Hockey star Ron Duguay meets with neurologist to learn more about APOE4 Gene Variant-

Ron Duguay, played 12 seasons in the National Hockey League, mostly as a center for the New York Rangers. Duguay recently found out that he has one copy of the APOE4 gene, which is a gene variant that, in combination with a moderate or severe head injury, may increase a person’s risk of Alzheimer’s disease as well as increase the risk for disease onset at an earlier age (Plassman et al. 2000).

Duguay, who was interviewed for a May 27, 2010, Sports Illustrated article titled “The Genetic Makings of an Athlete,” became well known in the 1970s and 1980s for playing professional hockey without a helmet. In the Sport’s Illustrated article, Duguay is quoted as saying:

“…if this gene is how you’re describing it,” and I knew I had it when I was playing, I would’ve seriously considered wearing a helmet” (Epstein 2010).

There is little possibility that Duguay could have known he had the APOE4 gene variant during his hockey career. It was not until 1993 that scientists published study results confirming the APOE4 gene variant could increase Alzheimer’s disease risk, and also that it was associated with an earlier age of disease onset (Strittmatter et al. 1993) (Corder et al. 1993).

In addition, the association between the APOE4 gene variant for increasing Alzheimer’s disease risk in individuals who have experienced a moderate or severe head injury was not confirmed until 2000 (Plassman et al. 2000).

Today, the APOE4 gene variant, which can be found in approximately 15% of the U.S. population, is the most well documented genetic risk factor for developing sporadic Alzheimer’s disease. Traumatic brain injury remains the most significant environmental factor associated with Alzheimer’s disease development.

For example, in one study, scientists found a 10-fold increase in the risk of Alzheimer’s disease when both APOE4 gene variant and a history of traumatic head injury were present, compared with a two-fold increase in risk with the APOE 4 gene variant alone (Mayeux et al. 1995).

But in spite of these statistics, it is also well known that gene variants do not act alone to cause Alzheimer’s disease. Gene variants combine with other factors to cause disease. These factors include environmental variables, other gene variants, gender, age, health, and other circumstances that we are not yet aware of. Disease risk will also be influenced by whether an individual has one or two copies of the gene variant. We receive two copies of every gene, one from our mother and one from our father. This is referred to as the gene dose.

Hence, Duguay’s actual risk for Alzheimer’s disease onset will be influenced by many variables, including some that may work in his favor to delay and/or prevent potential disease onset.

Nonetheless, Duguay is now facing the reality of his APOE4 genotype and trying to understand its implications.

In the Sports Illustrated article, we learned that Duguay visited Manhattan to talk to neurologist Dr. Eric Braverman to find out if there might be a way he could get help with his deteriorating memory. Duguay, who was told by his friends that he should write a book about his career, was concerned because, according to the article, “there was a lot he couldn’t remember” (Epstein 2010).

But Duguay does remember that “he may have had between one and three serious concussions during his career that spanned from 1977 to 1989, and he also frequently took sticks or pucks to his unprotected head during that same time period” (Ibid).

While Duguay was in New York, Dr. Braverman gave him a test that confirmed he had one copy of the APOE4 gene variant. He also gave Duguay a battery of memory tests and the article states that Duguay failed three of these. Duguay also took a brain processing speed test, which he also failed.

Duguay is not alone in the challenge he is facing.

Like Duguay, and some other Red Wing hockey players who placed themselves at increased risk for head injury while playing hockey without a helmet, professional boxers are also at increased risk for head injury

Furthermore, few if any boxers are medically genotyped to determine their APOE4 gene variant status. Having this genotype information might help a boxer determine the level of risk he wants to take. According to one author,

“Professional boxers are capable of delivering blows with forces that may exceed 100 times the force of gravity. Such blows applied to the movable head cause the soft brain to glide and swirl within the skull, tearing vessels and causing nerves to stretch and snap” (Lampert and Hardman 1984).

In 1928, the punch drunk syndrome was described in boxers who experienced brain damage as a result of repetitive sub-clinical head injuries (Martland 1928). Today, this brain damage is called “dementia pugilistica,” and it has been reported in 10- 20% of professional boxers with long careers (Ibid).

Glen Johnson, a 5’ 11” 41-year-old, light-heavyweight professional boxer from Jamaica that has fought in 65 fights, was also interviewed in the Sports Illustrated article. According to Johnson, “The older he gets, the more he wants every bit of information that can tell him what his life might be like after he quits boxing.” Regarding the APOE4 genotype, Johnson said, “I’d have to get a better understanding of [ApoE4], and I’d take a lot of other things and tests into consideration when I think about fighting again.” Johnson continues, “but I’d never hide from extra information” (Ibid).

To get that information, Johnson will need to have his DNA genotyped. But that won’t be as straightforward as it sounds. Johnson’s DNA genotyping should include the “ancestry informative markers” (AIMs) that will reflect the unique genetic signature of his diverse ethnic background. Unlike Duguay, who is Caucasian and originally from Canada, Johnson is African Jamaican.

Like Johnson, Africans in Jamaica predominantly have their origins in a number of West African countries, with perhaps some contribution from East Africa and Madagascar (McEvedy and Jones 1978). Although the APOE4 gene variant has been confirmed globally to place people at higher risk for developing Alzheimer’s disease, this risk has been shown to vary among ethnic populations. For example, there is a high frequency of the APOE4 gene variant (26%) in the African population, but it does not place Africans at higher risk for developing Alzheimer’s disease (Corbo and Scacchi 1999) (Zekraoui et al. 1997).

To what extent this decreased risk for developing Alzheimer’s disease is passed on to individuals with African ancestry, such as African Americans, or African Jamaicans like Glen Johnson, is currently a subject of interest to scientists.

For example, scientists don’t know why Africans, with the APOE4 gene variant are not at increased risk for Alzheimer’s disease. It could be due to something in the African’s environment that is not found in other geographical locations, such as a dietary component.

If the decreased risk for Alzheimer’s disease is found in an African’s genes, the extent to which it is inherited by individuals with African ancestry will depend on many factors.

One factor is how far removed in time an individual is from his African ancestry. Another factor is to what extent an individual has an admixed ancestry. In other words, to what extent the individual’s ancestry reflects the contribution of different ethnic groups as a result of intermarriage.

For example, African American admixed ancestry, which occurred as a result of admixing among Europeans, West Africans, and Native Americans, was estimated, in one study of individuals living in New York State to be 83% African, 15% European and 2% Native American (Stefflova, 2009).

Today, it is possible to study different proportion of admixed genes and determine what role they might play in a person’s risk for developing a disease.

For example, in a study conducted by Wassel and her colleagues, a clinically relevant diagnosis of sub-clinical cardiovascular disease was determined based on the European proportion of an African American’s admixed ancestry (Wassel et al. 2009). Wassel’s study-data showed that European ancestry was associated with an 8% higher coronary artery calcium (CAC) prevalence. Each single digit increase in European ancestry was also associated with a 2% lower common carotid intima media thickness. Both measures represented a clinically relevant diagnosis of sub-clinical cardiovascular disease in these African American study participants (Ibid).

Hence, it is possible that individuals with African Jamaican ancestry, like Glen Johnson, may have inherited some proportion of genetic ancestry from their African admixture that could influence their Alzheimer’s disease risk.

To date, studies conducted to determine an African American’s risk for developing Alzheimer’s disease have been inconsistent. But these studies have not taken into account genetic admixtures.

For example, “In one study of African Americans living in New York City, scientists found that there was an association between Alzheimer’s disease and the APOE-E4 gene variant, but only if an individual received two copies of the variant APOE4 gene (Maestre, Ottman and Stern 1995). According to that study, there was no risk if an individual received only one copy of the variant APOE4 gene” (Tang et al. 1998).

In another study scientists found “the presence of an APOE-e4 allele is a determinant of Alzheimer’s disease risk in whites, but African Americans and Hispanics have an increased frequency of Alzheimer’s disease regardless of their APOE genotype (Tang et al. 1998).

Looking at Alzheimer’s disease risk by taking admixed ancestry into account may help to explain these contradictory study results. It may also offer Glen Johnson better DNA genotyping data with which to understand his risk for Alzheimer’s disease.

In addition to Duguay, Johnson, and others at risk for getting head injuries while playing sports, the information about the APOE4 gene variant is also relevant for U.S. veterans of war. Veterans who have the APOE4 gene variant may be at increased risk for developing dementia and/or Alzheimer’s disease based on head injuries they received in combat. In 2009, USA Today reported that 300,000 veterans returned to the U.S. with head injuries from the Iran and Afghanistan wars. Many of these head injuries resulted primarily from road-side bomb explosions.

Many U.S. soldiers do not tell anyone about their head injuries because they are afraid they might be relieved from combat.

Of additional concern is information that many U.S. soldiers do not tell anyone about their head injuries because they are afraid they might be relieved from combat. As a result, some soldiers may be at increased risk for receiving a recurring head injury. These soldiers do not have information about their APOE4 genotype status and, as such, they are placing themselves in potential jeopardy.

If Duguay and others with the APOE4 genotype had been born 100,000 years ago, the APOE4 gene variant might have provided them with an advantage for survival.

APOE4 gene variant is the ancestral form of the APOE gene that was common 100,000 years ago when nomadic people foraged for their food (Zekraoui et al. 1997).

The APOE4 gene variant, which functions in lipid transport, was more efficient at absorbing fat from the intestine and redistributing it to organs for its use. According to one study, “This may have increased chances for survival during famine or at other times when the availability of food quality varied “ (Ibid).

Today, changes in an individual’s diet may increase the chances for survival for individuals with the APOE4 gene variant that are at higher risk for developing Alzheimer’s disease.

For example, one group of scientists found that the Mediterranean diet is related to lower risk for Alzheimer’s disease. According to the scientists, “In our previous work we reported that higher adherence to the Mediterranean diet seems to reduce risk for getting AD “ (Scarmeas et al. 2009).

Moreover, according to their study results, the Mediterranean diet seems to affect subsequent Alzheimer’s disease course as well. “We found that higher adherence to the Mediterranean diet was associated with lower mortality in AD” (ibid).

The scientists also found that the diet worked equally well for patients with and without the APOE4 genotype.

There are also many bioactive dietary components that scientists are studying to discover a means to prevent and treat Alzheimer’s disease. One such bioactive dietary component is apple juice. Scientists showed that supplementation with apple juice concentrate alleviated the oxidative damage and cognitive decline in adult mice that lacked the APOE protein when challenged with a vitamin-deficient oxidative stress-promoting diet (Chan and Shea 2006).

In a separate study, the same scientists showed that apple juice concentrate, when combined with drinking water, maintained the neurotransmitter acetylcholine levels that otherwise decline when adult and aged mice are maintained on a deficient diet. This is significant because the neurotransmitter acetylcholine declines with normal aging and Alzheimer’s disease. However, there is no data on whether apple juice concentrate will have similar effects in humans (Chan, Graves and Shea 2006).

The same scientists also note that, “Supplementation with blueberries, spinach or strawberries has been shown to reverse age-related declines in signal transduction as well as cognitive and behavioral deficits in rats” (Ibid).

Another bioactive dietary component that has been shown to be active on certain altered cell signaling pathways associated with Alzheimer’s disease is curcumin. Some scientists believe that it has the potential to inhibit the inflammation that occurs in Alzheimer’s disease. Curcumin has also been found, at a low dose, to effectively disaggregate Amyloid beta, as well as prevent Amyloid Beta fibril and Amyloid Beta oligomer formation (Yang et al. 2005).

At the same time, the action of curcumin is not always predictable. In one study, scientists demonstrated that curcumin unexpectedly promoted the progression of lung lesions from benign hyperplasias to adenocarcinomas and carcinomas (Dance-Barnes et al. 2009).

Another bioactive dietary component that some scientists believe may have potential for improving Alzheimer’s disease symptoms is Green Tea. According to one study, “In neurodegenerative diseases, human epidemiological and new animal data suggest that tea consumption inversely correlates with incidence of dementia, Alzheimer disease (AD), and Parkinson disease (PD) ”(Mandel et al. 2008).

Yet again, the results that might be obtained with green tea can also be unpredictable. For example, in one animal study that was conducted in anticipation of conducting a clinical trial with green tea for colon cancer, scientists found that, “These results indicate that green tea catechins do not inhibit, but rather may enhance colon carcinogenesis, while not influencing lung and thyroid carcinogenesis under the present experimental conditions” (Hirose et al. 2001).

Hence, it is important to be able to determine that you are achieving your goals when you experiment with bioactive dietary components. One way to accomplish this is to work with scientists and physicians by participating in studies they conduct in Alzheimer’s disease prevention or treatment with bioactive dietary components or other experimental compounds.

Today, new biomarkers have been discovered that scientists and physicians can use to measure if study participants are achieving their goals. If they are not achieving their goals, study participants have the opportunity to switch to a study that is testing a different bioactive dietary component or compound that might work better for them.

One of DNAScribe’s goals is to link readers to scientists and physicians who plan to conduct studies with bioactive dietary components and other therapies to prevent Alzheimer’s disease in individuals who are at higher risk because of their gene variants. If you are interested in this, please let us know.