Got the ApoE4 gene for Alzheimer’s? Don’t worry. Here’s what you need to know

This is a hopeful message for everyone with APOE4! having the APOE4 allele isn’t a definitive path to Alzheimer’s. Lets just get that clear. While it’s true that APOE4 can affect cholesterol efflux and amyloid deposition in the brain, there’s so much more to the story.

We now this is true because not all carriers of APOE4 will experience high amyloid levels. Some may even have low levels (this has been observed numerous time), proving that genetics is just one piece of the puzzle

The way our bodies manage cholesterol is crucial. Healthy systems can help balance the effects of APOE4, thereby promoting better cholesterol efflux and reducing unhealthy processing of amyloid precursor protein, which is a hallmark feature of Alzheimer’s as many of you know.

Many systems work together to influence brain health and cholesterol elfux. High levels of plasmalogen, for example, is one mechanism that can be leveraged to lower harmful amyloid production.

This highlights much of what I’ve been discussing with regard to genetics recently. We like to hyper-focus on one or two pathways or mechanisms, ignoring many of the compensatory and supportive systems involved in regulating various processes (like cholesterol efflux) in the body.

The body is smart and rarely leaves us with only one way to carry out important biological functions and processes.

In 2019, Dayan Goodenowe, published comprehensive epidemiological research exploring the correlation between APOE genotypes and blood plasmalogens in a cohort of 1,205 individuals aged 58 to 104, with an average age of 84. The key finding from this study was that elevated levels of blood plasmalogens appeared to mitigate the risk of dementia in APOE E4 carriers, bringing it down to levels comparable to those seen in E3 carriers. Additionally, the risk of dementia for E3 carriers was significantly lower than that for E2 carriers, with E2 carriers showing an almost negligible risk.

This research provides the first scientific evidence suggesting that the heightened Alzheimer's risk associated with the APOE4 allele can potentially be countered. This marks a significant breakthrough in our understanding of the genetic factors involved in Alzheimer's, challenging long-held beliefs that have persisted for three decades.

plasmalogens have the potential to alter the biochemical processes related to amyloid deposition, influencing the dementia risk for e4 carriers to align more closely with that of e3 carriers.

So how exactly does this mechanism operate? And to what extent can we generalize these biochemical effects?

Lets back up and dive a little deeper into the biochemistry

Apolipoprotein E (aka ApoE) is a protein involved in lipid metabolism, particularly in the transport and clearance of cholesterol and triglycerides in the body. It exists in several isoforms, with APOE2, APOE3 (considered the ‘healthy’ alleles), and APOE4 (the ‘unhealthy’) being the most notable. Of these, the APOE4 allele is most commonly associated with an increased risk of developing Alzheimer’s disease and other forms of dementia.

At the biochemical level, ApoE is synthesized primarily in the liver and brain, where it plays its biggest key role in the central nervous system by mediating the transport of cholesterol and other lipids to neurons. Why is this necessary? Well, believe it or not, cholesterol is vital for maintaining cell membrane integrity, supporting synaptic function, and facilitating communication between our neurons.

The APOE4 variant differs from its counterparts in its structure and function. APOE4 has a lower affinity for receptors that mediate cholesterol uptake, leading to impaired cholesterol efflux out of cells. This inefficiency contributes to elevated levels of cholesterol in cell membranes, which can skew the processing of amyloid precursor proteins. When APP is processed improperly, it produces beta-amyloid, a toxic peptide that aggregates to form plaques (beta amalyoid), a hallmark of Alzheimer’s disease.

Carriers of the APOE4 allele—estimated to be about 25% of the population—are at a heightened risk for cognitive decline. Approximately 80% of individuals diagnosed with Alzheimer’s have at least one copy of the APOE4 allele. However, possessing this allele does not guarantee that one will develop dementia; rather, it signifies a genetic predisposition that interacts with various environmental and lifestyle factors.

We know this is true because

1. There are other mechanisms that facilitate cholesterol efflux, allowing the body to compensate for the APOE4

2. Dysregulation or a loss of function in these complimentary efflux mechanisms also appears to contribute to Alzheimer’s pathology in individuals without APOE4.

3. As mentioned, some APOE4 carries will actually have LOW amyloid levels!

The role of plasmalogens

Plasmalogens are a class of phospholipids that are particularly abundant in the membranes of our cells, especially concentrated in our brain and heart cells. Plasmalogens play several roles in cellular function

1. They contribute to the structural integrity of cell membranes and help maintain fluidity.

2. Plasmalogens protect cells from oxidative stress, (acting as a sacrificial antioxidant similar to molecular hydrogen).

3.most importantly for our conversation today, they are involved in lipid metabolism and can influence cholesterol levels within membranes.

Good research has shown that high levels of brain membrane DHA-plasmalogen in particular (there are two kinds of plasmalogens, omega-9 and omega-3, aka DHA) can counteract the negative effects associated with the APOE4 allele. DHA-plasmalogen specifically can enhance cholesterol efflux from cells, which is particularly important for our APOE4 carriers who experience reduced cholesterol transport efficiency.

Here’s our big key points

1. In APOE4 carriers, the reduced mobility of cholesterol in cell membranes can lead to an accumulation of unhealthy amyloid processing.

2. DHA-plasmalogen can facilitate the removal of excess cholesterol from neurons, promoting a healthier lipid environment that supports proper APP processing.

3. By improving membrane composition and function, plasmalogens can help maintain a balance between healthy and unhealthy processing of APP. This potentially lowers the production of Ab142, the toxic form of amyloid that aggregates to form plaques in those with poor cholesterol efflux

4. The antioxidant properties of plasmalogens help mitigate oxidative damage in the brain, which is often exacerbated in neurodegenerative diseases. By protecting neurons from oxidative stress, plasmalogens promote better brain health and cognitive function, in addition to restoring structural damage done to the brain, seperate from their regulatory role in cholesterol efflux. Plasmalogens are multi-functional, helping to both restore neuronal function as well as support the underlying biochemical processes necessary to prevent disease onset. They are both rehabilitative and preventative

5. While the presence of the APOE4 allele is a significant risk factor for Alzheimer’s disease and dementia, it is essential to recognize that it is not a deterministic fate. The interplay between genetics and our lifestyle factors, such as diet, exercise, and overall health, plays a crucial role in brain health. Our diet is important for also maintaining our plasmalogen levels by supporting cell membrane intergrity.

6. You can also support cholesterol elffux by exercising, consuming healthy fats like omega-3’s (from fish, not fish oil) and olive oil, as well as B-vitamins (particularly niacin). There’s also some research showing C19 (a saturated, non-inflammatory fatty acid found in dairy) helps support efflux and membrane stability.

How do I supplement with plasmalogens?

As mentioned, there are two primary forms of plasmalogens: DHA and omega-9. While omega-9 and DHA can both be useful within the context of Alzheimer’s, DHA Plasmalogens are going to be the most important.

Plasmalogens are unfortunately not cheap, so it's important to provide this context. While those diagnosed with any neurodegenerative condition can and likely should benefit from using both forms, matching the right plasmalogens with the condition can help those on a budget.

Sample , theoretical dosing for different contexts. Information provided is not medical advice, and soley based on clinical and experimental evidence using plasmalogen replacement therapy in treating neuro degeneration

“I have diagnosed, early onset Alzheimer’s disease” — 1 serving of DHA omega-3 (ProdromeNeuro) plasmalogens for 6-12 months continuously and omega-9 plasmalogens (ProdromeGlial) until signicant improvements or a reversal is achieved. If budget is an issue, further dosing after this can be achieved by alternating days on and off. (One day on, one day off for each, or omitting glial.

“I have severe, late stage Alzheimer’s” — 2-3 servings of Prodrome Neuro and ProdromeGlial for 3-5 months (or until signifant symptoms are noted) before lowering down to 1 serving daily (6-8) months and then tapering to a maintained type dosing protocol. Those with severe, progressive disease may need even longer course durations or higher doses. I would get in contact with Dr. Dayan Goodenowe (the leader research and inventor of the worlds first oral plasmalogens) for personalized dosing recommendations in these circumstances

“I have the APOE4 genotype and want to mitigate my risk” — 1 serving of ProdromeNeuro for 2-3 months straight to build up plasmalogen levels. You can then cycle off for 1-2 months and then repeat a brief 1 month course occasionally to maintain your levels. Or you could just take it 2-3x a week continuously. This is an ideal way to save money. If you don’t have a budget, take it year round.

Where do I buy plasnalogens

You can find Plasmalogens on the ProdromeScience website linked bellow. You can use the code DrT25 for a massive 25% off. I don’t receive any commission of these. This is just a code I found online

At the time of writing this, ProdromeGlial is currently 30% off

https://prodrome.com