Age and the association between apolipoprotein E genotype and Alzheimer disease: A cerebrospinal fluid biomarker–based case–control study

Autoři: Hana Saddiki aff001;  Aurore Fayosse aff001;  Emmanuel Cognat aff002;  Séverine Sabia aff001;  Sebastiaan Engelborghs aff003;  David Wallon aff005;  Panagiotis Alexopoulos aff006;  Kaj Blennow aff007;  Henrik Zetterberg aff007;  Lucilla Parnetti aff010;  Inga Zerr aff011;  Peter Hermann aff011;  Audrey Gabelle aff012;  Mercè Boada aff013;  Adelina Orellana aff013;  Itziar de Rojas aff013;  Matthieu Lilamand aff002;  Maria Bjerke aff014;  Christine Van Broeckhoven aff014;  Lucia Farotti aff010;  Nicola Salvadori aff010;  Janine Diehl-Schmid aff006;  Timo Grimmer aff006;  Claire Hourregue aff002;  Aline Dugravot aff001;  Gaël Nicolas aff005;  Jean-Louis Laplanche aff015;  Sylvain Lehmann aff016;  Elodie Bouaziz-Amar aff015aff001;  Jacques Hugon aff002;  Christophe Tzourio aff017;  Archana Singh-Manoux aff001;  Claire Paquet aff002;  Julien Dumurgier aff001
Působiště autorů: Université de Paris, Inserm U1153, Epidemiology of Ageing and Neurodegenerative diseases, Paris, France aff001;  Cognitive Neurology Center, Lariboisiere—Fernand Widal Hospital, AP-HP, Université de Paris, Paris, France aff002;  Department of Neurology, Universitair Ziekenhuis Brussel, Center for Neurosciences, Vrije Universiteit Brussel, Brussels, Belgium aff003;  Department of Biomedical Sciences, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium aff004;  Inserm U1245, Rouen University Hospital, Department of Neurology and CNR-MAJ, Normandy Center for Genomic and Personalized Medicine, Rouen, France aff005;  Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Faculty of Medicine, Technical University of Munich, Munich, Germany aff006;  Department of Psychiatry and Neurochemistry, University of Gothenburg, Mölndal, Sweden aff007;  Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden aff008;  Department of Neurodegenerative Disease, Institute of Neurology, University College London, UK Dementia Research Institute, London, United Kingdom aff009;  Center for Memory Disturbances-Lab of Clinical Neurochemistry, Section of Neurology, University of Perugia, Italy aff010;  Department of Neurology, Clinical Dementia Center, University Medical Center Göttingen and German Center for Neurodegenerative Diseases, Göttingen, Germany aff011;  Department of Neurology, Memory Research and Resources Centre, University of Montpellier, Montpellier, France aff012;  Research Center and Memory Clinic, Fundació ACE, Institut Català de Neurciències Aplicades, Universitat International de Catalunya, Barcelona, Spain aff013;  VIB Center for Molecular Neurology, Institute Born-Bunge and Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium aff014;  Department of Biochemistry and Molecular Biology, Lariboisière Hospital, APHP, Paris, France aff015;  Department of Biochemistry, University of Montpellier, Montpellier, France aff016;  Bordeaux Population Health Research Center, Team HEALTHY, UMR1219, University of Bordeaux, Inserm, Bordeaux, France aff017;  Department of Epidemiology and Public Health, University College London, London, United Kingdom aff018
Vyšlo v časopise: Age and the association between apolipoprotein E genotype and Alzheimer disease: A cerebrospinal fluid biomarker–based case–control study. PLoS Med 17(8): e32767. doi:10.1371/journal.pmed.1003289
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003289



The ε4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of β-amyloid peptide (A, β-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD.

Methods and findings

This case–control study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44–96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimer’s Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44–94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE ε4 allele. Compared with non-ε4 carriers, heterozygous ε4 carriers had a 4.6 (95% confidence interval 4.1–5.2; p < 0.001) and ε4/ε4 homozygotes a 25.4 (20.4–31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one ε4 allele was greatest in the 65–70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE ε2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD.


In this study, we found that AD diagnosis based on biomarkers was associated with APOE ε4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65–70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE ε4 at the population level.

Klíčová slova:

Alzheimer's disease – Apolipoproteins – Biomarkers – Cardiovascular disease risk – Cerebrospinal fluid – Diagnostic medicine – Medical risk factors – Memory


1. Belloy ME, Napolioni V, Greicius MD. A Quarter Century of APOE and Alzheimer's Disease: Progress to Date and the Path Forward. Neuron. 2019; 101 (5): 820–838. doi: 10.1016/j.neuron.2019.01.056 30844401.

2. Zhong N, Weisgraber KH. Understanding the association of apolipoprotein E4 with Alzheimer disease: clues from its structure. J Biol Chem. 2009; 284 (10): 6027–6031. doi: 10.1074/jbc.R800009200 18948255.

3. Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 1993; 43 (8): 1467–1472. doi: 10.1212/wnl.43.8.1467 8350998.

4. Suri S, Heise V, Trachtenberg AJ, Mackay CE. The forgotten APOE allele: a review of the evidence and suggested mechanisms for the protective effect of APOE varepsilon2. Neurosci Biobehav Rev. 2013; 37 (10 Pt 2): 2878–2886. doi: 10.1016/j.neubiorev.2013.10.010 24183852.

5. Mahoney-Sanchez L, Belaidi AA, Bush AI, Ayton S. The Complex Role of Apolipoprotein E in Alzheimer's Disease: an Overview and Update. J Mol Neurosci. 2016; 60 (3): 325–335. doi: 10.1007/s12031-016-0839-z 27647307.

6. Kanekiyo T, Xu H, Bu G. ApoE and Abeta in Alzheimer's disease: accidental encounters or partners? Neuron. 2014; 81 (4): 740–754. doi: 10.1016/j.neuron.2014.01.045 24559670.

7. Simonovitch S, Schmukler E, Bespalko A, Iram T, Frenkel D, Holtzman DM, et al. Impaired Autophagy in APOE4 Astrocytes. J Alzheimers Dis. 2016; 51 (3): 915–927. doi: 10.3233/JAD-151101 26923027.

8. Sun X, Dong C, Levin B, Crocco E, Loewenstein D, Zetterberg H, et al. APOE epsilon4 carriers may undergo synaptic damage conferring risk of Alzheimer's disease. Alzheimers Dement. 2016; 12 (11): 1159–1166. doi: 10.1016/j.jalz.2016.05.003 27321472.

9. Wadhwani AR, Affaneh A, Van Gulden S, Kessler JA. Neuronal apolipoprotein E4 increases cell death and phosphorylated tau release in alzheimer disease. Ann Neurol. 2019; 85 (5): 726–739. doi: 10.1002/ana.25455 30840313.

10. Vermunt L, Sikkes SAM, van den Hout A, Handels R, Bos I, van der Flier WM, et al. Duration of preclinical, prodromal, and dementia stages of Alzheimer's disease in relation to age, sex, and APOE genotype. Alzheimers Dement. 2019. doi: 10.1016/j.jalz.2019.04.001 31164314.

11. Alzheimer's Association 2016 Alzheimer's disease facts and figures. Alzheimers Dement. 2016; 12 (4): 459–509. doi: 10.1016/j.jalz.2016.03.001 27570871.

12. Beach TG, Monsell SE, Phillips LE, Kukull W. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005–2010. J Neuropathol Exp Neurol. 2012; 71 (4): 266–273. doi: 10.1097/NEN.0b013e31824b211b 22437338.

13. Hofler M. The effect of misclassification on the estimation of association: a review. Int J Methods Psychiatr Res. 2005; 14 (2): 92–101. doi: 10.1002/mpr.20 16175878.

14. Johnson CY, Flanders WD, Strickland MJ, Honein MA, Howards PP. Potential sensitivity of bias analysis results to incorrect assumptions of nondifferential or differential binary exposure misclassification. Epidemiology. 2014; 25 (6): 902–909. doi: 10.1097/EDE.0000000000000166 25120106.

15. Dubois B, Feldman HH, Jacova C, Hampel H, Molinuevo JL, Blennow K, et al. Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria. Lancet Neurol. 2014; 13 (6): 614–629. doi: 10.1016/S1474-4422(14)70090-0 24849862.

16. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr., Kawas CH, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011; 7 (3): 263–269. doi: 10.1016/j.jalz.2011.03.005 21514250.

17. Jack CR Jr., Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018; 14 (4): 535–562. doi: 10.1016/j.jalz.2018.02.018 29653606.

18. Petersen RC, Aisen PS, Beckett LA, Donohue MC, Gamst AC, Harvey DJ, et al. Alzheimer's Disease Neuroimaging Initiative (ADNI): clinical characterization. Neurology. 2010; 74 (3): 201–209. doi: 10.1212/WNL.0b013e3181cb3e25 20042704.

19. Singh-Manoux A, Kivimaki M, Glymour MM, Elbaz A, Berr C, Ebmeier KP, et al. Timing of onset of cognitive decline: results from Whitehall II prospective cohort study. BMJ. 2012; 344: d7622. doi: 10.1136/bmj.d7622 22223828.

20. Dumurgier J, Elbaz A, Ducimetiere P, Tavernier B, Alperovitch A, Tzourio C. Slow walking speed and cardiovascular death in well functioning older adults: prospective cohort study. BMJ. 2009; 339: b4460. doi: 10.1136/bmj.b4460 19903980.

21. Dumurgier J, Laplanche JL, Mouton-Liger F, Lapalus P, Indart S, Prevot M, et al. The screening of Alzheimer's patients with CSF biomarkers, modulates the distribution of APOE genotype: impact on clinical trials. J Neurol. 2014; 261 (6): 1187–1195. doi: 10.1007/s00415-014-7335-6 24728335.

22. Saykin AJ, Shen L, Foroud TM, Potkin SG, Swaminathan S, Kim S, et al. Alzheimer's Disease Neuroimaging Initiative biomarkers as quantitative phenotypes: Genetics core aims, progress, and plans. Alzheimers Dement. 2010; 6 (3): 265–273. doi: 10.1016/j.jalz.2010.03.013 20451875.

23. Sabia S, Kivimaki M, Kumari M, Shipley MJ, Singh-Manoux. A Effect of Apolipoprotein E epsilon4 on the association between health behaviors and cognitive function in late midlife. Mol Neurodegener. 2010; 5: 23. doi: 10.1186/1750-1326-5-23 20515477.

24. Dufouil C, Richard F, Fievet N, Dartigues JF, Ritchie K, Tzourio C, et al. APOE genotype, cholesterol level, lipid-lowering treatment, and dementia: the Three-City Study. Neurology. 2005; 64 (9): 1531–1538. doi: 10.1212/01.WNL.0000160114.42643.31 15883313.

25. Mansournia MA, Altman DG. Population attributable fraction. BMJ. 2018; 360: k757. doi: 10.1136/bmj.k757 29472187.

26. Kukull WA, Schellenberg GD, Bowen JD, McCormick WC, Yu CE, Teri L, et al. Apolipoprotein E in Alzheimer's disease risk and case detection: a case-control study. J Clin Epidemiol. 1996; 49 (10): 1143–1148. doi: 10.1016/0895-4356(96)00195-3 8826994.

27. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21 (11): 1539–1558. doi: 10.1002/sim.1186 12111919.

28. Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993; 90 (5): 1977–1981. doi: 10.1073/pnas.90.5.1977 8446617.

29. Frisoni GB, Manfredi M, Geroldi C, Binetti G, Zanetti O, Bianchetti A, et al. The prevalence of apoE-epsilon4 in Alzheimer's disease is age dependent. J Neurol Neurosurg Psychiatry. 1998; 65 (1): 103–106. doi: 10.1136/jnnp.65.1.103 9667569.

30. Jarvik GP, Wijsman EM, Kukull WA, Schellenberg GD, Yu C, Larson EB. Interactions of apolipoprotein E genotype, total cholesterol level, age, and sex in prediction of Alzheimer's disease: a case-control study. Neurology. 1995; 45 (6): 1092–1096. doi: 10.1212/wnl.45.6.1092 7783869.

31. Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC, et al. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nat Genet. 2019; 51 (3): 414–430. doi: 10.1038/s41588-019-0358-2 30820047.

32. Ebbert MT, Ridge PG, Wilson AR, Sharp AR, Bailey M, Norton MC, et al. Population-based analysis of Alzheimer's disease risk alleles implicates genetic interactions. Biol Psychiatry. 2014; 75 (9): 732–737. doi: 10.1016/j.biopsych.2013.07.008 23954108.

33. Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet. 2007; 39 (1): 17–23. doi: 10.1038/ng1934 17192785.

34. Corneveaux JJ, Myers AJ, Allen AN, Pruzin JJ, Ramirez M, Engel A, et al. Association of CR1, CLU and PICALM with Alzheimer's disease in a cohort of clinically characterized and neuropathologically verified individuals. Hum Mol Genet. 2010; 19 (16): 3295–3301. doi: 10.1093/hmg/ddq221 20534741.

35. Andreasson U, Lautner R, Schott JM, Mattsson N, Hansson O, Herukka SK, et al. CSF biomarkers for Alzheimer's pathology and the effect size of APOE varepsilon4. Mol Psychiatry. 2014; 19 (2): 148–149. doi: 10.1038/mp.2013.18 23419830.

36. Mattsson N, Groot C, Jansen WJ, Landau SM, Villemagne VL, Engelborghs S, et al. Prevalence of the apolipoprotein E epsilon4 allele in amyloid beta positive subjects across the spectrum of Alzheimer's disease. Alzheimers Dement. 2018; 14 (7): 913–924. doi: 10.1016/j.jalz.2018.02.009 29601787.

37. Ward A, Crean S, Mercaldi CJ, Collins JM, Boyd D, Cook MN, et al. Prevalence of apolipoprotein E4 genotype and homozygotes (APOE e4/4) among patients diagnosed with Alzheimer's disease: a systematic review and meta-analysis. Neuroepidemiology. 2012; 38 (1): 1–17. doi: 10.1159/000334607 22179327.

38. Zhao N, Liu CC, Qiao W, Bu G. Apolipoprotein E, Receptors, and Modulation of Alzheimer's Disease. Biol Psychiatry. 2018; 83 (4): 347–357. doi: 10.1016/j.biopsych.2017.03.003 28434655.

39. Jansen WJ, Ossenkoppele R, Knol DL, Tijms BM, Scheltens P, Verhey FR, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 2015; 313 (19): 1924–1938. doi: 10.1001/jama.2015.4668 25988462.

40. Amieva H, Jacqmin-Gadda H, Orgogozo JM, Le Carret N, Helmer C, Letenneur L, et al. The 9 year cognitive decline before dementia of the Alzheimer type: a prospective population-based study. Brain. 2005; 128 (Pt 5): 1093–1101. doi: 10.1093/brain/awh451 15774508.

41. Buckley RF, Mormino EC, Amariglio RE, Properzi MJ, Rabin JS, Lim YY, et al. Sex, amyloid, and APOE epsilon4 and risk of cognitive decline in preclinical Alzheimer's disease: Findings from three well-characterized cohorts. Alzheimers Dement. 2018; 14 (9): 1193–1203. doi: 10.1016/j.jalz.2018.04.010 29803541.

42. Hsu D, Marshall GA. Primary and Secondary Prevention Trials in Alzheimer Disease: Looking Back, Moving Forward. Curr Alzheimer Res. 2017; 14 (4): 426–440. doi: 10.2174/1567205013666160930112125 27697063.

43. Hennessy S, Bilker WB, Berlin JA, Strom BL. Factors influencing the optimal control-to-case ratio in matched case-control studies. Am J Epidemiol. 1999; 149 (2): 195–197. doi: 10.1093/oxfordjournals.aje.a009786 9921965.

44. Kern S, Mehlig K, Kern J, Zetterberg H, Thelle D, Skoog I, et al. The distribution of apolipoprotein E genotype over the adult lifespan and in relation to country of birth. Am J Epidemiol. 2015; 181 (3): 214–217. doi: 10.1093/aje/kwu442 25609095.

45. Hendrie HC, Murrell J, Baiyewu O, Lane KA, Purnell C, Ogunniyi A, et al. APOE epsilon4 and the risk for Alzheimer disease and cognitive decline in African Americans and Yoruba. Int Psychogeriatr. 2014; 26 (6): 977–985. doi: 10.1017/S1041610214000167 24565289.

Článek vyšel v časopise

PLOS Medicine

2020 Číslo 8

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…

Kurzy Doporučená témata Časopisy
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.


Nemáte účet?  Registrujte se

VIRTUÁLNÍ ČEKÁRNA ČR Jste praktický lékař nebo pediatr? Zapojte se! Jste praktik nebo pediatr? Zapojte se!