Apolipoprotein E Polymorphism And It’s Lifestyle Impact
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Abstract
The Apolipoprotein E Polymorphism, with its three main allelic variants (APOE2, APOE3, and APOE4), has gained prominence in genetic research due to its critical implications for human health. This review article offers a concise introduction to the APOE protein polymorphism and its influence on individual’s way of life. The APOE gene encodes apolipoprotein E, a critical component of lipid metabolism that is essential for both cholesterol transport and neuron repair in the central nervous system. APOE ℇ4 raises Alzheimer's risk, ℇ2 protects, and ℇ3 is neutral. Lifestyle choices, such as diet, exercise, and cognitive engagement, predict susceptibility to chronic illnesses like Alzheimer's and cardiovascular disease (CVD). For APOE ℇ4 carriers, a heart-healthy lifestyle can reduce elevated risk, while ℇ2 carriers, being less vulnerable, may need less intervention.
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References
Rall Jr, S. C., Weisgraber, K. H., & Mahley, R. W. (1982). Human apolipoprotein E. The complete amino acid sequence. Journal of Biological Chemistry, 257(8), 4171-4178.
Mahley, R. W., & Huang, Y. (1999). Apolipoprotein E: from atherosclerosis to Alzheimer's disease and beyond. Current opinion in lipidology, 10(3), 207-217.
Mahley, R. W., & Rall Jr, S. C. (2000). Apolipoprotein E: far more than a lipid transport protein. Annual review of genomics and human genetics, 1(1), 507-537.
Wetterau, J. R., Aggerbeck, L. P., Rall, S. C., & Weisgraber, K. H. (1988). Human apolipoprotein E3 in aqueous solution. I. Evidence for two structural domains. Journal of Biological Chemistry, 263(13), 6240-6248.
Chen, J., Li, Q., & Wang, J. (2011). Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proceedings of the National Academy of Sciences, 108(36), 14813-14818.
Segrest, J. P., Jones, M. K., De Loof, H., Brouillette, C. G., Venkatachalapathi, Y. V., & Anantharamaiah, G. M. (1992). The amphipathic helix in the exchangeable apolipoproteins: a review of secondary structure and function. Journal of lipid research, 33(2), 141-166.
Westerlund, J. A., & Weisgraber, K. H. (1993). Discrete carboxyl-terminal segments of apolipoprotein E mediate lipoprotein association and protein oligomerization. Journal of Biological Chemistry, 268(21), 15745-15750.
Kh, W. (1981). Human E apoprotein heterogeneity: cysteine-argininen interchanges in the amino acid sequence of apoE isoforms. J Biol Chem, 256, 9077-9083.
Papaioannou, I., Simons, J. P., & Owen, J. S. (2012). Targeted in situ gene correction of dysfunctional APOE alleles to produce atheroprotective plasma ApoE3 protein. Cardiology research and practice, 2012.
Rall Jr, S. C., Weisgraber, K. H., Innerarity, T. L., & Mahley, R. W. (1982). Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects. Proceedings of the National Academy of Sciences, 79(15), 4696-4700.
Smith, L. C., Pownall, H. J., & Gotto Jr, A. M. (1978). The plasma lipoproteins: structure and metabolism. Annual Review of Biochemistry, 47(1), 751-777.
Utermann, G., Hees, M., & Steinmetz, A. (1977). Polymorphism of apolipoprotein E and occurrence of dysbetalipoproteinaemia in man. Nature, 269(5629), 604-607.
Ehnholm, C., Lukka, M., Kuusi, T., Nikkilä, E., & Utermann, G. (1987). Apolipoprotein E polymorphism in the Finnish population: gene frequencies and relation to lipoprotein concentrations. Journal of lipid research, 27(3), 227-235.
Eichner, J. E., Dunn, S. T., Perveen, G., Thompson, D. M., Stewart, K. E., & Stroehla, B. C. (2002). Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. American journal of epidemiology, 155(6), 487-495.
Nguyen, D., Dhanasekaran, P., Nickel, M., Nakatani, R., Saito, H., Phillips, M. C., & Lund-Katz, S. (2010). Molecular basis for the differences in lipid and lipoprotein binding properties of human apolipoproteins E3 and E4. Biochemistry, 49(51), 10881-10889.
Mahley, R. W. (1988). Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science, 240(4852), 622-630.
Zannis, V. I., Breslow, J. L., Utermann, G., Mahley, R. W., Weisgraber, K. H., Havel, R. J., ... & Blum, C. (1982). Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes. Journal of lipid research, 23(6), 911-914.
Zhang, H., Wu, L. M., & Wu, J. (2011). Cross-talk between apolipoprotein E and cytokines. Mediators of inflammation, 2011.
Dietschy, J. M., & Turley, S. D. (2004). Thematic review series: brain Lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. Journal of lipid research, 45(8), 1375-1397.
Saher, G., Brügger, B., Lappe-Siefke, C., Möbius, W., Tozawa, R. I., Wehr, M. C., ... & Nave, K. A. (2005). High cholesterol level is essential for myelin membrane growth. Nature neuroscience, 8(4), 468-475.
Mauch, D. H., Nagler, K., Schumacher, S., Goritz, C., Müller, E. C., Otto, A., & Pfrieger, F. W. (2001). CNS synaptogenesis promoted by glia-derived cholesterol. Science, 294(5545), 1354-1357.
Pfrieger, F. W. (2003). Cholesterol homeostasis and function in neurons of the central nervous system. Cellular and Molecular Life Sciences CMLS, 60, 1158-1171.
Poirier, J., Hess, M., May, P. C., & Finch, C. E. (1991). Astrocytic apolipoprotein E mRNA and GFAP mRNA in hippocampus after entorhinal cortex lesioning. Molecular brain research, 11(2), 97-106.
Bien-Ly, N., Gillespie, A. K., Walker, D., Yoon, S. Y., & Huang, Y. (2012). Reducing human apolipoprotein E levels attenuates age-dependent Aβ accumulation in mutant human amyloid precursor protein transgenic mice. Journal of Neuroscience, 32(14), 4803-4811.
Kim, J., Jiang, H., Park, S., Eltorai, A. E., Stewart, F. R., Yoon, H., ... & Holtzman, D. M. (2011). Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-β amyloidosis. Journal of Neuroscience, 31(49), 18007-18012.
Zannis, V. I., Breslow, J. L., Utermann, G., Mahley, R. W., Weisgraber, K. H., Havel, R. J., ... & Blum, C. (1982). Proposed nomenclature of apoE isoproteins, apoE genotypes, and phenotypes. Journal of lipid research, 23(6), 911-914.
Singh, P. P., Singh, M., & Mastana, S. S. (2006). APOE distribution in world populations with new data from India and the UK. Annals of human biology, 33(3), 279-308.
Ordovas, J. M., Litwack-Klein, L., Wilson, P. W., Schaefer, M. M., & Schaefer, E. J. (1987). Apolipoprotein E isoform phenotyping methodology and population frequency with identification of apoE1 and apoE5 isoforms. Journal of lipid research, 28(4), 371-380.
Hopkins, P. N., Wu, L. L., Hunt, S. C., & Brinton, E. A. (2005). Plasma triglycerides and type III hyperlipidemia are independently associated with premature familial coronary artery disease. Journal of the American College of Cardiology, 45(7), 1003-1012.
Lumsden, A. L., Mulugeta, A., Zhou, A., & Hyppönen, E. (2020). Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK Biobank. EBioMedicine, 59.
Hooijmans, C. R., & Kiliaan, A. J. (2008). Fatty acids, lipid metabolism and Alzheimer pathology. European journal of pharmacology, 585(1), 176-196.
Chiurazzi, M., Cozzolino, M., Orsini, R. C., Di Maro, M., Di Minno, M. N. D., & Colantuoni, A. (2020). Impact of genetic variations and epigenetic mechanisms on the risk of obesity. International Journal of Molecular Sciences, 21(23), 9035.
Lumsden, A. L., Mulugeta, A., Zhou, A., & Hyppönen, E. (2020). Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK Biobank. EBioMedicine, 59.
Kypreos, K. E., Karavia, E. A., Constantinou, C., Hatziri, A., Kalogeropoulou, C., Xepapadaki, E., & Zvintzou, E. (2018). Apolipoprotein E in diet-induced obesity: a paradigm shift from conventional perception. Journal of Biomedical Research, 32(3), 183.
Farup, P. G., Rootwelt, H., & Hestad, K. (2020). APOE–a genetic marker of comorbidity in subjects with morbid obesity. BMC Medical Genetics, 21, 1-9.
Burdge, G. C., & Calder, P. C. (2006). Dietary α-linolenic acid and health-related outcomes: a metabolic perspective. Nutrition research reviews, 19(1), 26-52.
Vedin, I., Cederholm, T., Basun, H., Eriksdotter, M., Hjorth, E., Schultzberg, M., ... & Palmblad, J. (2014). Transfer of omega-3 fatty acids across the blood-brain barrier after dietary supplementation with a docosahexaenoic acid-rich omega-3 fatty acid preparation in patients with Alzheimer's disease: the OmegAD study. Journal of Internal Medicine, 275(4), 428-436.
Smith, J. C., Nielson, K. A., Woodard, J. L., Seidenberg, M., Durgerian, S., Antuono, P., ... & Rao, S. M. (2011). Interactive effects of physical activity and APOE-ε4 on BOLD semantic memory activation in healthy elders. Neuroimage, 54(1), 635-644.
Kivipelto, M., Rovio, S., Ngandu, T., Kåreholt, I., Eskelinen, M., Winblad, B., ... & Nissinen, A. (2008). Apolipoprotein E ɛ4 magnifies lifestyle risks for dementia: a population‐based study. Journal of cellular and molecular medicine, 12(6b), 2762-2771.
Morris, M. C., Brockman, J., Schneider, J. A., Wang, Y., Bennett, D. A., Tangney, C. C., & van de Rest, O. (2016). Association of seafood consumption, brain mercury level, and APOE ε4 status with brain neuropathology in older adults. Jama, 315(5), 489-497.
Bredesen, D. E. (2014). Reversal of cognitive decline: a novel therapeutic program. Aging (Albany NY), 6(9), 707.
Huang, T. L., Zandi, P. P., Tucker, K. L., Fitzpatrick, A. L., Kuller, L. H., Fried, L. P., ... & Carlson, M. C. (2005). Benefits of fatty fish on dementia risk are stronger for those without APOE ε4. Neurology, 65(9), 1409-1414.
Barberger-Gateau, P., Raffaitin, C., Letenneur, L., Berr, C., Tzourio, C., Dartigues, J. F., & Alpérovitch, A. (2007). Dietary patterns and risk of dementia: the Three-City cohort study. Neurology, 69(20), 1921-1930.
Quinn, J. F., Raman, R., Thomas, R. G., Yurko-Mauro, K., Nelson, E. B., Van Dyck, C., ... & Aisen, P. S. (2010). Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. Jama, 304(17), 1903-1911.
Cole, G. M., & Frautschy, S. A. (2010). DHA may prevent age-related dementia. The Journal of nutrition, 140(4), 869-874.
Yassine, H. N., Rawat, V., Mack, W. J., Quinn, J. F., Yurko-Mauro, K., Bailey-Hall, E., & Schneider, L. S. (2016). The effect of APOE genotype on the delivery of DHA to cerebrospinal fluid in Alzheimer’s disease. Alzheimer’s Research & Therapy, 8, 25.
Vandal, M., Alata, W., Tremblay, C., Rioux‐Perreault, C., Salem Jr, N., Calon, F., & Plourde, M. (2014). Reduction in DHA transport to the brain of mice expressing human APOE 4 compared to APOE 2. Journal of neurochemistry, 129(3), 516-526.
Berti, V., Walters, M., Sterling, J., Quinn, C. G., Logue, M., Andrews, R., ... & Mosconi, L. (2018). Mediterranean diet and 3-year Alzheimer brain biomarker changes in middle-aged adults. Neurology, 90(20), e1789-e1798.
Scarmeas, N., Luchsinger, J. A., Schupf, N., Brickman, A. M., Cosentino, S., Tang, M. X., & Stern, Y. (2009). Physical activity, diet, and risk of Alzheimer disease. Jama, 302(6), 627-637.
Chai, B., Gao, F., Wu, R., Dong, T., Gu, C., Lin, Q., & Zhang, Y. (2019). Vitamin D deficiency as a risk factor for dementia and Alzheimer’s disease: An updated meta-analysis. BMC neurology, 19(1), 1-11.
R. Cardoso, B., Hare, D. J., Lind, M., McLean, C. A., Volitakis, I., Laws, S. M., ... & Roberts, B. R. (2017). The apoe ε4 allele is associated with lower selenium levels in the brain: Implications for alzheimer’s disease. ACS Chemical Neuroscience, 8(7), 1459-1464.
Dursun, E., Alaylıoğlu, M., Bilgiç, B., Hanağası, H., Lohmann, E., Atasoy, I. L., ... & Gezen-Ak, D. (2016). Vitamin D deficiency might pose a greater risk for ApoEɛ4 non-carrier Alzheimer’s disease patients. Neurological Sciences, 37, 1633-1643.
Oliveira, F. P., Moreira, A. P., De Mendonça, A., Verdelho, A., Xavier, C., Barroca, D., ... & Castelo-Branco, M. (2018). Can 11C-PiB-PET Relative Delivery R 1 or 11C-PiB-PET Perfusion Replace 18F-FDG-PET in the Assessment of Brain Neurodegeneration?. Journal of Alzheimer's Disease, 65(1), 89-97.
Radak, Z., Suzuki, K., Higuchi, M., Balogh, L., Boldogh, I., & Koltai, E. (2016). Physical exercise, reactive oxygen species and neuroprotection. Free Radical Biology and Medicine, 98, 187-196.
Cunha, T. F., Moreira, J. B., Paixão, N. A., Campos, J. C., Monteiro, A. W., Bacurau, A. V., ... & Brum, P. C. (2012). Aerobic exercise training upregulates skeletal muscle calpain and ubiquitin-proteasome systems in healthy mice. Journal of applied physiology, 112(11), 1839-1846.
Barrón-Cabrera, E., Ramos-Lopez, O., González-Becerra, K., Riezu-Boj, J. I., Milagro, F. I., Martínez-López, E., & Martínez, J. A. (2019). Epigenetic modifications as outcomes of exercise interventions related to specific metabolic alterations: a systematic review. Lifestyle genomics, 12(1-6), 25-44.
Horak, M., Zlamal, F., Iliev, R., Kucera, J., Cacek, J., Svobodova, L., ... & Bienertova-Vasku, J. (2018). Exercise-induced circulating microRNA changes in athletes in various training scenarios. PLoS One, 13(1), e0191060.
Piccarducci, R., Daniele, S., Fusi, J., Chico, L., Baldacci, F., Siciliano, G., ... & Martini, C. (2019). Impact of ApoE polymorphism and physical activity on plasma antioxidant capability and erythrocyte membranes. Antioxidants, 8(11), 538.
Daniele, S., Pietrobono, D., Fusi, J., Iofrida, C., Chico, L., Petrozzi, L., ... & Martini, C. (2018). α-Synuclein aggregates with β-amyloid or tau in human red blood cells: correlation with antioxidant capability and physical exercise in human healthy subjects. Molecular Neurobiology, 55, 2653-2675.
Kelly, B. B., & Fuster, V. (Eds.). (2010). Promoting cardiovascular health in the developing world: a critical challenge to achieve global health.
Schiele, F., De Bacquer, D., Vincent-Viry, M., Beisiegel, U., Ehnholm, C., Evans, A., ... & Siest, G. (2000). Apolipoprotein E serum concentration and polymorphism in six European countries: the ApoEurope Project. Atherosclerosis, 152(2), 475-488.
Eichner, J. E., Dunn, S. T., Perveen, G., Thompson, D. M., Stewart, K. E., & Stroehla, B. C. (2002). Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. American journal of epidemiology, 155(6), 487-495.
Jellinger, K. A. (2013). Pathology and pathogenesis of vascular cognitive impairment—a critical update. Frontiers in aging neuroscience, 5, 17.
Kalaria, R. N. (2003). Comparison between Alzheimer's disease and vascular dementia: implications for treatment. Neurological Research, 25(6), 661-664.
Laitinen, M. H., Ngandu, T., Rovio, S., Helkala, E. L., Uusitalo, U., Viitanen, M., ... & Kivipelto, M. (2006). Fat intake at midlife and risk of dementia and Alzheimer’s disease: a population-based study. Dementia and geriatric cognitive disorders, 22(1), 99-107.
Yin, Y. W., Li, J. C., Wang, J. Z., Li, B. H., Pi, Y., Yang, Q. W., ... & Zhang, L. L. (2012). Association between apolipoprotein E gene polymorphism and the risk of vascular dementia: a meta-analysis. Neuroscience letters, 514(1), 6-11.
Angelopoulou, E., Paudel, Y. N., Papageorgiou, S. G., & Piperi, C. (2021). APOE genotype and Alzheimer’s disease: the influence of lifestyle and environmental factors. ACS chemical neuroscience, 12(15), 2749-2764.
Liu, C. C., Kanekiyo, T., Xu, H., & Bu, G. (2013). Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nature Reviews Neurology, 9(2), 106-118.
Carrasquillo, M. M., Zou, F., Pankratz, V. S., Wilcox, S. L., Ma, L., Walker, L. P., ... & Younkin, S. G. (2009). Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease. Nature genetics, 41(2), 192-198.
Bertram, L., McQueen, M. B., Mullin, K., Blacker, D., & Tanzi, R. E. (2007). Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nature genetics, 39(1), 17-23.
Reiman, E. M., Arboleda-Velasquez, J. F., Quiroz, Y. T., Huentelman, M. J., Beach, T. G., Caselli, R. J., ... & Jun, G. R. (2020). Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nature communications, 11(1), 667.
Federoff, M., Jimenez-Rolando, B., Nalls, M. A., & Singleton, A. B. (2012). A large study reveals no association between APOE and Parkinson's disease. Neurobiology of disease, 46(2), 389-392.
Pulkes, T., Papsing, C., Mahasirimongkol, S., Busabaratana, M., Kulkantrakorn, K., & Tiamkao, S. (2011). Association between apolipoprotein E genotypes and Parkinson’s disease. Journal of Clinical Neuroscience, 18(10), 1333-1335.
Ryu, H. G., & Kwon, O. D. (2010). Apolipoprotein E epsilon 4 allele is not associated with age at onset or MMSE of Parkinson’s disease in a Korean study. Parkinsonism & related disorders, 16(9), 615-617.
Huang, X., Chen, P. C., & Poole, C. (2004). APOE-ε2 allele associated with higher prevalence of sporadic Parkinson disease. Neurology, 62(12), 2198-2202.
Li, Y. J., Hauser, M. A., Scott, W. K., Martin, E. R., Booze, M. W., Qin, X. J., ... & Vance, J. M. (2004). Apolipoprotein E controls the risk and age at onset of Parkinson disease. Neurology, 62(11), 2005-2009.
Gulliford, M. C., & Charlton, J. (2009). Is relative mortality of type 2 diabetes mellitus decreasing?. American journal of epidemiology, 169(4), 455-461.
Ripsin, C. M., Kang, H., & Urban, R. J. (2009). Management of blood glucose in type 2 diabetes mellitus. American family physician, 79(1), 29-36.
Risérus, U., Willett, W. C., & Hu, F. B. (2009). Dietary fats and prevention of type 2 diabetes. Progress in lipid research, 48(1), 44-51.
Li, L., & Hölscher, C. (2007). Common pathological processes in Alzheimer disease and type 2 diabetes: a review. Brain research reviews, 56(2), 384-402.
Ribalta, J., Vallvé, J. C., Girona, J., & Masana, L. (2003). Apolipoprotein and apolipoprotein receptor genes, blood lipids and disease. Current Opinion in Clinical Nutrition & Metabolic Care, 6(2), 177-187.
Greenow, K., Pearce, N. J., & Ramji, D. P. (2005). The key role of apolipoprotein E in atherosclerosis. Journal of molecular medicine, 83, 329-342.
Guan, J., Zhao, H. L., Baum, L., Sui, Y., He, L., Wong, H., ... & Chan, J. C. (2009). Apolipoprotein E polymorphism and expression in type 2 diabetic patients with nephropathy: clinicopathological correlation. Nephrology Dialysis Transplantation, 24(6), 1889-1895.
Zhang, G. W., Zhang, A. Z., & Xu, Z. F. (2007). Association study of apolipoprotein E gene polymorphism and type 2 diabetic nephropathy in Chinese population. Zhejiang Clin Med J, 9, 735-736.
Ramachandran, A., Snehalatha, C., Baskar, A. D. S., Mary, S., Sathish Kumar, C. K., Selvam, S., ... & Vijay, V. (2004). Temporal changes in prevalence of diabetes and impaired glucose tolerance associated with lifestyle transition occurring in the rural population in India. Diabetologia, 47, 860-865.
Xie, Y. Q., Wang, H., Wu, Y. P., Yin, D. H., Wang, Z. S., & Huang, Y. H. (2011). Association of APOE polymorphisms and insulin resistance with TCM syndromes in type 2 diabetes patients with macroangiopathy. Molecular Medicine Reports, 4(6), 1219-1223.
Dore, G. A., Elias, M. F., Robbins, M. A., Elias, P. K., & Nagy, Z. (2009). Presence of the APOE ε 4 allele modifies the relationship between type 2 diabetes and cognitive performance: the Maine–Syracuse Study. Diabetologia, 52, 2551-2560.
Berer, K., & Krishnamoorthy, G. (2014). Microbial view of central nervous system autoimmunity. FEBS letters, 588(22), 4207-4213.
Milo, R., & Kahana, E. (2010). Multiple sclerosis: geoepidemiology, genetics and the environment. Autoimmunity reviews, 9(5), A387-A394.
Pericak-Vance, M. A., Rimmler, J. B., Haines, J. L., Garcia, M. E., Oksenberg, J. R., Barcellos, L. F., ... & Clerget-Darpoux, F. (2004). Investigation of seven proposed regions of linkage in multiple sclerosis: an American and French collaborative study. Neurogenetics, 5, 45-48.
Sawcer, S., Maranian, M., Setakis, E., Curwen, V., Akesson, E., Hensiek, A., ... & Compston, A. (2002). A whole genome screen for linkage disequilibrium in multiple sclerosis confirms disease associations with regions previously linked to susceptibility. Brain, 125(6), 1337-1347.
Parmenter, B. A., Shucard, J. L., Benedict, R. H., & Shucard, D. W. (2006). Working memory deficits in multiple sclerosis: Comparison between the n-back task and the Paced Auditory Serial Addition Test. Journal of the International Neuropsychological Society, 12(5), 677-687.
Savettieri, G., Messina, D., Andreoli, V., Bonavita, S., Caltagirone, C., Cittadella, R., ... & Quattrone, A. (2004). Gender-related effect of clinical and genetic variables on the cognitive impairment in multiple sclerosis. Journal of neurology, 251, 1208-1214.
Pinholt, M., Frederiksen, J. L., & Christiansen, M. (2006). The association between apolipoprotein E and multiple sclerosis. European journal of neurology, 13(6), 573-580.
Shi, J., Zhao, C. B., Vollmer, T. L., Tyry, T. M., & Kuniyoshi, S. M. (2008). APOE ε4 allele is associated with cognitive impairment in patients with multiple sclerosis. Neurology, 70(3), 185-190.
van der Walt, A., Stankovich, J., Bahlo, M., Taylor, B. V., Van der Mei, I. A. F., Foote, S. J., ... & Butzkueven, H. (2009). Apolipoprotein genotype does not influence MS severity, cognition, or brain atrophy. Neurology, 73(13), 1018-1025.
Koutsis, G., Panas, M., Giogkaraki, E., Potagas, C., Karadima, G., Sfagos, C., & Vassilopoulos, D. (2007). APOE ε4 is associated with impaired verbal learning in patients with MS. Neurology, 68(8), 546-549.
Lill, C. M., Liu, T., Schjeide, B. M. M., Roehr, J. T., Akkad, D. A., Damotte, V., ... & Zipp, F. (2012). Closing the case of APOE in multiple sclerosis: no association with disease risk in over 29 000 subjects. Journal of medical genetics, 49(9), 558-562.
Lopez, A. D., Mathers, C. D., Ezzati, M., Jamison, D. T., & Murray, C. J. (2006). Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. The lancet, 367(9524), 1747-1757.
Treger, I., Froom, P., Ring, H., & Friedman, G. (2003). Association between apolipoprotein E4 and rehabilitation outcome in hospitalized ischemic stroke patients. Archives of physical medicine and rehabilitation, 84(7), 973-976.
Paternoster, L., Martínez González, N. A., Lewis, S., & Sudlow, C. (2008). Association between apolipoprotein E genotype and carotid intima-media thickness may suggest a specific effect on large artery atherothrombotic stroke. Stroke, 39(1), 48-54.
Visser, M. E., Dallinga-Thie, G. M., Pinto-Sietsma, S. J., Defesche, J. C., Stroes, E. S., & van der Valk, P. R. (2012). APOE1 mutation in a patient with type III hyperlipoproteinaemia: detailed genetic analysis required. Neth J Med, 70(6), 278-280.