to fight infection and low levels may persist for a latent infection. Additionally, mitochondrial dysfunction (due to toxins, metals, etc) generates higher levels of ROS.
Aging brings on higher levels of cellular senescence, with accompanying cytokines and ROS. Melatonin is also an important intracellular antioxidant in the brain, and melatonin levels decrease with age as the pineal gland calcifies.
One promising area of research in preventing Alzheimer's focuses on a type of antioxidant called ethanolamine plasmalogen.
Plasmalogens as antioxidants and cell membrane components:
A source of cellular antioxidants that isn't talked about much is ethanolamine plasmalogen. This is a phospholipid that makes up about 20% of the cell membrane in brain cells. Much of the fatty acid composition of ethanolamine plasmalogens is composed of DHA (omega-3 fatty acid from fish oil).
Ethanolamine plasmalogen is important for two reasons:
one, it is a more flexible part of the plasma membrane, allowing for greater movement of vesicles in and out of the cell
two, the type of bond in ethanolamine plasmalogen allows it to bind and neutralize oxidized lipids and ROS
When ROS levels in the brain overwhelm the brain's antioxidant capacity (glutathione, Nrf2, melatonin), the rest of the oxidative stress can be neutralized by plasmalogens. However, neutralizing oxidation degrades the plasmalogen, and it will need to be replaced in the cell. All is good - until plasmalogen levels drop too low.
Given the importance of plasmalogens in brain health, researchers have investigated their role in Alzheimer's disease.
So what is known about plasmalogens and Alzheimer's?
Multiple research studies show that ethanolamine plasmalogen is decreased in Alzheimer's brains.[ref][ref] While plasmalogen levels decrease for everyone in aging, in Alzheimer's patients they are a lot lower than in aged-matched, healthy control groups. In fact, one study found the levels to be <75% of normal people of the same age.[ref] (This isn't exactly new science, either, with studies showing the low ethanolamine plasmalogen levels dating back 30 years[ref])
Importantly, the severity of dementia in Alzheimer's patients correlates to the ethanolamine plasmalogen content in the cortex and hippocampus areas of the brain. Additionally, circulating serum ethanolamine plasmalogen levels are significantly decreased in patients with dementia, and the severity of the decrease mirrors the severity of the dementia.[ref]
One thing that goes wrong in the brain of people with AD is the build-up of amyloid-beta plaques of different lengths. In addition to all the other roles that plasmalogens play in keeping neurons healthy and functioning well, ethanolamide plasmalogen also reduces the activity of γ–secretase, which is an enzyme needed for the formation of the amyloid-beta plaque.[ref]
The APOE E4 allele is one of the strongest genetic risk factors for late-onset Alzheimer's disease. Similarly, the APOE E2 allele is one of the strongest genetic protectors against Alzheimer's. A study showed that people with APOE E4 alleles have lower plasmalogen levels, while people with APOE E2 have higher levels.[ref]
Considering the decreased plasmalogen levels in Alzheimer's patients, researchers have explored ways to restore these critical antioxidants.
Restoring depleted plasmalogen levels:
If plasmalogens are the last line of defense, can they be restored?
It seems like in the early stages of cognitive impairment the answer is yes.
Clinical trials in Japan have shown supplemental plasmalogen to be effective at improving memory in people with Alzheimer's. It seems to be more effective in mild AD and in younger patients.[ref][ref]
Very importantly, research shows that optimal plasmalogen levels can mitigate the increased APOE E4 risk in Alzheimer's disease.[ref][ref]
What's the catch? Well, the plasmalogen supplements are currently pretty expensive and will likely cost hundreds of dollars a month. If you're facing going into nursing care for Alzheimer's, a few hundred a month is an easy cost benefit. But if you are just trying to prevent cognitive decline a decade or two in the future, then it is a harder decision to make.
While it may seem obvious, the best way to have higher plasmalogen levels is to not let them get depleted from oxidative stress in the brain. So everything you read about brain health - antioxidants, avoiding toxicants, stable blood glucose, avoiding heavy metals, etc - all still applies. For example, a cell study using neurons showed that increasing vitamin B12 levels protected plasmalogens from oxidative stress.[ref]
Supplements to boost plasmalogens:
For those interested in increasing their plasmalogen levels quickly with supplements, several options are available on the market.
Prodrome (https://prodrome.com/) is one company that specializes in plasmalogen supplements and research. They are synthesizing the plasmalogens in a lab rather than trying to derive them from shellfish. In addition, Prodrome offers a blood test kit ($499) to see if you need their products. I haven't used anything from this company, so be sure to do your own research into whether it is a valid product.
Other supplements include NeuroRegain and NeuroPlas Plamalogen Complex (both on Amazon). Be sure to check the serving sizes and amount of plasmalogens in each.
While supplements can be effective, dietary changes can also help increase plasmalogen levels naturally.
How can I increase plasmalogens in my diet:
If expensive supplements aren't a good option for you, then you may want to consider optimizing your diet to increase plasmalogen levels.
Ethanolamine plasmalogen levels are highest in seafood and chicken:[ref]
shrimp
clams
squid
mussels
certain types of fish (tuna and salmon are higher than bream or amberjack)
chicken
lamb
Plasmalogens are also found in beef and pork, but these skew more to the choline plasmalogens instead of ethanolamine plasmalogens (still good, just more for heart health than brain health).
Cooking methods likely matter here. Plasmalogens in meat are very susceptible to oxidation and degradation during cooking at high heat.[ref] A recent Japanese study found that the surface of fried meat had decreased plasmalogen levels, while the plasmalogen levels were reduced throughout the meat in roasting and long boiling.[ref]
Mediterranean keto? A preprint study from 2023 also found that a ketogenic diet improved plasmalogen levels (both ethanolamine and choline plasmalogens) in 20 elderly adults with early signs of cognitive impairment. The study was a cross-over design with participants eating either a modified Mediterranean ketogenic diet or the low-fat American Heart Association diet for 6 weeks. This was followed by a 6-week washout period of eating their normal diet, and then the participants crossed over and ate the other diet for six weeks. The results seem to show marked improvements in lipid profiles for the modified Mediterranean keto diet compared to either the AHA diet or normal eating patterns.[ref]
Bigger picture:
While plasmalogens are a crucial piece of the puzzle, it's essential to remember that maintaining brain health requires a multi-faceted approach. Antioxidants, clean living, good sleep, and melatonin production at night -- all are still very important in brain health. This information on plasmalogens is one more part of the big picture for preventing Alzheimer's, explaining what goes wrong in the end when the last line of cellular defense is breached.
The research on plasmalogens goes well beyond just preventing dementia. Even in healthy young adults, a placebo-controlled trial showed that plasmalogen supplements for four weeks boosted mood and enhanced concentration.[ref] Another recent study showed the likely role of ethanolamide plasmalogens in MS.[ref]
I'm sure there will be a lot more research to come out on the topic over the next few years.