Causitive Factors of Dementia and Alzheimer’s Disease
It is generally believed that the onset of dementia and Alzheimer’s disease is the consequences of complex interactions among: 1
- genetic factors
- environmental factors
- lifestyle factors
The main features of dementia and Alzheimer’s disease are the presence of:
- extracellular amyloid beta protein plaques
- intracellular neurofibrillary tangles of tau proteins (NFTs)
- loss of neurons and synapses in the cerebral cortex and certain subcortical regions in the brain
Figure 1. Amyloid beta protein plaques and intracellular neurofibrillary tangles of tau proteins (Source)
Figure 2. Loss of neurons and synapses in the cerebral cortex (Source)
This article focuses on the genetic factors as a potential cause for the late-onset of Alzheimer’s disease and what actions can be taken to modulate these genetic factors as it related to the most important genetic factor known as apolipoprotein E (ApoE).
Studies have demonstrated that Alzheimer’s disease is related to polymorphisms of at least four (4) genes:
- amyloid precursor protein (APP)
- presenilin (PS-1)
- presenilin (PS-2)
- apolipoprotein E (ApoE)
Polymorphisms in the three genes, amyloid protein precursor (APP), presenilin (PS)-1 and PS-2, is estimated to be the cause of early-onset (which is less than 60 years of age) autosomal dominant Alzheimer’s disease, which accounts for less than 1% of Alzheimer’s disease cases. 2
There are multiple genetic, environmental and lifestyle factors involved in late-onset Alzheimer’s disease, yet impairment in amyloid-beta clearance by ApoE is a major contributor to development of the disease.
Apolipoprotein E (ApoE)
Apolipoprotein E (ApoE) is a class of apolipoprotein found in the chylomicron and Intermediate-density lipoprotein (IDLs) that is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.
ApoE is mainly produced by astrocytes, and transports cholesterol to neurons via ApoE receptors, which are members of the low density lipoprotein receptor gene family. ApoE is the principal cholesterol carrier in the brain and encodes for a protein that transports cholesterol, fats and fat-soluble vitamins through the blood.
ApoE also contributes to the maintenance and repair of nerve cells.
Figure 3. Apolipoprotein E (ApoE) (Source)
There are three (3) major polymorphisms or alleles in the ApoE gene:
- ApoE-ε2 (good one)
- ApoE-ε3 (neutral)
- ApoE-ε4 (problematic)
Since we carry two copies of the APOE gene, one from our mother and one from our father, the combination of alleles determines our ApoE3 genotype, for which there are six possible genotypes:
The ApoE-ε2 polymorphism, the most desirable to have, is associated with lower cholesterol levels and it actually may protect against Alzheimer’s disease in some populations and may decrease the risk. 3
The ApoE-ε3 allele has a frequency of approximately 79 percent and is considered the “neutral” Apo E genotype. This means that for 79% of the population, a genetic polymorphism of this gene does not cause dementia or heart disease.
The E2 allele is the one that is the most efficient in clearing and removing the amyloid-beta plaques from the brain. The second most efficient allele is the E3 version, which does an average job of removing amyloid-beta plaques.
The E4 allele is the least efficient version in removing and clearing amyloid-beta plaques from the brain. This results in more plaques building up and creating a much greater risk of developing Alzheimer’s disease.
The best genotype to have is E2/E2.
The worst genotype to have is E4/E4.
There are certain percentages of the population that carry certain genotypes:
- Around 55% of the population have the E3/E3 genotype, which is the most common, equating to average risk
- Around 25% of the population have the E3/E4 genotype
- Around 15% of the population have the E2/E3 genotype
ApoE-ε4 is a major genetic risk factor for late-onset Alzheimer’s disease.
Individuals carrying the E4 allele are at an increased risk of Alzheimer’s disease. Having one allele of ApoE4 increases the risk of Alzheimer’s disease, and if two ApoE4 alleles are present, the risk is even higher. 15
However, many individuals with the ApoE-ε4 allele never develop the disease and many patients with Alzheimer’s disease do not have the ApoE-ε4 allele.
With an allele frequency of approximately 14%, the ApoE-ε4 polymorphism has been implicated in the following diseases:
- atherosclerosis 4
- Alzheimer’s disease 5
- impaired cognitive function 6
- reduced hippocampal volume 7
- HIV 8
- faster disease progression in multiple sclerosis 9
- unfavorable outcome after traumatic brain injury 10
- ischemic cerebrovascular disease 11
- sleep apnea 12
- accelerated telomere shortening 13
- reduced neurite outgrowth 14
Figure 4. Apolipoprotein E and Alzheimer disease (Source)
Those patients with two ε4 alleles of the APOE gene have up to 20 times the risk of developing Alzheimer’s disease. 16 The lifetime risk estimate of developing Alzheimer’s disease for individuals with one copy of the apoE4 allele (approximately 25% of the population) is approximately 30%. 17
According to the National Institute of Health, inheriting a single copy of ApoE4 from a parent increases the risk of Alzheimer’s disease by about three-fold. Inheriting two copies, one from each parent, increases the risk by about 12-fold.
ApoE generally is an anti-inflammatory and is able to break down the amyloid beta proteins that are a cause of Alzheimer’s disease. The ApoE-ε4 allele is limited in its ability to function as an anti-inflammatory and to break down amyloid beta proteins. 18
Increasing the Production and Function of ApoE-ε4
If a person has one E4 allele or two E4 alleles (E4/E4, which is the worst and carries the highest risk for Alzheimer’s disease), then they can and should take proactive and aggressive preventive action to increase the production and function of the ApoE-ε4 allele.
You ultimately want your ApoE working effeciently to help control and remove the harmful buildup of amyloid-beta plaques.
Since the ApoE-ε4 allele does not function as efficiently as the ApoE-ε2, there are certain behaviors that can be done and substances that can be taken to increase its production and function.
There are certain behavioral actions that can be taken to increase to production and function of the ApoE, such as:
Natural Substances that Increase the Production and Function of ApoE-ε4
There are also natural substances that be consumed that have shown to increase the production and function of ApoE, especially in the case of a low functioning E4 single of double allele.
These substances are listed in the Table below:
Increasing the Production and Function of ApoE-ε4
Category Substance Reference
Fatty Acids DHA Ref.
Polyphenols Curcumin Ref. Ref.
Vitamins Vitamin A (Retinol) Ref.
Citicoline (cytidine diphosphate-choline (CDP-Choline) Ref.
In order to see what your genotype in the ApoE gene, especially if your have the ApoE-ε4 polymorphism, you need to order a DNA and Genetic Test. There are a number of testing companies. The most popular are:
Once you have ordered and received your DNA and Genetic Test from the testing company, you can then download your data to one of a number of websites that will analyze your genetic data and provide information on the polymorphisms of the ApoE gene and your specific genotype.
A number of companies will analyze your genetic data and include:
All of the 5 companies above will receive the 23andMe genetic data.
Another way to test for your genotype and the ApoE-ε4 polymorphism can be done by ordering the following test from Life Extension:
Sample Report (PDF)
Dr. Ben Lynch – Alzheimer’s Dirty Gene APOE4
AHS16 – Steven Gundry – Dietary Management of the Apo E 4
NutritionFacts.org – The Alzheimer’s Gene: Controlling ApoE
Apo E Gene’s connection with Alzheimer’s Disease, Heart Disease and more
Do you have Apo E 4 Dementia risk, Heart Attack diet risk; Apo(e) 4 and alcohol