What is Alzheimer’s Disease?
Alzheimer’s Disease is a neurodegenerative disease that affects elderly persons. It was used to be called Senile Dementia of the Alzheimer’s Type or Alzheimer’s Dementia. Now it is commonly referred to as just Alzheimer’s Disease (AD). The type of neurodegeneration that occurs in AD causes dementia. AD is rare in persons under the age of 75. By age 95, approximately 1 in 3 persons will have AD or a related dementia. AD is serious and life-threatening. The average time to death from a diagnosis of AD is only 4.5 years.
What is dementia?
Dementia is a neurological disease that affects your ability to think properly. Dementia occurs when certain types of neurons undergo neurodegeneration. The common early symptoms of dementia are:
Memory loss, generally noticed by the near and dear ones
Difficulty in communication, especially finding the right words to communicate
Reduced ability to organize, plan, reason, or solve problems
Difficulty handling complex tasks
Confusion and disorientation
What is neurodegeneration?
Neurodegeneration is what happens when neurons begin to stop working properly. At first there is just reduced functionality, next there is shrinkage and finally the neuron will actually die. Theoretically, neuronal cells can be rescued (regenerated) at any time before they die.
What are neurons?
Very simply, neurons are the electrical wiring of your body. They are organized by type and by location. Each neurodegenerative disease affects a certain type of neuron in a certain location. For example, in AD, it is the cholinergic neurons in the nucleus basalis that are affected.
How do neurons work?
Neurons work by switching each other on and off, like a light switch on your wall. However, unlike electrical wiring that is made up of copper wires and metal switches, the neuron wires in your body are living biological cells and they communicate with each other using synapses, neurotransmitters and receptors. The sending neuron releases neurotransmitters into the synapse (which is the connecting space between the two neurons) and the receiving neuron catches the neurotransmitters using receptors. This is how one neuron communicates with another neuron.
What are neurotransmitters and receptors?
Neurotransmitters are small chemicals that neurons use to communicate with each other across the synaptic cleft. They are coded in pairs like a lock and key. The post-synaptic neuron contains the locks (call receptors) and the pre-synaptic neuron contains the keys (neurotransmitters). When the presynaptic neuron releases the neurotransmitters into synaptic cleft, they attach to receptors on the post-synaptic neuron and activate the post-synaptic neuron. The neurotransmitters are then re-absorbed into to the presynaptic neuron so that the presynaptic neuron can be recharged for the next signal.
How does a neuron know when to turn on?
Since there is nobody to manually turn the neurons on and off, they are autoregulated by a process called an action potential threshold. A neuronal action potential threshold is no different from a mother’s response threshold to their son saying “mommy, mommy, mommy, mommy”, until finally the mother says, “WHAT?!” Neurons receive multiple inputs, but send out only one output. Incoming signals are sensed by dendrites that fan out in multiple directions and when the combination of dendrite signals reach a certain threshold, the neuron yells “WHAT?!” through its axon to its axon tips (called presynaptic boutons). By yelling, “WHAT?!” (the arriving action potential) the neuron cell body tells its presynaptic boutons to release its neurotransmitters into the synaptic cleft as depicted in the following figure:
What is a membrane?
Membranes are the walls that separate the cells in your body from each other. The core structure of a membrane is called a phospholipid bilayer. The characteristics of the membrane (stiff or fluid) depends on the type and amount of phospholipid in the membrane.
What is a phospholipid?
Phospholipids are the building blocks of cell membranes. They have a polar head group (called hydrophilic, which means it likes water) and non-polar tail (called hydrophobic, which means it does not like water). They form what is called a phospholipid bilayer in which the non-polar tails are orientated to the inside and the polar headgroups are orientated to the outside. When this happens, you end up with a physical barrier – like a wall. There are many different types of phospholipids and each type has its own special properties and function in the body
How does neurodegeneration affect the function of the neurons?
In neurodegeneration the presynaptic membrane becomes damaged resulting in a decreased ability to release neurotransmitters. When this happens the signal strength of the neuron is decreased. If the signal strength decreases too much, then the neuron stops firing altogether and the presynaptic bouton shrinks and shrivels up (but the whole neuron is still alive).
The communication between neurons occurs via the fusion of presynaptic vesicles containing neurotransmitters with the presynaptic membrane and the release of neurotransmitters into the synaptic cleft. This is a core feature of all neurons.
Also as described above, every neuron receives multiple small inputs from multiple dendrites and that these small inputs accumulate until a depolarization threshold is reached. When neurodegeneration causes presynaptic boutons to shrink, then the number of postsynaptic connections begin to decrease as well. For example, say a neuron normally has 100 dendritic (incoming) connections and say 50 signals (in a short period of time) are needed to reach a depolarizing threshold. This would mean that normally only 50% or more of these connections need to be activated for the neuron to propagate a signal. In neurodegeneration, the presynaptic boutons begin to shrink and become inactive. Now the receiving neuron only has 75 connections that are working. Now, 2/3 (50/75) of the connections must be activated before a signal gets propagated. Eventually, the number of connections degenerates until there is no longer enough to trigger a signal.
So, in summary, there are 2 variables that drive signal propagation – the number of connections and the strength of each connection.
What are plasmalogens?
Plasmalogens are a special type of phospholipid. They are essential for the proper functioning of synaptic membranes and myelin sheaths. In addition to their role in membrane structure and function, plasmalogens also act as an antioxidant.
Where do plasmalogens come from?
There are no significant dietary sources of plasmalogens. Plasmalogens are synthesized in your liver and then transported to your brain and organs via the blood.
What do plasmalogens do?
The most critical function of plasmalogens is the vesicular fusion and release of neurotransmitters. The role of plasmalogens in this process is biophysical. For membranes to fuse, the polar head groups have to come together and re-arrange themselves. Research has shown that membranes low in plasmalogens will not fuse. The process of vesicular fusion is depicted below. Step 4 and 5 require plasmalogens in the membrane.
How/why do plasmalogen levels decrease in the brain when we get older?
Normally your body maintains the plasmalogen levels in your membranes by making them in your liver and transporting them throughout the body. However, when we get older things happen in our body that can accelerate the breakdown of plasmalogens or negatively affect our ability to make enough new plasmalogens. When the body’s ability to make new plasmalogens becomes less than the amount of plasmalogens being consumed by the body, plasmalogen levels in the membranes gradually begin to decrease. Low levels of plasmalogens in the blood and in the brain is associated with an increased risk of dementia and death.
What is the plasmalogen hypothesis of neurodegeneration and dementia?
The plasmalogen hypothesis of neurodegeneration is that the degeneration of neurons is caused by decreased membrane plasmalogens and that neurodegeneration can be prevented by maintaining optimal membrane levels of plasmalogens.
What type of research studies support the plasmalogen hypothesis of neurodegeneration?
There is an extensive body of research on plasmalogens and neurodegeneration. Human epidemiological studies have shown that low blood plasmalogen levels are associated with an increased risk of dementia, an increased risk of becoming demented, and an increased risk of dying. Low human brain levels are associated with dementia and Parkinson’s. Animal studies have shown that neurotoxins that induce neurodegeneration decrease brain plasmalogen levels and that plasmalogen supplementation prevents neurodegeneration. In brain damaged monkeys, plasmalogen supplementation improves neurological function.
What is the scientific evidence that plasmalogens are reduced in the brain of persons suffering from a neurodegenerative disease?
Two independent research groups have shown that plasmalogens are reduced in the brains of persons diagnosed with AD. In 2001, Researchers at the University of Washington analyzed the brains of 30 persons with varying degrees of cognitive impairment prior to death. They showed that plasmalogen levels in the brain decreased with increasing levels of dementia (Han et al., 2001). These finding were independently confirmed by Dr. Goodenowe and his collaborators at Rush University in Chicago. They measured plasmalogen levels in the brains of 100 persons with varying degrees of cognitive impairment and observed that plasmalogen levels in the brain decreased with increasing cognitive impairment (Goodenowe et al., 2016).
When do plasmalogens begin to decrease in the blood?
Overall population data indicates that blood levels begin to decrease after age 50 and by age 85 they are approximately one-half to two-thirds of the levels observed in persons aged 30-49 (Wood et al, 2011)
Is there a difference in plasmalogen levels between men and women?
Yes. Women typically have lower blood plasmalogen levels than men. However, the rate of decline with age is the same in men and women. Since women have lower starting blood levels than men, this could explain why women typically get AD at a younger age than men.
How can plasmalogen levels be restored or increased in the blood and brain?
Research in animals have shown that plasmalogen supplementation increases blood plasmalogen levels in a dose-dependent manner (dose dependent means that higher doses result in a greater increase in blood levels).
What do plasmalogen supplements look like and how are they taken?
Plasmalogen supplements have an appearance similar to fish oil and can be packaged in gel capsules or in a medicine dropper to be added to beverages or food.
What is the scientific evidence that increasing plasmalogen levels prevents neurodegeneration?
Independent research performed using two different models of neurodegeneration at two different universities have shown that plasmalogen supplements prevent neurodegeneration.
Prevention of Parkinson’s-like neurodegeneration:
Researchers at Laval University who are experts in animal models of Parkinson’s Disease, investigated the effect of pre-treating mice with plasmalogen precursors prior to administering a neurotoxin called MPTP. MPTP causes neurodegeneration similar to that observed in humans with Parkinson’s disease. Mice that were pre-treated with plasmalogen precursors were protected from MPTP-induced neurodegeneration (Miville-Godbout et al., 2016)
Prevention of Multiple Sclerosis-like neurodegeneration:
Researchers at McGill University investigated the effect of pre-treating mice with plasmalogen precursors prior to administering a neurotoxin called cuprizone. Cuprizone causes neurodegeneration similar to that observed in humans with Multiple Sclerosis. Mice that were pre-treated with plasmalogen precursors were protected from Cuprizone-induced neurodegneration (Goodenowe et al., 2016; Wood et al., 2011)
What is the scientific evidence that increasing plasmalogen levels improves neurological function?
Researchers at Laval University who are experts in animal models of Parkinson’s Disease, investigated the effect of treating parkinsonian monkeys with plasmalogen to see if plasmalogen precursors could improve neurological function in animals AFTER they have already suffered neurodegeneration. The main drug therapy for Parkinson’s disease is L-DOPA. However, prolonged treatment with L-DOPA creates abnormal movements called dyskinesias. These researchers observed that plasmalogen precursor therapy reduced these abnormal movements showing that plasmalogen precursors can improve neurological function even after neurodegeneration has occurred (Gregoire et al., 2015).
Are plasmalogens lower in persons with and APOE e4 genotype?
No. APOE genotype has no effect on blood or brain plasmalogen levels. However, persons with the high risk APOE e4 allele that have high blood plasmalogens do not have an increased risk of AD indicating that high blood plasmalogens are protective against the negative effects of the APOE e4 genotype.
What biological mechanisms are affected by plasmalogen levels?
The biochemical mechanisms associated with plasmalogens are related to their roles in membrane structure and function. The observations made in laboratory experiments are consistent with observations made in human studies.
Plasmalogens have been shown to increase cholesterol esterification and clearance – this is a key mechanism involved in reverse cholesterol transport (Mankidy et al., 2010). In humans, persons with high plasmalogens have a more healthy (higher) HDL/LDL ratio (Goodenowe et al., 2015; Goodenowe & Senanayake, 2019).
The biochemical mechanism responsible for the Amyloid accumulation observed in AD has been extensively researched. The precursor to the bad protein (called AB1-42), is called APP (amyloid precursor protein). This protein can be processed by two enzymes: alpha-secretase or beta-secretase. Alpha secretase is the good enzyme. If APP is processed by alpha-secretase, there is no production of AB1-42. If APP is processed by the beta-secretase, then the bad protein AB1-42 is produced. Plasmalogen precursors increase the amount of APP processed by alpha-secretase and decrease the amount of APP processed by beta-secretase and dose-dependently decrease AB1-42 (Wood et al., 2011). Humans that have high plasmalogen levels in their brain have lower brain amyloid levels (Goodenowe et al., 2016).
Laboratory studies have definitively shown that increasing membrane levels of plasmalogens increase the number of membrane fusion events (Glaser, 1995). Humans that have high plasmalogens in their brain have higher brain function (better cognition). Since cognition is related to the vesicular release of neurotransmitters, this is indirect evidence that high plasmalogens in the brain increase vesicular fusion events in the brain.