Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterised by amyloid beta (Aβ) plaques and tau neurofibrillary tangles in the brain. Human apolipoprotein E (ApoE) is a lipid transport protein coded by the polymorphic APOE gene, with three major alleles: ε2, ε3 and ε4. After age, the ε4 allele is the greatest risk factor for developing sporadic AD, conferring an increased risk of 3–4 and 8–12 times for one or two copies of the allele, respectively. This risk is reported to vary by demographic factors including sex, ethnicity and geography. In order to understand the risk of ApoE ε4 in relation to age, the primary risk factor for developing AD, we need to understand how the prevalence of APOE genotypes changes with age. Here, we present the first data on age-related prevalence of APOE ε4 in AD in three AD cohorts in Australia and the USA. There is a significant association between age and ε4 prevalence, particularly for ε4 homozygotes, such that as age increases the prevalence of ε4 decreases. Further studies on a random, population-based sample of the population are needed to provide more generalizable data, particularly in the >90-year-old age group.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
This is the net price. Taxes to be calculated in checkout.
ABS (2014). Australian Bureau of Statistics. Causes of Death, Australia 2012. ABS cat. no. 3303.0. Canberra:ABS.
ALZGENE (2010). Meta-analysis of all published AD association studies (case-control only) APOE_E2/3/4. Available from http://www.alzgene.org/meta.asp?geneID=83. Date accessed: 9 March 2016.
Bang OY, Kwak YT, Joo IS, Huh K (2003) Important link between dementia subtype and apolipoprotein E: a meta-analysis. Yonsei Med J 44:401–413
Castellano JM, Kim J, Stewart FR, et al. (2011) Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med 3:89ra57
Chen J, Li Q, Wang J (2011) Topology of human apolipoprotein E3 uniquely regulates its diverse biological functions. Proc Natl Acad Sci U S A 108:14813–14818
Corder EH, Saunders AM, Risch NJ, et al. (1994) Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet 7:180–184
Corder EH, Saunders AM, Strittmatter WJ, et al. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261:921–923
Cramer PE, Cirrito JR, Wesson DW, et al. (2012) ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335:1503–1506
Das HK, McPherson J, Bruns GA, Karathanasis SK, Breslow JL (1985) Isolation, characterization, and mapping to chromosome 19 of the human apolipoprotein E gene. J Biol Chem 260:6240–6247
Davignon J, Gregg RE, Sing CF (1988) Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis 8:1–21
Deloukas P, Kanoni S, Willenborg C, et al. (2013) Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet 45:25–33
Eichner JE, Dunn ST, Perveen G, Thompson DM, Stewart KE, Stroehla BC (2002) Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol 155:487–495
Eisenberg DT, Kuzawa CW, Hayes MG (2010) Worldwide allele frequencies of the human apolipoprotein E gene: climate, local adaptations, and evolutionary history. Am J Phys Anthropol 143:100–111
El-Lebedy D, Raslan HM, Mohammed AM (2016) Apolipoprotein E gene polymorphism and risk of type 2 diabetes and cardiovascular disease. Cardiovasc Diabetol 15:12
Ellis KA, Bush AI, Darby D, et al. (2009) The Australian imaging, biomarkers and lifestyle (AIBL) study of aging: methodology and baseline characteristics of 1112 individuals recruited for a longitudinal study of Alzheimer's disease. Int Psychogeriatr 21:672–687
Elosua R, Ordovas JM, Cupples LA, et al. (2004) Association of APOE genotype with carotid atherosclerosis in men and women: the Framingham Heart Study. J Lipid Res 45:1868–1875
Farrer LA, Cupples LA, Haines JL, et al. (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis APOE and Alzheimer Disease Meta Analysis Consortium JAMA 278:1349–1356
Farrer LA, Cupples LA, van Duijn CM, et al. (1995) Apolipoprotein E genotype in patients with Alzheimer’s disease: implications for the risk of dementia among relatives. Ann Neurol 38:797–808
Frieden C, Garai K (2013) Concerning the structure of apoE. Protein Sci 22:1820–1825
Garai K, Verghese PB, Baban B, Holtzman DM, Frieden C (2014) The binding of apolipoprotein E to oligomers and fibrils of amyloid-beta alters the kinetics of amyloid aggregation. Biochemistry 53:6323–6331
Giau VV, Bagyinszky E, An SSA, Kim SY (2015) Role of apolipoprotein E in neurodegenerative diseases. Neuropsychiatr Dis Treat 11:1723–1737
Golabek AA, Soto C, Vogel T, Wisniewski T (1996) The interaction between apolipoprotein E and Alzheimer's amyloid beta-peptide is dependent on beta-peptide conformation. J Biol Chem 271:10602–10606
Havel RJ, Kane JP (1973) Primary dysbetalipoproteinemia: predominance of a specific apoprotein species in triglyceride-rich lipoproteins. Proc Natl Acad Sci U S A 70:2015–2019
Holtzman DM, Bales KR, Tenkova T, et al. (2000) Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A 97:2892–2897
Holtzman DM, Herz J, Bu G (2012) Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harbor Perspectives in Medicine 2:a006312
Huang Y (2010) Mechanisms linking apolipoprotein E isoforms with cardiovascular and neurological diseases. Curr Opin Lipidol 21:337–345
Innerarity TL, Friedlander EJ, Rall SC, Weisgraber KH, Mahley RW (1983) The receptor-binding domain of human apolipoprotein E. Binding of apolipoprotein E fragments Journal of Biological Chemistry 258:12341–12347
Jiang Q, Lee CYD, Mandrekar S, et al. (2008) ApoE promotes the proteolytic degradation of Aβ. Neuron 58:681–693
Keene CD, Cudaback E, Li X, Montine KS, Montine TJ (2011) Apolipoprotein E isoforms and regulation of the innate immune response in brain of patients with Alzheimer’s disease. Curr Opin Neurobiol 21:920–928
Kim J, Basak JM, Holtzman DM (2009) The role of apolipoprotein E in Alzheimer’s disease. Neuron 63:287–303
Kim J, Jiang H, Park S, et al. (2011) Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-beta amyloidosis. J Neurosci 31:18007–18012
Kim J, Yoon H, Basak J, Kim J (2014) Apolipoprotein E in synaptic plasticity and Alzheimer’s disease: potential cellular and molecular mechanisms. Mol Cells 37:767–776
LaDu MJ, Falduto MT, Manelli AM, Reardon CA, Getz GS, Frail DE (1994) Isoform-specific binding of apolipoprotein E to beta-amyloid. J Biol Chem 269:23403–23406
Lim, Y. Y., Laws, S. M., Villemagne, V. L., et al. (2016). A beta-related memory decline in APOE epsilon4 noncarriers: implications for Alzheimer disease. Neurology.
Liu CC, Kanekiyo T, Xu H, Bu G (2013) Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9:106–118
Louhija J, Miettinen HE, Kontula K, Tikkanen MJ, Miettinen TA, Tilvis RS (1994) Aging and genetic variation of plasma apolipoproteins. Relative loss of the apolipoprotein E4 phenotype in centenarians. Arterioscler Thromb 14:1084–1089
Mahley RW, Rall SC Jr (2000) Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 1:507–537
Mahley RW, Weisgraber KH, Huang Y (2006) Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci U S A 103:5644–5651
Mahley RW, Weisgraber KH, Huang Y (2009) Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J Lipid Res 50:S183–S188
Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 82:4245–4249
Mayila W, Fang MW, Cheng ZH, Qiu CC (2005) Polymorphism of apolipoprotein E gene and natural longevity in the Xinjiang Uighur people: an association study. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 22:462–463
Mohamad, E. H., Antoine, P., Amouyel, P., Lambert, J. C., Pasquier, F. and Kapogiannis, D. (2016). Apolipoprotein E (APOE) epsilon4 and episodic memory decline in Alzheimer’s disease: A review. Ageing Res Rev.
Mozaffarian D, Benjamin EJ, Go AS, et al. (2016) Executive Summary: Heart Disease and Stroke Statistics—2016 update: a report from the American Heart Association. Circulation 133:447–454
Nolte RT, Atkinson D (1992) Conformational analysis of apolipoprotein A-I and E-3 based on primary sequence and circular dichroism. Biophys J 63:1221–1239
OMIM (2016). Online ‘Mendelian Inheritance in Man’ (OMIM) Apolipoprotein E; APOE -107741. Available from https://omim.org/entry/107741. Date accessed: 9 March 2016.
Pietrzak RH, Lim YY, Ames D, et al. (2015) Trajectories of memory decline in preclinical Alzheimer's disease: results from the Australian Imaging, Biomarkers and Lifestyle Flagship Study of ageing. Neurobiol Aging 36:1231–1238
Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP (2013) The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 9:63–75.e62
R Core Team (2015) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL http://www.R-project.org/.
Ryu S, Atzmon G, Barzilai N, Raghavachari N, Suh Y (2016) Genetic landscape of APOE in human longevity revealed by high-throughput sequencing. Mech Ageing Dev 155:7–9
Schachter F, Faure-Delanef L, Guenot F, et al. (1994) Genetic associations with human longevity at the APOE and ACE loci. Nat Genet 6:29–32
Shore VG, Shore B (1973) Heterogeneity of human plasma very low density lipoproteins. Separation of species differing in protein components Biochemistry 12:502–507
Singh PP, Singh M, Mastana SS (2006) APOE distribution in world populations with new data from India and the UK. Ann Hum Biol 33:279–308
Sparrow JT, Sparrow DA, Fernando G, Culwell AR, Kovar M, Gotto AM (1992) Apolipoprotein E: phospholipid binding studies with synthetic peptides from the carboxyl terminus. Biochemistry 31:1065–1068
Strittmatter WJ, Weisgraber KH, Huang DY, et al. (1993) Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci U S A 90:8098–8102
Sweet RA, Seltman H, Emanuel JE, et al. (2012) Effect of Alzheimer’s disease risk genes on trajectories of cognitive function in the Cardiovascular Health Study. Am J Psychiatry 169:954–962
Tai LM, Ghura S, Koster KP, et al. (2015) APOE-modulated Abeta-induced neuroinflammation in Alzheimer's disease: current landscape, novel data, and future perspective. J Neurochem 133:465–488
Todd S, Barr S, Roberts M, Passmore AP (2013) Survival in dementia and predictors of mortality: a review. Int J Geriatr Psychiatry 28:1109–1124
Tombaugh TN, McIntyre NJ (1992) The mini-mental state examination: a comprehensive review. J Am Geriatr Soc 40:922–935
Verghese PB, Castellano JM, Holtzman DM (2011) Apolipoprotein E in Alzheimer’s disease and other neurological disorders. Lancet Neurol 10:241–252
Visvikis-Siest S, Marteau JB (2006) Genetic variants predisposing to cardiovascular disease. Curr Opin Lipidol 17:139–151
Weisgraber KH, Innerarity TL, Mahley RW (1982) Abnormal lipoprotein receptor-binding activity of the human E apoprotein due to cysteine-arginine interchange at a single site. J Biol Chem 257:2518–2521
Weller RO, Hawkes CA, Kalaria RN, Werring DJ, Carare RO (2015) White matter changes in dementia: role of impaired drainage of interstitial fluid. Brain Pathol 25:63–78
WHO (2011). Global Atlas on cardiovascular disease prevention and control. Edited by Mendis S, Puska P and Norrving B. World Health Organisation, Geneva. Available from: http://www.who.int/cardiovascular_diseases/publications/atlas_cvd/en/.
Wilson C, Wardell M, Weisgraber K, Mahley R, Agard D (1991) Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E. Science 252:1817–1822
Zannis VI, Kardassis D, Zanni EE (1993) Genetic mutations affecting human lipoproteins, their receptors, and their enzymes. Adv Hum Genet 21:145–319
The authors gratefully acknowledge Simone Wilk, Chris Fowler and James Doecke for assistance with data retrieval; Oliver Thomas for advice on statistical analysis and Laura Cortes Castrillon for assistance with PyMol. ALH is funded by a Dementia Research Development Fellowship (APP1106911); PP is funded by an Australian Postgraduate Award and an International Postgraduate Research Scholarship. We wish to thank ADNI, AIBL and the National Alzheimer’s Coordinating Centre including all investigators, participants and their families. A complete list of principle investigators and funding sources can be found in the Supplementary Material. The Florey Institute acknowledges the strong support from the Victorian Government and in particular the funding from the Operational Infrastructure Support Grant.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Electronic supplementary material
About this article
Cite this article
Heffernan, A.L., Chidgey, C., Peng, P. et al. The Neurobiology and Age-Related Prevalence of the ε4 Allele of Apolipoprotein E in Alzheimer’s Disease Cohorts. J Mol Neurosci 60, 316–324 (2016). https://doi.org/10.1007/s12031-016-0804-x
- Alzheimer’s disease
- Apolipoprotein E
- Population demographics