Alzheimer's, Homocysteine and Methylation Engine

September 19, 2021

Alzheimer's Disease, Homocysteine, and the Methylation Pump

All of us are on the path to cognitive decline. No kidding. All of us. It's just whether you want your turn to show up at age 73 or at age 297. We are all on that path. It's a path that is becoming better understood, which means we may be able to lower the slope, the rate at which it is occurring if we understand its driving cause. Let me give it a try.

Your neurons in your brain have a few problems. They are each attached to some 4,000 other neurons by long, fragile axons. That gives us some 4 quadrillion links (synapses) between axons (that's quadrillion, with a Q). We are diagnosed with cognitive decline when we have lost some 75% of those links, because our brain has amazing redundancy and hence resilience. Each axon can lose a certain number of synapses and still survive, but there is a threshold beyond which it can no longer make it. The problem with 4000 synapses is that they all have to be energized, supplied with fuel, and they tend to have that need a long way away from the core cell, the nucleus wherein resides the instructions manual and manufacturing facilities. Think about it. The neuron has so ship mitochondria to make energy, and many neurotransmitters, proteins, and such all the way down those axons. That is no small distance. In your brain, from one side to another it's some 5-6 inches. But your spinal cord to your feet is.....3-4 feet. A little bitty neuron has to ship enough neurotransmitters 3-4 feet!

There is a second problem. Your brain has to have neurotransmitters to function. Some 70% of your neurotransmitter need is acetyl-choline, made from choline. What happens if you don't have enough choline? Well, your neurons have to have it. No questions asked. They must have it, or you are dead. So, they take it. They borrow from Peter to pay Paul. They steal choline from their own membranes, wherein reside plasmalogens, made from ethanolamine or choline, both of which can be robbed to make acetyl-choline. The axon is made from some 70% plasmalogens, so you have a big reservoir, but not an endless one. And plasmalogens think they can fill several shoes. They are the only lipids that can shapeshift in your body, allowing them to merge membranes and secrete neurotransmitters. And they are the only lipids that have a precious "vinyl-ether" bond, a bond that can neutralize peroxide, the universal oxidant. We live in an oxidizing world that also acts to deplete plasmalogens. Big problem.

The third problem is getting new plasmalogens, new neurotransmitters, new mitochondria out to the tippy tip, tip of the neuron. We now know that that is another unique "engine" in the cell. Like in mitochondria, where we know that the final step in making ATP is a spinning protein that acts like a miniature engine, you have a second rotary engine in the neuron that pumps fluids down the neurofibrils of your brain. Much like the Mazda rotary engine of yore, your brain's neurons pump organelles like mitochondria and packets of neurotransmitters down the conveyor belts (microtubules) of your neurons. To properly do that, they need methylation of proteins to activate the turning proteins.

And that's the rub. What happens if you have your methylation system all mucked up because you are using too much of it to make creatine for your muscles? Or you don't have enough methyl groups because you haven't taken enough B12 or folate? Your neuronal rotary engine can't pump. You accumulate broken tubules in your brain, and we call those neurofibrillatory tangles. (Classic for Alzheimer's). What’s step #1? Probably the loss of plasmalogens.

Did you get all that? It sounds complex and the question arises as to which is the most important. But they are all part of the same ecosystem. We can measure your "methylation demand" by measuring homocysteine. A low enough homocysteine level is an indicator that you have enough methylation to make your "pump" in the neuron work. A sufficient plasmalogen level means you have enough choline for your neurons to shape-shift, to protect themselves from peroxide, to keep your membranes fluid and rapidly functioning. A sufficient choline supply means you have reserve. No one is the most important, they all interact and work in concert.

And we can now measure and fix all of those deficits.   It just takes measuring and identifying the deficits and replacing them before you have used up all your redundancy.  Replacing isn't some arcane, toxic drug that is foreign to your biology.  It is just the right foods and micronutrients.  

www.What will Work for me. I'm totally fascinated by the fact that our bodies run on teeny, tiny, little mechanical engines. The first one, ATP synthase, we found was in the mitochondria where we attach a phosphate to ADP to make ATP. The protein that comprises that tiny engine actually mechanically turns as the proton crosses the membrane of your inner mitochondria. Now we have a second engine that pumps the transport system in our brain. The tau protein in our neurons actually spin and push organelles down the axon. And all of that is tied up with methylation signaling. Hence homocysteine, the universal marker of sufficient methylation capacity measures the ability of that engine to pump. I now believe that we can all adjust and modify the rate at which we decline. The tantalizing vision is that we can actually halt and reverse some of that decline if we catch it in time. Your brain always wants to rebuild redundancy. If only it is provided with the tools to do so. And that's why I am supplementing all of them for myself. It's worth it.

References: Nat Rev NeuroSci, Frontiers Molecular Neurosci., Neuron, J NeuroSci.,

Pop Quiz

1. Each neuron in our central nervous system is attached to its neighbor next to it by wires. T or F. Answer: Arrgh. False. It sends wires out to some 4000 distant other neurons, thousands of cells distant. In fact, several feet distant in some cases.

2. Those connections are filled with what? Answer: A transport system built on microtubules that carry mitochondria to make energy and other organelles to function properly.

3. How does that transport system work? Answer: So glad you asked! It's an amazing little circular engine that pumps fluid out the axon, carrying mitochondria and etc.

4. What is the key to make the pump work? Answer: sufficient methylation capacity, indicated in your blood by a low enough homocysteine.

5. What is the connection of all this to plasmalogens? Answer: they are all integrated into the same system. You need the plasmalogens to make your neurons protected from oxidation, to shapeshift and excrete neurotransmitters, and to allow that to happen rapidly. You make plasmalogens from choline, that need 4 methyl groups to be made, driving methylation demand. That competes with making sufficient neurotransmitters.