Omega-3s, ApoE Genotype and Cognitive Decline
The most recent statistics indicate that dietary intake of omega-3 PUFA is insufficient in >95% of Americans. Deficits in omega-3s have been shown to contribute to inflammatory signaling, apoptosis, and neuronal dysfunction in all cause dementia, including Alzheimer's disease. DHA (22:6[n-3]), specifically, is a critical contributor to cell structure and function in the nervous system, and a recently identified DHA-derived messenger, neuroprotecting D1 (NPD1) has been found to regulate brain cell survival and to promote non-amyloidogenic processing of amyloid precursor protein, thus protecting against Alzheimer's disease by inhibiting formation of β-amyloid. Studies utilizing omega-3 supplementation to improve cognitive function in elders, however, have had mixed outcomes, an inconsistency which newly published research indicates is related to ApoE genotype. ApoE ε4 carriers have not been able to benefit from omega-3s. This article discusses why and what can be done to enable carriers of the ApoeE ε4 allele to receive the neuroprotective benefits of omega-3s.
Should you prescribe an omega-3 supplement to all your aging patients to help stave off cognitive decline? New research provides insight into which of your patients will be likely to benefit, which may not, and why.
The most recent statistics indicate that dietary intake of omega-3 fatty acids is insufficient in >95% of Americans.1 2 Supplementation to support healthy brain function appears advisable since docosahexaenoic acid (DHA; 22:6[n-3]) is a critical contributor to cell structure and function in the nervous system, and deficits in DHA have been shown to contribute to inflammatory signaling, apoptosis, and neuronal dysfunction in all cause dementia, including Alzheimer's disease.3
Furthermore, just published studies add to the rationale for ensuring DHA adequacy to maintain health in the aging brain. A recently identified DHA-derived messenger, neuroprotecting D1 (NPD1) is involved in regulating brain cell survival and repair through neurotrophic, antiapoptotic and anti-inflammatory signaling. NPD1 also plays an important role in non-amyloidogenic processing of amyloid precursor protein (APP), thus preventing the formation of β-amyloid, protecting synapses and decreasing the number of activated microglia in the hippocampus. This elucidates another mechanism whereby DHA deficiency is associated with Alzheimer's disease.3 4
As explained in an earlier article in Longevity Medicine Review titled "Reducing Amyloid Plaque in Alzheimer's Disease and the Aging Brain: a Review of Available Options," the plaques characteristic of Alzheimer's disease are composed of β-amyloid, a peptide snipped from a larger protein called amyloid precursor protein (APP), which is located in the neuron's membrane. In the non-amyloidogenic pathway encouraged by DHA via NPD1, APP is cleaved by the α-secretase enzyme, producing "α-secretase cleaved soluble APP (APPsa), which plays a protective role in neuronal survival and repair after injury. In the amyloidogenic pathway, however, APP is proteolytically processed by the β- and γ-secretase enzymes to release the neurotoxic β-amyloid peptide.
Given these facts, one would expect omega-3 supplementation to benefit all aging brains. So why has intake of omega-3s been found, only in some, but not in other studies, to improve cognitive function in elders?5 6 7 8
Research published in the December 2008 issue of the American Journal of Clinical Nutrition may explain why evidence for an inverse relationship between intake of omega-3 essential fatty acids and age-related cognitive decline has been inconsistent. It appears that omega-3s are protective only in individuals who are not carriers of the apolipoprotein E epsilon4 (ApoE ε4) allele.9
British researchers evaluated 120 volunteers, whose IQ at 11 years of age was available, as well as at ages 64, 66 and 68. At the onset of the study, omega-3 concentrations (total n-3 PUFA and DHA concentrations) in erythrocyte membranes were measured, and ApoE genotype was determined. Six cognitive tests were administered at onset and at each follow up. Cognitive benefits were associated with higher erythrocyte omega-3 content, but were significant only in subjects who did not carry the ApoE ε4 allele.
Similar findings were noted in earlier research conducted at Tufts University (the Cardiovascular Health Cognition Study) and in France (the Three-City Cohort Study). In the Cardiovascular Health Cognition Study, subjects consuming fatty fish more than twice per week were found to have a 28% reduction in risk for dementia and a 41% reduction in risk for Alzheimer's disease, compared to those who ate fish less than once a month. Stratification of the data by ApoE genotype revealed this effect was seen only in those who were not carriers of the ApoE ε4 allele.10
In the Three-City Cohort Study, weekly fish consumption was associated with a 35% reduction in risk of Alzheimer's disease and all cause dementia, but again, only among those who were not ApoE ε4 carriers. The protective effect of omega-3s was even more clearly seen in non-carriers of ApoE ε4 who regularly consumed omega-6-rich oils and did not compensate by also regularly consuming omega-3 rich oils or fish. Risk of dementia in these individuals was more than doubled, increasing 212%.11
What's ApoE ε4 Got to Do with It?
The ApoE ε4 allele appears to have been conserved in the human genome since it offers protection against certain infectious diseases. ApoE ε4 is associated, for example, with less severe Giardia infections in Brazilian shantytown children, a protective role in the cognitive and physical development of children with heavy burdens of diarrhea in early childhood, and with protection against hepatitis C-induced liver damage. These findings suggest the ApoE ε4 allele confers a survival advantage in pathogen resistance, particularly in undernourished populations in developing countries, and the higher incidence of the ApoE ε4 allele in pre-industrialized countries supports this theory. In Westernized populations, however, where infectious diseases are no longer the major killers, the ApoE ε4 genotype is disadvantageous.12
The ApoE ε4 allele increases serum LDL cholesterol levels since the resulting isoform binds preferentially to larger liquid-rich lipoproteins (VLDL and LDL), while ApoE ε2 and ApoE ε3 prefer smaller lipoproteins such as HDL. The protein folding in the ApoE ε4 allele that results in this preference also modifies ApoE ε4's antioxidant properties, which are the least of all the ApoE alleles (apolipoprotein antioxidant capability runs E2>E3>E4), and lastly, increases ApoE ε4's influence on the production of inflammatory cytokines and other mediators of the inflammatory response, which is the strongest of all the apolioproteins (E4>E3>E2).13
The end result is greatly increased risk of atherosclerosis, hypertension and ischemia in the brain of ApoE ε4 carriers, which decreases oxygenation and increases oxidative stress, setting up ideal conditions for β-amyloid generation and neuronal degeneration. It is not surprising that the most severe cerebral hypoperfusion seen in Alzheimer's disease patients is found in those carrying the ApoE ε4 allele.14
The brain is also one of the most cholesterol-rich organs of the body, containing almost 25% of total body cholesterol, which is concentrated within lipid rafts in the neuronal cell membrane and is involved in the formation and maintenance of synaptic connections. Since ApoE is an integral part of the cholesterol molecule, ApoE ε4 is present in significant quantities in the brains of individuals carrying this allele.15
Not only are individuals expressing the ApoE ε4 allele predisposed to cardiovascular disorders associated with increased risk of cerebral hypoperfusion, but ApoE also plays a role in amyloid metabolism. ApoE is present along with cholesterol in the core of β-amyloid plaques, and evidence is accumulating that ApoE ε4 enhances β-amyloid aggregation by stimulating amyloidogenic processing of APP and reducing β-amyloid clearance.16
Understanding how cholesterol, or its precursors, affects membrane proteins such as APP is one of the most rapidly developing areas in biochemistry today. Cholesterol's distribution throughout the membrane is not uniform. Some patches of membrane, termed lipid rafts, contain high densities of cholesterol, along with high amounts of sphingolipids, which are lipids that promote the activity and stability of many membrane proteins. However, sphingolipids do not bundle well, so cholesterol is used to enable their orderly packing. Because cholesterol is a rigid molecule, lipid rafts are regions of low membrane fluidity. It was in studying membrane fluidity that researchers discovered the complementary nature of β-amyloid and APPsα (the non/amyloidogenic pathway) production.17
Sites of γ-secretase activity and β-amyloid production are associated with membrane regions with high cholesterol content, such as lipid rafts. In contrast, sites of APPsα production occur in membrane regions with low cholesterol content and high fluidity. Thus, the ApoE ε4 allele, which promotes high membrane cholesterol content, favors β-amyloid production, while DHA, which not only promotes membrane fluidity, but is also able to shift cholesterol out of the neuronal membrane, promotes APPsα production. This helps explain both the inhibition of β-amyloid formation seen with DHA supplementation, and the increased risk for Alzheimer's disease seen in ApoE ε4 carriers.17
Another way that ApoE ε4 contributes to susceptibility to cognitive decline is that this ApoE polymorphism is associated with a reduction in mRNA for the neuronal sortilin-related receptor SorLA/LR11. LR11 is a neuronal sorting protein that reduces amyloid precursor protein (APP) trafficking to the β- and γ-secretases that generate β-amyloid. Thus, a genetic polymorphism, e.g. ApoE ε4, which reduces LR11 expression increases risk for Alzheimer's disease. In contrast, DHA significantly increases LR11.18
So, why does the research consistently show DHA ineffective in preventing cognitive decline in carriers of ApoE ε4? Research reviewed in the remainder of this article not only attempt to explain this mystery, but indicates DHA may be even more important for ApoE ε4 carriers. The unacknowledged 600-pound gorilla in the equation is epigenetic. For DHA to provide protection against Alzheimer's disease in carriers of ApoE ε4, the key issue is cellular redox status, which is largely determined by diet and lifestyle.
The Key Issue: Eat Right for Your ApoE Type
Native Americans, among whom prevalence of ApoE ε4 is high, offer a striking example of the effects of this allele when plunged into an inappropriate environment. (Prevalence of the ApoE ε4 geneotype among Native Americans averages ~ 25%.19 For comparison, the frequency of the ApoE ε4 allele in Caucasians ranges from 12 to 15%.20)
Native Americans are known to have a disproportionately high incidence of cardiovascular disease (CVD) and related risk factors, including type 2 diabetes, high blood pressure, high cholesterol, obesity and smoking.21 A number of epidemiologic studies have focused on the relationship between diabetes and CVD in Native Americans since the relative risk of CVD among diabetic men is twice that of non-diabetic men, and the risk among diabetic women is threefold that of nondiabetic women.22 Results from The Strong Heart Study, which investigated CVD and key risk factors in American Indians in 13 communities in Arizona, Oklahoma, and South/North Dakota, found diabetes to be the most significant independent predictor of CVD in both men and women.23
The prevalence of both diabetes and CVD among the Pima Indians of Arizona has become legendary. Prevalence of type 2 diabetes mellitus in the Pima Indians was 19 times that of the predominantly white population of Rochester, Minnesota in 1978, and these statistics have not improved.24 A recent study examining trends in the incidence rate of type 2 diabetes among Pima Indians between 1965 and 2003 found that while the overall incidence of diabetes had remained stable, the incidence rate in the youth (subjects aged 5-14 years) was 5.7 times as high in the last as in the first period.25
However, despite the disproportionately high prevalence of ApoE ε4, cardiovascular disease and diabetes among Native Americans, and the Pima Indians, specifically, research examining a Native American rural population in nearby New Mexico clearly shows that carrying the ApoE ε4 allele does not increase the risk for any of these conditions in people eating a low fat diet and following an active lifestyle.20
Researchers examined plasma lipid levels and the common ApoE alleles in 142 randomly selected adults ranging in age from 21-55, who were living in their native communities in western Mexico and consuming a low-fat, unrefined carbohydrate-rich (i.e., plant-centered) diet. Although the omega-3 content of the diet was not quantified, intake of alpha linolenic acid, the parent of the omega-3 family of fats, would have to be considerable since ALA is found primarily in the leaves and other green parts of plants and is thus richly supplied in an unrefined plant-based diet.27
The majority of the subjects were handicraftsmen or laborers. The men were involved in ~10 hours of moderate to intense physical work each day. The women stayed at home, but the majority walked at least a mile for water and food supplies daily.
Although 30.1% of these individuals were carriers of the ApoE ε4 allele, their average BMI was 25.7. Plasma cholesterol, triglycerides, LDL C and HDL C averaged 165, 126, 98, and 42 mg/dl, respectively. Ninety-one per cent of the subjects had Lp(a) concentrations below 20 mg/dl, and 30% had non-detectable concentrations of this atherogenic lipoprotein.
Sixty-three percent were carriers of the ApoE ε3 allele, but no difference was observed in LDL C concentrations, cholesterol and apoB levels between the ApoE ε3 and ε4 subjects. (ApoE ε3 is considered the common allele and is present in 77% of Caucasian subjects.)
Only 4.8% were carriers of the ApoE ε2 allele, which is thought to confer protection against cardiovascular disease and insulin resistance and is known to have a very low prevalence among Native Americans. According to the Strong Heart Study, the ApoE ε2 frequencies in Native Americans living in Arizona, Oklahoma and Dakota are 4, 3 and 1.6%, respectively.26
Clearly, the increase in risk factors for cardiovascular disease, diabetes and Alzheimer's disease associated with the ApoE ε4 allele are the result, not of genetic determinism, but of this genotype's immersion in the Western diet and lifestyle.
The ApoE ε4 Allele and the Janus Face of Omega-3s
Docosahexaenoic acid (DHA), the longest, most desaturated fatty acid in animal tissues, constitutes up to 60% of all fatty acids in the cell membranes of the central nervous system (CNS) and brain, where its unique ability to shift its shape millions of times per second provides the neuronal membrane fluidity required for nerve cell signaling, and brain synaptic terminals are also highly enriched in DHA.27 3
The bioavailability of free unesterified DHA is a highly regulated event, and free unesterified DHA is normally undetectable under basal conditions, but increases during brain injury, cerebral ischemia, seizures, and other pathological conditions. Once freed, DHA can go down two different pathways—one protective, the other damaging.3
DHA, the Bright Side
Liberated DHA may be enzymatically oxygenated to generate neuroprotection D1 (NPD1), which in turn elicits potent bioactivity against excessive oxidative stress and neuroprotective functions in immediate proximity to the site of DHA liberation.
DHA and this recently identified DHA-derived mediator, NPD1 are involved in a number of protective regulatory actions including:
- Maintaining membrane functional integrity and lipid bilayer fluidity
- Recruitment and upregulation of antiapoptotic members of the Bcl-2 gene family
- Suppression of inflammatory gene expression that results in inhibition of the activation of inflammatory signaling mediators, such as cyclooxygenase-2
- Modulation of kinase mediated phosphorylation of the antiapoptotic Bcl-2 gene family
- Inhibition of proapaptotic signaling
One of NPD1's most recently identified protective activities is its activation of sorting receptor sortilin-1 (SORL1), which sends APP down the non-amyloidogenic pathway by stimulating α-secretase activities. In addition, SORL1 interacts with ApoE within cholesterol-enriched membrane domains, lessening ApoE ε4's proclivity to increase the generation of β-amyloid peptides by stimulating β-amyloid cleavage enzyme (BACE) and presenilin 1 (PS1). (The tandem actions of BACE and PS1 are often referred to in sum as beta-gamma-secretase signaling, which as noted above, takes amyloid precursor protein (APP) down the amyloidogenic pathway.)
Cardiovascular Benefits of Omega-3s also Promote Brain Health
Numerous studies suggest that supplementation with omega-3s may also help to improve the availability of nutrients to the brain by improving cardiovascular function and therefore, brain blood supply. Omega-3s have been shown to prevent arrhythmias, lower plasma triacylglycerols, decrease blood pressure, decrease platelet aggregation, improve vascular reactivity, and decrease atherosclerosis and inflammation.28
DHA, the Dark Side
On the other hand, when excessive levels of reactive oxygen species have depleted cellular redox reserves, DHA is nonenzymatically oxidized to form neuroprostanes, a class of peroxidized lipids that further contribute to oxidative stress, neuronal dysfunction and apoptosis.3
In addition, even membrane-bound omega-3 fatty acids are highly susceptible to lipid peroxidation due to the presence of their double bonds and bis-allylic positions in the fatty acyl chain, which, under oxidative conditions, favor radical formation and subsequent damage. So, DHA-enriched membranes are more susceptible to oxidative threat.
Oxidative stress targeting phospholipids containing DHA and age-related DHA depletion are associated with the progressive erosion of normal cognitive function in Alzheimer's disease, and neurological diseases that exhibit excessive markers for oxidative stress also display reduced NPD1 levels and are associated with progressive neuronal decline and neurodegeneration.3
Since nonenzymatic reactions can be quenched by specific antioxidants and free radical scavengers, the redox state of brain cells determines which pathway free unesterified DHA will take—the neurotrophic or the oxidative neurotoxic route. For DHA supplementation to provide optimal benefit, rather than an increase in neuroprostanes and oxidized lipids, the individual's cellular redox status, which may be compromised by a poor diet, exposure to heavy metals and other toxins, and even by chronic mental stress, must be taken into account.29
Can ApoE ε4 Carriers Benefit from Omega-3 Supplementation?
Yes, but only in the context of adopting major changes from the typical Western diet and lifestyle. ApoE ε4 carriers are the canaries in the mine of the Western way of life. Individuals with this genetic heritage cannot afford the "normal" level of dietary and lifestyle insults typical of life in the modern industrialized world because the ApoE ε4 allele magnifies the risks inherent in the Western diet and lifestyle.
The Western diet contains high levels of saturated and pro-inflammatory omega-6 fats, which, particularly in combination with high levels of refined carbohydrates and a sedentary lifestyle, has produced an escalating epidemic of obesity, hypercholesterolemia, and hypertension, causing atherosclerosis, coronary artery disease, and type 2 diabetes—all of which are aggravated in people carrying the ApoE ε4 allele, and all of which are major risk factors for cognitive decline and Alzheimer's disease.30 3 1 32
Supplementing ApoE ε4 carriers with omega-3s—without also simultaneously and significantly reducing their intake of refined carbohydrates and saturated and pro-inflammatory fats, and increasing their consumption of protective phytonutrient-rich foods and antioxidants, while also prescribing a program of regular physical activity—is simply not going to do the job.
Conclusion – A Healthy Redox Balance Should Allow Carriers of ApoE ε4 to Benefit from Omega-3s
A number of studies have shown that the APOE ε4 allele does not promote cardiovascular disease or dementia progression in individuals in developing countries where the diet is necessarily centered on unrefined plant foods, which are rich in alpha linolenic acid, the parent fat of the omega-3 family.12 13 20 33 Furthermore, ApoE ε4 carriers have been found to be highly responsive to dietary interventions,13 20 22 29 30 33 34 35 36 so much so that it has been proposed that a change in diet significantly decreasing refined carbohydrates and increasing omega 3s may effectively prevent AD in all people, carriers as well as non-carriers of ApoE ε4.35
Changes in the redox balance of brain cells, modulated in part by diets enriched in antioxidants as well as omega-3s, can positively affect the path taken by freed DHA, bolstering the synthesis of NPD1. In a recent study, simply combining supplementation of DHA with antioxidant carotenoids was shown to significantly improve cognitive abilities in older women (aged 60-80).36
Obviously, the change in redox balance that would result from moving from the phytonutrient-depleted Standard American Diet with its 20:1 omega-6:omega-3 ratio to a phytonutrient-rich whole foods diet including bi-weekly consumption of fatty fish, in which the omega-6:omega-3 ratio would be 4:1 or even lower, would be magnitudes larger. The resulting healthy redox balance would prevent the emergence of the dark side of omega-3s, enabling even carriers of the ApoE ε4 allele, who have been found to be both more vulnerable to environmental factors and more responsive to lifestyle interventions, to receive the benefit of these essential fats' numerous brain-protective actions.
Ervin RB, et al. Dietary Intake of Fats and Fatty Acids for the United States Population:1999-2000. Advance Data from Vital and Health Statistics, 2004. (Hyattsville,Maryland:National Center or Health Statistics). p. 348 DHHS Publication No. (PHS) 2005-1250 04-0565. ↑
van Gelder BM, Tijhuis M, Kalmijn S, et al. Fish consumption, n-3 fatty acids, and subsequent 5-y cognitive decline in elderly men: the Zutphen Elderly Study. Am J Clin Nutr. 2007 Apr;85(4):1142-7. ↑
Freund-Levi Y, Eriksdotter-Jonhagen M, Cederholm T, et al. Omega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch Neurol. 2006 Oct;63(10):1402-8. ↑
Schaefer EJ, Bongard V, Beiser AS, et al. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch Neurol. 2006 Nov;63(11):1545-50. ↑
Whalley LJ, Deary IJ, Starr JM, et al. n-3 Fatty acid erythrocyte membrane content, ApoE varepsilon4, and cognitive variation: an observational follow-up study in late adulthood. Am J Clin Nutr. 2008 Feb;87(2):449-54. ↑
Oriá RB, Patrick PD, Blackman JA, et al. Role of apolipoprotein E4 in protecting children against early childhood diarrhea outcomes and implications for later development. Med Hypotheses. 2007;68(5):1099-107. Epub 2006 Nov 13. ↑
Ma QL, Teter B, Ubeda OJ, et al. Omega-3 fatty acid docosahexaenoic acid increases SorLA/LR11, a sorting protein with reduced expression in sporadic Alzheimer's disease (AD): relevance to AD prevention. J Neurosci. 2007 Dec 26;27(52):14299-307. ↑
Kataoka S, Robbins D, Cowan L, et al. Apolipoprotein E polymorphism in American Indians and its relation to plasma lipoproteins and diabetes. The Strong Heart Study. Arterioscler Thromb Vasc Biol. 1996 Aug;16(8):918-25. ↑
Aguilar CA, Talavera G, Ordovas JM, et al. The apolipoprotein E4 allele is not associated with an abnormal lipid profile in a Native American population following its traditional lifestyle. Atherosclerosis. 1999 Feb;142(2):409-14. ↑
Knowler WC, Bennett PH, Hamman RF, et al. Diabetes incidence and prevalence in Pima Indians: a 19-fold greater incidence than in Rochester, Minnesota. Am J Epidemiol. 1978 Dec;108(6):497-505. ↑
Kataoka S, Robbins D, Cowan L, et al. Apolipoprotein E polymorphism in American Indians and its relation to plasma lipoproteins and diabetes. The Strong Heart Study. Arterioscler Thromb Vasc Biol. 1996 Aug;16(8):918-25. ↑
Allport S. The Queen of Fats. University of California Press. Los Angeles, 2006. ↑
Florent-Béchard S, Malaplate-Armand C, Koziel V, et al. Towards a nutritional approach for prevention of Alzheimer's disease: biochemical and cellular aspects. J Neurol Sci. 2007 Nov 15;262(1-2):27-36. ↑
Kivipelto M, Rovio S, Ngandu T, et al. Apolipoprotein E epsilon4 Magnifies Lifestyle Risks for Dementia: A Population Based Study. J Cell Mol Med. 2008 Mar 4;12(6B):2762-71. Epub 2008 Feb 8. ↑
Kalaria RN, Maestre GE, Arizaga R, et al. Alzheimer's disease and vascular dementia in developing countries: prevalence, management, and risk factors. Lancet Neurol. 2008 Sep;7(9):812-26. Epub 2008 Jul 28. ↑
Laitinen MH, Ngandu T, Rovio S, et al. Fat intake at midlife and risk of dementia and Alzheimer's disease: a population-based study. Dement Geriatr Cogn Disord. 2006;22(1):99-107. Epub 2006 May 19. ↑
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Lara Pizzorno is a member of the American Medical Writers Association with 25+ years of experience writing for physicians and the public, Lara is Editor for Longevity Medicine Review as well as Senior Medical Editor for SaluGenecists, Inc. Read more...
Lara Pizzorno, MDiv, MA, LMT
John Morgenthaler has been active in the field of nutritional medicine since 1986. Today, John travels the world looking for breakthrough nutraceuticals and anti-aging therapies. He also continues to publish cutting-edge nutrition and medical science books and periodicals. Read more...
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