Genetic risk factor APOEε4 associates with plasma amyloid beta in amnestic mild cognitive impairment and alzheimer’s disease
Background: APOEε4 is a strong genetic risk factor for Alzheimer’s disease (AD). AD itself has been associated with reduced Aβ clearance from the brain and plasma. Understanding the potential pathogenic link between APOEε4 and plasma Aβ might allow for earlier identification of people at risk of developing AD. The aim of this study is to find out the correlation between APOEε4 and plasma Aβ in amnestic mild cognitive impairment (aMCI) and AD patients.
Methods: This is a comparative cross-sectional study of patients attending a memory clinic in Siloam Hospital Lippo Karawaci, Tangerang, during the period of 2013-2014. Subjects were categorized into three categories: normal aging, aMCI, and AD. We performed blood test to examine APOEε4, plasma Aβ4o level, and plasma Aβ42 level. All data analyses were performed using correlation test and logistic regression.
Results: Sixty subjects (normal aging = 23, aMCI = 17, AD = 20) were included. There were 19 (31.7%) subjects with APOEε4 positive. Subjects carrying ε4 allele were more likely to have AD by 3.9-fold than subjects with APOE ε4 allele negative. There is a significant difference between the mean of plasma Aβ40 in aMCI group and AD group. We also found correlation between APOEε4 (+) and higher plasma Aβ42 (p<0.05).
Conclusion: There is a correlation between APOEε4 and plasma Aβ42 level, which supports the hypothesis that this genetic isoform accelerates the rate and progression of AD through Aβ-dependent pathways.
Alzheimer's Association. 2012 Alzheimer's disease facts and figures. Alzheimers Dement. 2012;8(2):131–68. http://dx.doi.org/10.1016/j.jalz.2012.02.001
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 2002;297(5580):353-6. http://dx.doi.org/10.1126/science.1072994
Ballard C, Gauthier S, Corbett A, Brayne C, Aarsland D, Jones E. Alzheimer's disease. Lancet. 2011;377(9770):1019–31. http://dx.doi.org/10.1016/S0140-6736(10)61349-9
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. 1993;261(5123):921–3. http://dx.doi.org/10.1126/science.8346443
Bu G. Apolipoprotein E and its receptors in Alzheimer's disease: pathways, pathogenesis and therapy. Nat Rev Neurosci. 2009;10(5):333–44. http://dx.doi.org/10.1038/nrn2620
Huang Y, Mucke L. Alzheimer mechanisms and therapeutic strategies. Cell. 2012;148(6):1204–22. http://dx.doi.org/10.1016/j.cell.2012.02.040
Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, et al. 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. 1997;278(16):1349–56. http://dx.doi.org/10.1001/jama.1997.03550160069041
Rebeck GW, Reiter JS, Strickland DK, Hyman BT. Apolipoprotein E in sporadic Alzheimer's disease: allelic variation and receptor interactions. Neuron. 1993;11(4):575–80. http://dx.doi.org/10.1016/0896-6273(93)90070-8
Morris JC, Storandt M, Miller JP, McKeel DW, Price JL, Rubin EH, et al. Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol. 2001;58(3):397–405. http://dx.doi.org/10.1001/archneur.58.3.397
Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56(3):303–8. http://dx.doi.org/10.1001/archneur.56.3.303
Smith GE, Bohac DL, Waring SC, Kokmen E, Tangalos EG, Ivnik RJ, et al. Apolipoprotein E genotype influences cognitive 'phenotype' in patients with Alzheimer's disease but not in healthy control subjects. Neurology.1998;50(2):355–62. http://dx.doi.org/10.1212/WNL.50.2.355
Farlow MR, He Y, Tekin S, Xu J, Lane R, Charles HC. Impact of APOE in mild cognitive impairment. Neurology. 2004;63(10):1898–901. http://dx.doi.org/10.1212/01.WNL.0000144279.21502.B7
Ramakers IH, Visser PJ, Aalten P, Bekers O, Sleegers K, van Broeckhoven CL, et al. The association between APOE genotype and memory dysfunction in subjects with mild cognitive impairment is related to age and Alzheimer pathology. Dement Geriatr Cogn Disord. 2008;26(2):101–8. http://dx.doi.org/10.1159/000144072
Dik MG, Jonker C, Bouter LM, Geerlings MI, van Kamp GJ, Deeg DJ. APOE-epsilon4 is associated with memory decline in cognitively impaired elderly. Neurology. 2000;54(7):1492–7. http://dx.doi.org/10.1212/WNL.54.7.1492
Whitehair DC, Sherzai A, Emond J, Raman R, Aisen PS, Petersen RC, et al. Influence of apolipoprotein E varepsilon4 on rates of cognitive and functional decline in mild cognitive impairment. Alzheimers Dement. 2010;6(5):412–9. http://dx.doi.org/10.1016/j.jalz.2009.12.003
Cosentino S, Scarmeas N, Helzner E, Glymour MM, Brandt J, Albert M, et al. APOE epsilon 4 allele predicts faster cognitive decline in mild Alzheimer disease. Neurology. 2008;70(19Pt2):1842–9. http://dx.doi.org/10.1212/01.wnl.0000304038.37421.cc
Fleisher AS, Sowell BB, Taylor C, Gamst AC, Petersen RC, Thal LJ, et al. Clinical predictors of progression to Alzheimer disease in amnestic mild cognitive impairment. Neurology. 2007;68(19):1588–95. http://dx.doi.org/10.1212/01.wnl.0000258542.58725.4c
Elias-Sonnenschein LS, Viechtbauer W, Ramakers IH, Verhey FR, Visser PJ. Predictive value of APOE-ε4 allele for progression from MCI to AD-type dementia: a meta-analysis. J Neurol Neurosurg Psychiatry. 2011;82(10):1149–56. http://dx.doi.org/10.1136/jnnp.2010.231555
Petersen RC, Smith GE, Ivnik RJ, Tangalos EG, Schaid DJ, Thibodeau SN, et al. Apolipoprotein E status as a predictor of the development of Alzheimer's disease in memory-impaired individuals. JAMA. 1995;273(16):1274–8. http://dx.doi.org/10.1001/jama.1995.03520400044042
Vemuri P, Wiste HJ, Weigand SD, Knopman DS, Shaw LM, Trojanowski JQ, et al. Effect of apolipoprotein E on biomarkers of amyloid load and neuronal pathology in Alzheimer disease. Ann Neurol. 2010;67(3):308–16. http://dx.doi.org/10.1002/ana.21953
Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013;9(2):106–18. http://dx.doi.org/10.1038/nrneurol.2012.263
Reiman EM, Chen K, Liu X, Bandy D, Yu M, Lee W, et al. Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease. Proc Natl Acad Sci U S A. 2009;106(16):6820–5. http://dx.doi.org/10.1073/pnas.0900345106
Namba Y, Tomonaga M, Kawasaki H, Otomo E, Ikeda K. Apolipoprotein E immunoreactivity in cerebral amyloid deposits and neurofibrillary tangles in Alzheimer's disease and kuru plaque amyloid in Creutzfeldt-Jakob disease. Brain Res. 1991;541(1):163–6. http://dx.doi.org/10.1016/0006-8993(91)91092-F
Kok E, Haikonen S, Luoto T, Huhtala H, Goebeler S, Haapasalo H, et al. Apolipoprotein E-dependent accumulation of Alzheimer disease-related lesions begins in middle age. Ann Neurol. 2009;65(6):650–7. http://dx.doi.org/10.1002/ana.21696
Polvikoski T, Sulkava R, Haltia M, Kainulainen K, Vuorio A, Verkkoniemi A, et al. Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein. N Engl J Med. 1995;333(19):1242–7. http://dx.doi.org/10.1056/NEJM199511093331902
Schmechel DE, Saunders AM, Strittmatter WJ, Crain BJ, Hulette CM, Joo SH, et al. Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proc Natl Acad Sci U S A. 1993;90(20):9649–53. http://dx.doi.org/10.1073/pnas.90.20.9649
Head D, Bugg JM, Goate AM, Fagan AM, Mintun MA, Benzinger T, et al. Exercise engagement as a moderator of the effects of APOE genotype on amyloid deposition. Arch Neurol. 2012;69(5):636–43. http://dx.doi.org/10.1001/archneurol.2011.845
Prince JA, Zetterberg H, Andreasen N, Marcusson J, Blennow K. APOE epsilon4 allele is associated with reduced cerebrospinal fluid levels of Abeta42. Neurology. 2004;62(11):2116–8. http://dx.doi.org/10.1212/01.WNL.0000128088.08695.05
Swaminathan S, Risacher SL, Yoder KK, West JD, Shen L, Kim S, et al. Association of plasma and cortical amyloid beta is modulated by APOEε4 status. Alzheimers Dement. 2014;10(1):e9–18. http://dx.doi.org/10.1016/j.jalz.2013.01.007
Toledo JB, Vanderstichele H, Figurski M, Aisen PS, Petersen RC, Weiner MW, et al. Factors affecting Ab plasma levels and their utility as biomarkers in ADNI. Acta Neuropathol. 2011;122(4):401–13. http://dx.doi.org/10.1007/s00401-011-0861-8
Lui JK, Laws SM, Li QX, Villemagne VL, Ames D, Brown B, et al. Plasma amyloid-beta as a biomarker in Alzheimer's disease: the AIBL study of aging. J Alzheimers Dis. 2010;20(4):1233–42. http://dx.doi.org/10.3233/JAD-2010-090249
Devanand DP, Schupf N, Stern Y, Parsey R, Pelton GH, Mehta P, et al. Plasma Ab and PET PiB binding are inversely related in mild cognitive impairment. Neurology. 2011;77(2):125–31. http://dx.doi.org/10.1212/WNL.0b013e318224afb7
Bunce D, Fratiglioni L, Small BJ, Winblad B, BÃ¤ckman L. APOE and cognitive decline in preclinical Alzheimer disease and non-demented aging. Neurology. 2004;63(5):816–21. http://dx.doi.org/10.1212/01.WNL.0000137041.86153.42
Lin AL, Laird AR, Fox PT, Gao JH. Multimodal MRI neuroimaging biomarkers for cognitive normal adults, amnestic mild cognitive impairment, and Alzheimer's disease. Neurol Res Int. 2012;2012:907409. http://dx.doi.org/10.1155/2012/907409
Caselli RJ, Reiman EM, Locke DE, Hutton ML, Hentz JG, Hoffman-Snyder C, et al. Cognitive domain decline in healthy apolipoprotein E epsilon4 homozygotes before the diagnosis of mild cognitive impairment. Arch Neurol. 2007;64(9):1306–11. http://dx.doi.org/10.1001/archneur.64.9.1306
Caselli RJ, Reiman EM, Osborne D, Hentz JG, Baxter LC, Hernandez JL, et al. Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele. Neurology. 2004;62(11):1990–5. http://dx.doi.org/10.1212/01.WNL.0000129533.26544.BF
Caselli RJ, Dueck AC, Osborne D, Sabbagh MN, Connor DJ, Ahern GL, et al. Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect. N Engl J Med. 2009;361(3):255–63. http://dx.doi.org/10.1056/NEJMoa0809437
Mayeux R, Schupf N. Blood-based biomarkers for Alzheimer's disease: plasma Ab40 and Ab42, and genetic variants. Neurobiol Aging. 2011;32(Suppl1):S10–9. http://dx.doi.org/10.1016/j.neurobiolaging.2011.09.004
Song F, Poljak A, Valenzuela M, Mayeux R, Smythe GA, Sachdev PS. Meta-analysis of plasma amyloid-b levels in Alzheimer's disease. J Alzheimers Dis. 2011;26(2):365–75. http://dx.doi.org/10.3233/JAD-2011-101977
Koyama A, Okereke OI, Yang T, Blacker D, Selkoe DJ, Grodstein F. Plasma amyloid-b as a predictor of dementia and cognitive decline: a systematic review and meta-analysis. Arch Neurol. 2012;69(7):824–31. http://dx.doi.org/10.1001/archneurol.2011.1841
Thambisetty M, Lovestone S. Blood-based biomarkers of Alzheimer's disease: challenging but feasible. Biomark Med. 2010;4(1):65–79. http://dx.doi.org/10.2217/bmm.09.84
Graff-Radford NR, Crook JE, Lucas J, Boeve BF, Knopman DS, Ivnik RJ, et al. Association of low plasma Abeta42/Abeta40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease. Arch Neurol. 2007;64(3):354–62. http://dx.doi.org/10.1001/archneur.64.3.354
Seppälä TT, Herukka SK, Hänninen T, Tervo S, Hallikainen M, Soininen H, et al. Plasma Abeta42 and Abeta40 as markers of cognitive change in follow-up: a prospective, longitudinal, population-based cohort study. J Neurol Neurosurg Psychiatry. 2010;81(10):1123–7. http://dx.doi.org/10.1136/jnnp.2010.205757
Ishii K, Tamaoka A, Mizusawa H, Shoji S, Ohtake T, Fraser PE, et al. Abeta1–40 but not Abeta1–42 levels in cortex correlate with apolipoprotein E epsilon4 allele dosage in sporadic Alzheimer's disease. Brain Res. 1997;748(1–2):250–2. http://dx.doi.org/10.1016/S0006-8993(96)01363-7
Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, et al. Human apoE isoforms differentially regulate brain amyloid-b peptide clearance. Sci TransI Med. 2011;3(89):89ra57. http://dx.doi.org/10.1126/scitranslmed.3002156
Sharman MJ, Morici M, Hone E, Berger T, Taddei K, Martins IJ, et al. APOE genotype results in differential effects on the peripheral clearance of amyloid-beta42 in APOE knock-in and knock-out mice. J Alzheimers Dis. 2010;21(2):403–9. http://dx.doi.org/10.3233/JAD-2010-100141
Nishitsuji K, Hosono T, Nakamura T, Bu G, Michikawa M. Apolipoprotein E regulates the integrity of tight junctions in an isoform-dependent manner in an in vitro blood-brain barrier model. J Biol Chem. 2011;286(20):17536–42. http://dx.doi.org/10.1074/jbc.M111.225532
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