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ApoE, Diet, CADz, Alzheimer's Dz: Why you should get tested.

Posted Jan 05 2013 12:00am

ApoE, diet, heart disease risk and Alzheimer’s Disease:
A reason to get tested

Edited material reviewed by JP Saleeby, MD

The Apolipoprotein E (APOE) gene located on chromosome 19, is the major genetic source of the common forms of late-onset Alzheimer disease (Alzheimer's disease), cardiovascular disease and matching the ‘’best dietary recommendations’’ for individuals. This gene is polymorphic and has three allelic isoforms or variants (ApoE2, ApoE3, and ApoE4) and five common genotypes (2/3, 3/3, 2/4, 3/4, and 4/4).  The Apolipoproteins themselves are what is transcribed from the gene and they are 299 amino acids long.  The protein ApoE is an Apolipoprotein class found in chylomicrons and Intermediate-Density Lipoproteins (IDLs) responsible for normal catabolism of triglyceride-rich lipoprotein constituents.  Besides lipid transport importance, there is function with immunoregulation and cognition.

Making sense out of these letters.
For the sake of nomenclature ApoE4 (APOE4)  is the protein (apolipoprotein E4) while  Apoε4  is the allele (gene designation, sometimes also noted as ApoE4 allele).
Regarding the genotypes, 7% of the population has E2 (E2/E2) and these individuals may clear dietary fat slowly and be at greater risk for CADz.  94.4% have the E2/E2 pattern.
E3 is called neutral or “native’’ and the vast majority of the population (79%) have this type of allele, (E3/E3).  This genotype is by far the most common.
The ApoE4 allele is found in about 14% of the population.

ApoE and  Alzheimers Disease.
ApoE4 allele increases the risk and decreases the average age of dementia onset in a dose-related fashion, such that the risk of Alzheimer disease is lowest in patients with the 3/3 genotype, higher for the 3/4 genotype, and highest for the 4/4 genotype.  Those with 4/4 have a 10 to 30 times the risk for developing late onset AD.  The ApoE2 allele lowers the risk of Alzheimer disease (AD).
However, ApoE4 accounts for only part of the genetic risk for Alzheimer disease. A family history of dementia, regardless of ApoE4 status, can also increase the risk of developing the disorder. Specifically, persons with a first-degree relative with dementia have a 10-30% increased risk of developing Alzheimer disease.

The underlying mechanism through which ApoE influences Alzheimer disease risk has not yet been determined. Scientists have explored several possibilities, including the idea that ApoE may play a role in cholesterol transport, neuronal integrity, and amyloid deposition.
Additional studies revealing the true mechanism could eventually lead to more specific treatments for Alzheimer disease. Indeed, studies of asymptomatic ApoE4 carriers show that these persons are more likely to display subtle abnormalities on brain scans, such as positron emission tomography (PET) or magnetic resonance imaging (MRI) scans.  Although 40-65% of AD patients have at least one copy of the 4 allele, ApoE4 is not a determinant of the disease - at least a third of patients with AD are ApoE4 negative and some ApoE4 homozygotes never develop the disease.  ApoE(2,3) is the lowest risk, but interestingly ApoE(2,4) and ApoE(3,3) carry the same rate of AD.
Thus, combining information on ApoE4 carrier status with other informative biological-marker data is a promising research strategy for detecting individuals who might be candidates for Alzheimer disease prevention strategies.

Despite concerns about genetic testing, studies of individuals who have learned that they are ApoE4 carriers have not demonstrated higher rates of anxiety or depression. Rather, some ApoE4 carriers are motivated to adapt a healthier lifestyle to maximize brain health. [1-9]

In industrialized countries, cardiovascular diseases are widespread and are amongst the most frequent causes of death.  In particular, increased cholesterol and triglyceride values in the blood are risk factors in this case. Along with an unhealthy lifestyle, genetic changes may also cause an increase in blood lipid levels.  Apolipoprotein E (ApoE) is, for example, also affected by such changes.  In the homozygotic presentation, the ApoE2 allele (E2/E2) is associated with type III hyperlipoproteinaemia.  This clinical picture leads to an increased risk of arteriosclerosis.  Testing for the presence of the ApoE2 allele can support the diagnosis of type III hyperlipoproteinaemia and should be performed if the disease is suspected.  Even in the case of ApoE4 allele carriers, there can be after-effects on health due to disrupted lipid metabolism. Carriers of this allele are exposed, for example, to an increased risk of coronary heart disease. Therefore, for patients with increased cholesterol and triglyceride values, gene typing is likewise recommended in order to clarify any genetic causes.10

The highest ApoE3 frequencies are found in populations with a long-established agricultural economy (Gerdes et al. 1996) such as those of the Mediterranean basin or East Asia.  It is possible that the metabolic properties of the E3 isoform proved to be particularly advantageous in the transition from food collection to food production At present, the frequency of ApoE4 within all the major human groups remains higher in those populations…where an economy of foraging still existsor food supply is now or has until recently been scarce, sporadically available or qualitatively poor. Under these environmental conditions, carrying the ApoE4 could be still useful. For example, most of these populations have lower plasma cholesterol levels than those observed among Western countries. Since ApoE4 is associated with both a higher absorption of cholesterol at intestinal level, and higher plasma cholesterol levels, individuals carrying it would be favored because this allele could help in rebalancing cholesterol levels which would otherwise be too low (Scacchi et al. 1997).  However, with a Western (American) diet, this type of allele expression has proven detrimental to our health with regard to cardiovascular disease and dementia.

Hopefully this just means one should eat primal, who really wants to eat a low cholesterol diet. It is clearly a gene-environment interaction that leads to high levels of heart disease (CAD) and Alzheimer’s (AD) for ApoE4s.  Because the developing world (3rd world countries) have more E4s yet far less CAD & AD, there is certainly an environmental component to disease expression.11

How does Alcohol play into things?
The effect of alcohol drinking on LDL-cholesterol concentrations is unclear. The reported variability may be due to interactions between genetic factors and alcohol intake.  A study was conducted to examine Apolipoprotein E gene (ApoE) locus association between alcohol drinking and LDL cholesterol.  The study was a cross-sectional design in a healthy population-based sample of 1014 men and 1133 women from the Framingham Offspring Study.

In male nondrinkers, LDL cholesterol was not significantly different across ApoE allele groups [APOE*E2 (E2), APOE*E3 (E3), and APOE*E4(E4)].  However, in male drinkers, differences were observed; those with the E2 allele had the lowest concentrations. LDL cholesterol in men with the E2 allele was significantly lower in drinkers than in nondrinkers but was significantly higher in drinkers than in nondrinkers in men with the E4 allele. This ApoE alcohol interaction remained significant after age, body mass index, smoking status, and fat and energy intakes were controlled for.  In women, the expected effect of ApoE alleles on LDL cholesterol occurred in both drinkers and nondrinkers.  Multiple linear regression models showed a negative association between alcohol and LDL cholesterol in men with the E2 allele but a positive association in men with the E4 allele. No significant associations were observed in men or women with the E3 allele.  Therefore, in men, the effects of alcohol intake on LDL cholesterol are modulated in part by variability at the ApoE locus.  So if a male with an ApoE2 allele drinks alcohol it can lower the LDL.  If however, he has the ApoE4 it will raise LDL-C.  That is likely the reason we see lower cholesterol levels in some men who drink heavily.  Unless you know which allele you possess, drinking alcoholic beverages can be a coin toss.12

How can determining your ApoE gene type help with weight loss?
Overall, carriers of the ApoE2 allele had lower LDL-cholesterol concentrations and a tendency to higher triglycerides (TGs) concentrations relative to carriers of the ApoE3 and ApoE4 alleles. In addition, there was a positive association between dietary sucrose (6–7% of the total energy intake) and plasma TG concentrations only in carriers of the ApoE2 allele.

Although it is difficult to speculate about the mechanisms behind these effects, one can envision several possibilities. First, E2 allele carriers may have a compromised clearance system for TG-rich lipoproteins, thus they should avoid high fat diets and high sugar (carb) diets. Even a modestly increased VLDL production in response to sucrose could result in an increased plasma TG concentration. Alternatively, in addition to affecting uptake of TG-containing remnant particles, the ApoE polymorphism may play a role in the intrahepatic synthesis and catabolism of TG-rich lipoproteins.  Those with the ApoE4 genotype, having already mentioned this as being the “thrifty gene” and their inability to process cholesterol very well, are likely to benefit from a low cholesterol and dietary fat diet.  This is helpful when directing patients to follow a particular type of diet or weight loss program.  Depending on your ApoE allele type there may be better weight loss and weight management programs than picking one at random.  This is likely a reason why one diet plan (low Carb/high Protein) is seen to work in one individual while not in another.13

The Diets.
Regardless of genotype, everybody benefits from eating an anti-inflammatory diet rich in antioxidants, healthy fats, fruits and vegetables, and whole grains.  Another key is approaching food as fuel and eating small meals and snacks about every three hours.  McDonald believes that determining the best “fuel” for your body depends on your genotype.
ApoE2 – For example, those with genotypes including ApoE2 prefer fat and operate optimally with 30 to 35 percent of daily calories from healthy fats such as olive oil, avocados, nuts, and omega 3-rich foods like salmon and walnuts.  A sample dinner for this genotype carrier might be salmon, broccoli with chopped almonds, and a baked potato.  A diet similar to the Adkins approach may be ideal for this phenotype. ApoE3/3 - This genotype processes fat normally and does best with a moderate fat diet including slightly smaller portions of healthy fats, such as a dinner of salmon, green beans, and brown rice.  Exercise is likely a good aspect to focus on. ApoE4 - People with genotype pairings containing ApoE4 don’t use fat for fuel very well and should aim for limiting it to 20 percent of total calories, deriving more calories from complex carbohydrates and plant proteins.  For example, dinner could be beans, rice, avocado, and broccoli.14
WellnessOne in Myrtle Beach and WellnessFirst in Charleston, SC have teamed up with a laboratory to test clients for ApoE variants, along with other in-depth cardiovascular and cancer biomarkers.  The center can also provide dietary protocol options and guidance.15



1.       Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of Apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. Aug 13 1993;261(5123):921-3. 2.       Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC Jr, et al. Protective effect of Apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. Jun 1994;7(2):180-4. 3.       Van Duijn CM, Clayton D, Chandra V, Fratiglioni L, Graves AB, Heyman A, et al. Familial aggregation of Alzheimer's disease and related disorders: a collaborative re-analysis of case-control studies. EURODEM Risk Factors Research Group. Int J Epidemiol. 1991;20 Suppl 2:S13-20. 4.       Huang W, Qiu C, von Strauss E, Winblad B, Fratiglioni L. APOE genotype, family history of dementia, and Alzheimer disease risk: a 6-year follow-up study. Arch Neurol. Dec 2004;61(12):1930-4. 5.       Small GW, Bookheimer SY, Thompson PM, Cole GM, Huang SC, Kepe V, et al. Current and future uses of neuroimaging for cognitively impaired patients. Lancet Neurol. Feb 2008;7(2):161-72. 6.       Keller L, Xu W, Wang HX, et al. The obesity related gene, FTO, interacts with APOE, and is associated with Alzheimer's disease risk: a prospective cohort study. J Alzheimers Dis. 2011;23(3):461-9. 7.       Huang Y, Zheng L, Halliday G, et al. Genetic polymorphisms in sigma-1 receptor and Apolipoprotein E interact to influence the severity of Alzheimer's disease. Curr Alzheimer Res. Nov 2011;8(7):765-70. 8.       Apolipoprotein E genotyping in Alzheimer's disease. National Institute on Aging/Alzheimer's Association Working Group. Lancet. Apr 20 1996;347(9008):1091-5. 9.       Author (1-9)  (Alzheimer Disease and APOE4)
Gary W Small, MD  Professor of Psychiatry and Biobehavioral Sciences, Parlow-Solomon Professor on Aging, Director of Geriatric Psychiatry, Director of the UCLA Center on Aging, University of California, Los Angeles, David Geffen School of Medicine. 
Bruce Buehler, MD  Professor, Department of Pediatrics and Genetics, Director RSA, University of Nebraska Medical Center. 
10. 11.    Corbo, R.M., Scacchi, R., Apolipoprotein E (APOE) allele distribution in the world. Is APOE*4 a ‘thrifty’ allele?. Annals of Human Genetics, 1999; 63: 301–310. 12.    Corella, D., Tucker, K., et. al, Alcohol drinking determines the effect of the APOE locus on LDL-cholesterol concentrations in men: the Framingham Offspring Study, Am J Clin Nutr. 2001 73: 4 736-745. 13.    Berglund L. The APOE gene and diets--food (and drink) for thought. Am J Clin Nutr. 2001 Apr;73(4):669-70. 14.    WellnessOne/WellnessFirst, and

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