50 Percent of Alzheimer’s Cases Due to Gene Allele, Lifestyle Factors Key for Prevention

50 Percent of Alzheimer’s Cases Due to Gene Allele, Lifestyle Factors Key for Prevention
Although only about 20 percent of the human population carries ApoE4, it accounts for an estimated 40 to 65 percent of Alzheimer's disease (AD) cases. (Kateryna Kon/Shutterstock)
Stephanie Zhang, Ph.D.
1/4/2023
Updated:
3/22/2023
Alzheimer’s disease (AD) is a multifactorial disease, in which genetic factors account for 70 percent of its causes. There are two types of AD: familial and sporadic AD. Genes of familial AD are related to family history; while that of sporadic AD, the apolipoprotein E4 (ApoE4) gene allele, is the most significant genetic risk.
ApoE gene has three forms—E2, E3, and E4. The E2 form performs a protective function as it can protect the carrier from AD incidence; the E3 form is the most common, it presents in the average population and is not related to AD; and the E4 form is a risk factor that increases the incidence of AD.  
Although only about 20 percent of the human population carries ApoE4, it accounts for an estimated 40 to 65 percent of AD cases. Depending on whether a carrier has one or two copies, ApoE4 increases AD risk by three- to twelve-fold. Therefore, taking action to alleviate the risk of AD is essential if you carry the ApoE4 gene allele.

APOE4 Associated With Cholesterol Metabolism

A recent article published in the journal Nature revealed that altered cholesterol levels in the brain along with the ApoE4 gene could be the reason for learning and memory deficits in AD patients. The results indicated that ApoE4 gene expression was associated with cholesterol metabolism. Abnormally deposited cholesterol inhibited the electrical activity of neurons, resulting in the isolation of neurons and neural cell death. 
The research suggested that facilitating cholesterol transportation might be a solution to increase axonal information transportation and improve learning and memory in ApoE4 carriers. 

How Do You Know if You Are an APOE4 Gene Carrier?

A genetic test can reveal whether an individual has the ApoE4 risk gene. The 23andMe Genetic Health Risk Test can identify whether an individual has genes associated with the risk of 10 diseases and conditions, including ApoE4. 
Unlike the tests for deterministic genes of familial AD, the test for ApoE4 is not highly recommended. The reason is that even if an individual has the ApoE gene, it does not guarantee that the person will develop AD; thus the ApoE4 gene is considered a “risk gene” for AD. Many people with the ApoE4 gene never experience AD symptoms, while many AD cases do not have any copies of ApoE4. 
Understanding the risk for certain diseases based on genetics is complicated, and people considering such tests may want to consider genetic counseling. Individuals should seek the services of a genetic counselor before and after taking the test. A genetic counselor can be found online through the National Society of Genetic Counselors (nsgc.org). 

Nutrition Suggestions for ApoE4 Carriers

The effects of ApoE4 on the human brain still need to be fully understood, which hinders the opportunity to develop targeted therapeutics. However, some guidance on nutrition might affect the impact of ApoE4 on the human brain from the perspective of its critical role in cholesterol metabolism. 
  1. Low Carbohydrate and Low Cholesterol Diets
There are two types of cholesterol. Low-density cholesterol, also called “bad” cholesterol, can cause fatty accumulation in your liver and heart. High-density cholesterol, termed “good” cholesterol, is a necessary lipid, as research has proven that it helps promote estrogen, progesterone, and vitamin D levels.
Eating more meat, bacon, and cheese, and less bread, fruit, and sweets may help you lose weight, but it may not help lower low-density “bad” cholesterol. On the contrary, it does the opposite.
Instead, eating a low-carb, low-cholesterol, primarily plant-based diet effectively reduces unhealthy, low-density cholesterol. This type of diet includes vegetables, low-carb fruits, and plant proteins such as beans, lentils, and peas. 
A low-carbohydrate, low-cholesterol diet can control hypertension, optimize cerebral blood flow—especially important in ApoE4 carriers—and prevent the incidence of AD.
  1. Ketogenic Diets and β-Hydroxybutyrate
A ketogenic diet is a much more advanced option on the spectrum of the low-glycemic index and low-carbohydrate diets. Instead of using glucose as an energy source, the ketogenic diet provides an alternative fuel source to the brain. It focuses on therapeutic carbohydrate restriction, in which carbohydrate intake is reduced to a level,  usually below ~25 g of net carbohydrates per day, such that the liver converts body or dietary fat in the ketone body to β-Hydroxybutyrate (βhB). 
Diet-induced nutritional ketosis, also called the ketogenic diet, can be complemented by many other dietary strategies, including vegetarian, carnivore, or Mediterranean.
A ketogenic diet as a dietary intervention can increase βhB and decrease inflammation, oxidative stress, mitochondrial dysfunction, and other basic metabolic pathologies that contribute to AD, thus improving AD symptoms. 
In addition, it has been shown to improve cognition in ApoE4 carriers. ApoE4 genotype shifts metabolic dependency from glucose to ketones, therefore, a ketogenic diet could be protective against ApoE4-associated metabolic deficits and reduce AD risk.
  1. Mediterranean Dietary Components
The Mediterranean diet is associated with low AD rates and improved disease progression. It can reduce the risk of cognitive impairment by 33 percent
Interestingly, research has found that carriers of ApoE4 who lived in Italy and ate a traditional Mediterranean diet for most of their lives could live to be 95 years old for men and 99 for women, similar to non-carriers. By contrast, ApoE4 carriers who lived in the U.S. had a significantly reduced chance of living into late old age. The data indicated that the Mediterranean diet was closely related to AD incidence.  
Extra virgin olive oil in the Mediterranean diet contains neuroprotective phenolic compounds, including oleocanthal and hydroxytyrosol, which have anti-amyloid and anti-tau properties. These compounds may also impact AD pathways and help to improve lipid metabolism, which is often impaired in ApoE4 carriers.
Fatty fish are essential to Mediterranean diets, with wild salmon, mackerel, and sardines being the most healthful and available. These foods are a rich source of the two long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). 
DHA in the Mediterranean diet, in particular, is essential for brain function. Brain DHA levels are lower in individuals with AD compared to controls, and greater fish consumption and DHA are associated with lower AD rates. Fatty fish consumption was associated with a reduced risk of dementia and AD for those without the ApoE4 allele. DHA dose and timing also matter. ApoE4 carriers may need higher DHA doses because they contain β-oxidized DHA at higher rates than non-carriers. 
  1. Limit Alcohol
ApoE4 carriers may be more vulnerable to environmental factors. Lifestyle interventions may significantly modify dementia risk, particularly among genetically susceptible individuals. Consumption of any amount of alcohol may increase the risk of AD for ApoE4 carriers. ApoE4 carriers who consumed alcohol one or more times per month had a higher risk of AD than those who never drank alcohol. In the study, the risk of AD for carriers increased with increasing amounts of alcohol consumption. These data suggest that alcohol consumption should be limited, especially in ApoE4 carriers.
  1. B Vitamins
B vitamins can improve homocysteine levels, which is a risk factor for AD, and are positively associated with ApoE4 status. It can slow brain atrophy by 70 percent in the ApoE4 carriers, and increase homocysteine baseline and serum omega-3 levels. 
A combination of omega-3 and sufficient B vitamins might act synergistically to slow cognitive decline; it also synergizes with fatty fish intake and DHA supplementation to prevent brain atrophy. Therefore, ApoE4 carriers may consider supplementing with a full-spectrum B-vitamin complex. 
  1. Lithium
Lithium can increase Aβ clearance from the brain, and higher levels of trace lithium in drinking water are associated with lower incidences of AD and AD-related mortality in Scandinavian and American populations. 
  1. Supplementation
  • DHA or Krill oil, 2 g/day 
  • Quercetin 25 to 100 mg/kg/day
  • Resveratrol 2 g/day 
  • Vitamins D3 and K2, 5000 IU vitamin D3 and a range from 45 to 180 µg/day K2 
Stephanie Zhang, Ph.D., is a columnist for The Epoch Times, focusing on brain and neurodegenerative diseases. She has over 20 years of research experience in neuroscience and neurotoxicity, and was a former research scientist in the Memory Impairment and Neurodegenerative Dementia (MIND) Center at The University of Mississippi Medical Center. She earned her doctorate in public health.
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