Hi friends, Dr Dennis here, and thanks for reading this series of four on all things Dementia (Alzheimer’s disease is the most common brain degenerative disease that leads to Dementia). For those who have been reading from the beginning,
A quick summary of ApoE4: It is the single most important genetic
risk factor for Alzheimer’s.
In part one of this blog, we have had a bird’ s-eye view of the ApoE4 gene and its potential influence on inflammation, reduced glucose metabolism, Amyloid clearance, etc. We will explore its other influences on different aspects of cellular functions. This gene has been involved in mitochondrial (cellular powerhouse) survival, nerve growth factor, transport of nutrients across the membrane, toxin clearance, insulin actions, etc. ApoE4 has also been found to bind with 1700 promoters’ sites; these genetic transcriptions involve trophic support, programmed cell death, synaptic functions between neurons (for memory formation, for instance) and many others (2).
The Concept of Genetic Variant
Human genetic variants exist to make us all unique. These variations represent the differences in DNA sequences between organisms, such as humans. It takes as subtle a change as one base pair to make one different. Humans have 25,000 protein-coding and many more regulatory genes. These genetic’ “codes” are critical in enzymatic action that processes amyloids, transporters that let nutrients across the cell membrane, hormone activators, and cytokines (molecules) involved in inflammatory response post-injury. The underlying message is this: doing a blood test will not give us these molecular details; it will only reveal the deficiencies of nutrients, hormones, and vitamins due to genetic variants.
A Closer Look at ApoE4 & Future Clinical and Social Implications
Friends, let us revisit some of the earlier prevalence I spoke about and expand it by putting it into the proper context. The ApoE4 allele has been found in more than 70% of those who have been diagnosed as having Alzheimer’s before the age of 80. About 65% (studies ranged widely from 40% to 80%) of all cases of Alzheimer’s were found to be ApoE4 allele carriers. Let me stop right here. Does that mean that about one-third of all cases are due to bad luck or happened serendipitously? Maybe it is because there are more than ApoE4 genes; we call them candidate genes that we have yet to discover. Does our environment interact with our genetic makeup and determine the ultimate “manifestation” of who we are? This is the concept of epigenetics (1). There is a lot more to answer. Although blood tests can’t tell you the genetics, do we want to know, or will we assume we are positive (after all, we know the prevalence of the ApoE4 allele is about 25% worldwide)? Will the genetic test add value? Perhaps, as we know from Dr Dale Bredesen’s research, ApoE4 individuals need to have a different management plan; they need to fast longer for ketosis, some subtypes of Alzheimer’s have a higher prevalence of ApoE4 allele, etc. But, as we know, patients with over 60% of symptomatic AD patients carry at least one APOE ε4 allele (3), so why can’t we assume most of our sufferers are positive? What about our life insurance policy? Will the genetic status change our “insurability” and affect our employment? Will positivity affect our retirement age? Will insurance companies add genetic tests in the future? I am raising these questions here for us to think about.
I am not against testing for mutation, but we must use the information wisely. Being able to counsel ApoE ε4 appropriately can help with prevention – but often can create less fear and develop better plans if you have more information.
Other Candidate Genes (Potential)
- Apo Epsilon (ε) 2 & (ε) 3 -While ApoE4 increased the risk of Alzheimer’s, ApoE2 reduces the risk, but it is the least common form of APOE family. ApoE3 has an unknown effect on the risk and is the most common form.
- Researchers don’t know much about the role of PLD3 in the brain, but it appears to increase the risk of Alzheimer’s.
- TREM2. This gene affects how the brain responds to inflammation. Rare changes in this gene have been observed to be linked with an increased risk of Alzheimer’s.
- CLU. This gene is associated with amyloid-beta clearance. Researchers suggest that an imbalance in the production and clearance of amyloid-beta is the fundamental basis of Amyloid(Aβ42) production.
- Tomm40. This gene is also co-located with the ApoE4 gene on the same chromosome. It is thought that the risk of Alzheimer’s increases if this mutation is co-inherited with ApoE4. TOMM40 is believed to be associated with mitochondrial (cell powerhouse) the survival and the repairability of Mitochondria.
Friends, this list is incomplete! We all hope every new finding will contribute to understanding this disease and provide more therapeutic options.
What are the main take-home messages?
- ApoE4: It is the single most important genetic risk factor for Alzheimer’s.
- There are three primary forms of APOE (Apolipoprotein E), 2,3 & 4. They each have their unique functionality and risk of developing Alzheimer’s. While ApoE4, the second most common allele, is a risk, ApoE2 reduces the risk, but it is unknown about ApoE3.
- Besides ApoE, there are many other candidate genes. The jury is still out of their significance and risk of Alzheimer’s.
Please call my PA, Melissa, on 0422 678 660, leave a message, or email info@mind4lifecoaching.com.au, and we will respond to you if you have any questions.