Genetics and Alzheimer’s Disease: Exploring the Crucial APOE-e4 Connection

September 12, 2023

Alzheimer’s disease, the most common form of dementia, affects an estimated 6.7 million Americans over the age of 65, a number that is expected to grow to almost 13 million by 2050. 

Dementia is an umbrella term that refers to changes in brain function that result in cognitive and functional decline.  There are several different types of dementia including Alzheimer’s disease, vascular dementia, frontotemporal dementia, and Lewy body dementia. 

Alzheimer’s disease is thought to be caused by the buildup of beta-amyloid and tau proteins, ultimately damaging neurons.  Neurons are the nerve cells within the brain that are responsible for communication required for intellectual and physical functioning.  As neurons are impaired, individuals may experience changes in memory, language, and thinking.  As more neurons are affected, symptoms may also involve changes in behavior and difficulty with self-care. 

While a small degree of age-related cognitive decline may be common, Alzheimer’s disease is different in that it affects memory and cognition in a progressively deteriorating manner.  

Risk Factors for Alzheimer’s Disease 

Protecting ourselves from disease is a complex challenge.  Some risk factors for Alzheimer’s can be controlled or managed – like getting regular exercise, managing your blood pressure, or reducing sugar intake – and we call these ‘modifiable’ risk factors.  On the other hand, there are also ‘non-modifiable’ risk factors, which are predetermined and out of our control.  These non-modifiable risk factors include your age, gender, family history, and genetics, all of which can have a major impact on the risk of developing neurodegenerative diseases such as Alzheimer’s.    

Age – The risk of Alzheimer’s disease increases with age.  An estimated 5% of those 65 and older, 13% of those 75 and older, and 33% of those over the age of 85 are currently diagnosed with the disease. 

Gender - Women tend to be at a higher risk of developing Alzheimer’s disease than men, with women currently making up two thirds of those who are diagnosed.  According to the ‘Estrogen Hypothesis’, estrogen hormones such as 17β-estradiol protect the female brain from disease until the hormone drastically decreases and almost disappears at the onset of menopause.1    

Family History – Having one or more close relatives with Alzheimer’s disease, such as a parent, sibling, or grandparent, increases one’s risk, and having more than one close relative further increases risk.  It is important to note, however, that compared to age, genetics, and some modifiable risk factors, family history plays a smaller role in determining risk. 

Genetics – Genes within each cell of the body are how different traits are passed on from parents to their children.  Humans share 99.99% or more of the same genetic code, and it is the small differences that are the basis for differences in characteristics, including disease risk and risk of Alzheimer’s disease.  Alzheimer’s disease is highly heritable, meaning that the risk of developing the disease has a genetic component. 

Alzheimer’s Disease and Genetics – The APOE Gene 

Is there a history of Alzheimer’s disease in your family?  If so, it’s likely the ApoE gene was involved, as it is estimated to play a role in more than half of all Alzheimer’s cases.2 

ApoE is the strongest and most prevalent genetic risk factor for Alzheimer’s disease.  We all inherit a version of the ApoE gene, and while a family history of neurodegenerative disease does not necessarily raise your own risk, it’s valuable to be aware of this inheritance.3  The APOE gene contains the code to make a protein called “apolipoprotein E,” which is responsible for moving fat throughout the body.  Each person carries two copies of the APOE gene, one from each parent.  The APOE gene comes in three forms: APOE-e2, APOE-e3, and APOE-e4, resulting in six possible individual combinations: e2/e2, e2/e3, e2/e4, e3/e3, e3/e4, and e4/e4. 

The APOE-e2 form may decrease the risk for Alzheimer’s disease.  APOE-e3, the most common form of APOE, is associated with an average risk of Alzheimer’s disease.  It is the APOE-e4 version of the gene that is associated with an increased risk of developing the disease.  It is estimated that having one copy of the APOE-e4 gene increases risk 3-fold and having two copies increases risk up to 12-fold.4 

How APOE-e4 Exerts Its Effect on the Brain  

APOE-e4 influences brain health through several vital processes that are associated with both Alzheimer’s disease and accelerated ageing.  If you possess one APOE-e4 allele, and especially if you have two copies of APOE-e4, that inheritance could become critically important for your risk of developing neurodegenerative disease.  APOE-e4 plays a part in controlling levels of sugar and cholesterol in the brain, has implications for the brain’s inflammatory response, affects the permeability of the blood-brain barrier, and accumulation of amyloid beta plaques, which are a key pathological hallmark of Alzheimer’s.  Let’s look at these roles in detail.   

Cholesterol.  One of the ApoE gene’s main functions is the transport and metabolism of cholesterol, a waxy, fatty substance which plays important roles in the body.  Only 2% of your body’s mass is in your brain, but it contains 20-25% of your cholesterol, all of which must be made locally in the brain because the chemical container for cholesterol cannot pass through the blood-brain barrier.  Alzheimer’s sufferers often exhibit impaired processing of brain cholesterol due to the influence of the APOE-e4 gene.5  This leaves the brain lacking in this important substance, which is a precursor for the ‘mother hormone’ pregnenolone, from which all other hormones are derived.  Low levels of the hormones estrogen and progesterone can result in Alzheimer’s symptoms including brain fog, depression, anxiety, and problems with memory and sleep.6    

Inflammation.  APOE-e4 is also thought to have an important role in brain inflammation, which is considered a central mechanism for Alzheimer’s.  This is because the brain’s own immune cells, called microglia, tend to have a more severe inflammatory response to amyloid plaques in people with APOE-e4.  This sustained inflammation can have damaging effects, leading to depressive and cognitive symptoms.7   

Blood-brain barrier aging and omega-3.  APOE-e4 carriers experience problems with the effectiveness and efficiency of the blood-brain barrier.  This is especially a problem for the movement of the critical omega-3 fatty acid, DHA, into the brain from the bloodstream.  DHA is required for building cell membranes and as a precursor for a whole class of important anti-inflammatory molecules.8  Those with the APOE-e4 gene find difficulty in moving DHA into the brain due to breakdown in the blood-brain barrier, a shortfall which can contribute to the effects of neurodegeneration.9  As a result, specialized forms of DHA called phospholipids can be important to “bypass” the hurdle that APOE-e4 presents.  

Insulin resistance.  Created in the pancreas, insulin is a hormone that helps sugar (like glucose) enter cells and regulates your blood sugar level.  Insulin resistance, on the other hand, is when insulin becomes unable to ‘shepherd’ sugar into cells, and it is the hallmark of type-2 diabetes.  If your brain cells becomes insulin resistant, the resulting shortfall in glucose metabolism (energy) and other insulin dysfunction can encourage the presence of amyloid beta, the protein which forms Alzheimer’s-related plaques in the brain.10  APOE-e4 exacerbates this process by making it more difficult for insulin to perform its functions. 

Ultimately, it leads to amyloid plaque build-up.  A key hallmark of Alzheimer’s, amyloid plaques form between neurons within the brain and are encouraged by all four of the above processes.  Also, clearing-out the plaques becomes more difficult.  While your glympathic system clears out some of these plaques while you sleep, APOE-e4 is only 1/20th as efficient as ApoE3 when it comes to performing this vital task ‘garbage removal’ task.11 

Despite APOE’s role in Alzheimer’s disease risk, it is important to note that one’s APOE status is not a diagnosis.  Instead, the APOE gene speaks to a component of one’s risk, of which there are many other contributing factors.  In fact, it is possible to have one or even two copies of the APOE-e4 gene and not develop Alzheimer’s disease.  It is also possible to carry no copies of the APOE-e4 gene and still develop the disease.  This is an important reminder that there are many factors that go into risk for developing Alzheimer’s disease.  

Rare Familial Alzheimer’s Disease  

The more well-known form of Alzheimer’s disease discussed thus far is termed “common” or “sporadic” Alzheimer’s disease, which speaks to the prevalence as well as the fact that several risk factors contribute to disease development.  This differs from the rare “familial” form of Alzheimer’s disease, which affects less than 1% of those diagnosed.    

Familial Alzheimer’s disease is caused by changes in specific genes that result in a very high likelihood of developing an early-onset form of the disease, which is when symptoms appear before the age of 65.  

The genes associated with familial Alzheimer’s disease are known as APP, PSEN1, and PSEN2.  These genes are considered diagnostic, which means that having one or more high-risk versions is highly associated with ultimate disease development.  This type of diagnostic genetic test is comparable to those used for other diseases, such as Huntington’s disease.  

These rare genes are most commonly evaluated with healthcare provider or genetic counselor oversight in situations when an individual has a strong family history of early-onset Alzheimer’s disease. 

Alzheimer’s Disease and Genetics – Additional Genes 

While the APOE gene is thought to play the largest role in the genetic risk for Alzheimer’s disease, several other genes have been identified that are thought to contribute to risk as well.  These genes, including CLU, CR1, PICALM, SORL1, and ABCA7, may be either protective or risk-promoting, making them important to one’s overall genetic risk.  

The following table describes just a few of these additional genes:   

Other Genes Risk

There are many others, and we can expect more to be discovered.  Genes involved with the body’s immune response, lipid metabolism and transport, amyloid production and clearance, and overall longevity all work together to generate our risk of Alzheimer’s.  The growing power of genetic testing means that your individual mutations can be assessed to create a polygenic score which paints a more accurate picture of your risk.  Remember also that some genes (such as APOE-e2) confer protection against Alzheimer’s.26 

You can explore more APOE4 specific nutrient recommendations by downloading our FREE e-guide on “Living with APOE4: Strategies to Reduce Risk”, click here to get the guide.  

For June, Alzheimer's and Brain Awareness Month, we have a special offer featuring Dr. Annie Fenn's "Brain Health Kitchen Cookbook." This cookbook focuses on reducing the risk of Alzheimer's through diet, with over 100 recipes and science breakdowns, making it relevant for anyone looking to maintain brain health.  Additionally, the offer includes 3 bottles of RELEVATE.  Our brain health supplement, RELEVATE, contains 17 vital nutrients from the Mediterranean and MIND diets, helping keep your brain sharp and strong.  Formulated to work together, these nutrients help your brain stays covered nutritionally, even when you struggle with your diet.  Plus, a stainless steel RTIC tumbler for hydration, which is super important for the brain. Learn more about this limited offer here.  

Genetics – Diagnosis versus Risk 

As a reminder, assessing one’s genetic risk for developing Alzheimer’s disease, including APOE status and the GenoRisk polygenic risk score, is meant to be predictive of risk – not diagnostic.  Several other factors, including those that are modifiable, like lifestyle and nutrition, also play a significant role in reducing or increasing the risk of developing the disease. 

References

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  2. Raulin, AC., Doss, S.V., Trottier, Z.A. et al. ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies. Mol Neurodegeneration 17, 72 (2022). https://doi.org/10.1186/s13024-022-00574-4 
  3. Alzheimer’s Disease Genetics Fact Sheet | National Institute on Aging. (n.d.). Retrieved September 11, 2023, from https://www.nia.nih.gov/health/alzheimers-disease-genetics-fact-sheet 
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  11. Patrick, Rhonda P. “Role of phosphatidylcholine-DHA in preventing APOE4-associated Alzheimer's disease.” FASEB journal : official publication of the Federation of American Societies for Experimental Biology vol. 33,2 (2019): 1554-1564. doi:10.1096/fj.201801412R 
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  14. CR1 complement C3b/C4b receptor 1 (Knops blood group) [Homo sapiens (human)] - Gene - NCBI. (n.d.). Retrieved September 11, 2023, from https://www.ncbi.nlm.nih.gov/gene/1378 
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