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Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 2004 Jun;75(6):828–833. doi: 10.1136/jnnp.2003.021493

Risk and protective effects of the APOE gene towards Alzheimer's disease in the Kungsholmen project: variation by age and sex

C Qiu 1, M Kivipelto 1, H Aguero-Torres 1, B Winblad 1, L Fratiglioni 1
PMCID: PMC1739059  PMID: 15145993

Abstract

Background: The risk effect of APOE ε4 allele for Alzheimer's disease is acknowledged, whereas the putative protective effect of ε2 allele remains in debate.

Objectives: To investigate whether those inconsistent findings may be attributable to differences in age and sex composition of the study populations.

Methods: A community dementia free cohort (n = 985) aged ⩾75 years was followed up to detect Alzheimer's disease cases (DSM-III-R criteria). Data were analysed using Cox models with adjustment for major potential confounders.

Results: Over a median 5.6 year follow up, Alzheimer's disease was diagnosed in 206 subjects. Compared with APOE ε3/ε3 genotype, the relative risk (RR) of Alzheimer's disease was 1.4 (95% confidence interval (CI), 1.0 to 2.0; p = 0.03) for heterozygous ε4 allele and 3.1 (95% CI, 1.6 to 5.9) for homozygous ε4 allele. The association between ε4 allele and Alzheimer's disease risk was stronger in men than in women (RR related to the interaction term ε4 allele by sex, 0.4; 95% CI, 0.2 to 0.9). The ε4 allele accounted for one third of Alzheimer's disease cases among men, but only one tenth among women. The ε2 allele was related to a reduced Alzheimer's disease risk mainly in people aged <85 years (RR, 0.4; 95% CI, 0.2 to 0.8). The RR of Alzheimer's disease related to the interaction term of ε2 allele by age was 2.4 (95% CI, 1.0 to 6.0; p = 0.06).

Conclusions: The APOE genotype specific effects on Alzheimer's disease vary by age and sex, in which the ε4 allele has a stronger risk effect in men, and the ε2 allele confers a protective effect only in younger-old people.

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Selected References

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  1. Amato C., Elia M., Musumeci S. A., Bisceglie P., Moschini M. Transient MRI abnormalities associated with partial status epilepticus: a case report. Eur J Radiol. 2001 Apr;38(1):50–54. doi: 10.1016/s0720-048x(00)00284-9. [DOI] [PubMed] [Google Scholar]
  2. Anttila T., Helkala E-L, Kivipelto M., Hallikainen M., Alhainen K., Heinonen H., Mannermaa A., Tuomilehto J., Soininen H., Nissinen A. Midlife income, occupation, APOE status, and dementia: a population-based study. Neurology. 2002 Sep 24;59(6):887–893. doi: 10.1212/wnl.59.6.887. [DOI] [PubMed] [Google Scholar]
  3. Bash S., Hathout G. M., Cohen S. Mesiotemporal T2-weighted hyperintensity: neurosyphilis mimicking herpes encephalitis. AJNR Am J Neuroradiol. 2001 Feb;22(2):314–316. [PMC free article] [PubMed] [Google Scholar]
  4. Basun H., Corder E. H., Guo Z., Lannfelt L., Corder L. S., Manton K. G., Winblad B., Viitanen M. Apolipoprotein E polymorphism and stroke in a population sample aged 75 years or more. Stroke. 1996 Aug;27(8):1310–1315. doi: 10.1161/01.str.27.8.1310. [DOI] [PubMed] [Google Scholar]
  5. Brightbill T. C., Ihmeidan I. H., Post M. J., Berger J. R., Katz D. A. Neurosyphilis in HIV-positive and HIV-negative patients: neuroimaging findings. AJNR Am J Neuroradiol. 1995 Apr;16(4):703–711. [PMC free article] [PubMed] [Google Scholar]
  6. Evans Denis A., Bennett David A., Wilson Robert S., Bienias Julia L., Morris Martha Clare, Scherr Paul A., Hebert Liesi E., Aggarwal Neelum, Beckett Laurel A., Joglekar Rajiv. Incidence of Alzheimer disease in a biracial urban community: relation to apolipoprotein E allele status. Arch Neurol. 2003 Feb;60(2):185–189. doi: 10.1001/archneur.60.2.185. [DOI] [PubMed] [Google Scholar]
  7. Farrer L. A., Cupples L. A., Haines J. L., Hyman B., Kukull W. A., Mayeux R., Myers R. H., Pericak-Vance M. A., Risch N., van Duijn C. M. 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 Oct 22;278(16):1349–1356. [PubMed] [Google Scholar]
  8. Fratiglioni L., Grut M., Forsell Y., Viitanen M., Winblad B. Clinical diagnosis of Alzheimer's disease and other dementias in a population survey. Agreement and causes of disagreement in applying Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, Criteria. Arch Neurol. 1992 Sep;49(9):927–932. doi: 10.1001/archneur.1992.00530330049015. [DOI] [PubMed] [Google Scholar]
  9. Fratiglioni L., Viitanen M., Bäckman L., Sandman P. O., Winblad B. Occurrence of dementia in advanced age: the study design of the Kungsholmen Project. Neuroepidemiology. 1992;11 (Suppl 1):29–36. doi: 10.1159/000110958. [DOI] [PubMed] [Google Scholar]
  10. Fratiglioni L., Viitanen M., von Strauss E., Tontodonati V., Herlitz A., Winblad B. Very old women at highest risk of dementia and Alzheimer's disease: incidence data from the Kungsholmen Project, Stockholm. Neurology. 1997 Jan;48(1):132–138. doi: 10.1212/wnl.48.1.132. [DOI] [PubMed] [Google Scholar]
  11. Frikke-Schmidt R., Nordestgaard B. G., Thudium D., Moes Grønholdt M. L., Tybjaerg-Hansen A. APOE genotype predicts AD and other dementia but not ischemic cerebrovascular disease. Neurology. 2001 Jan 23;56(2):194–200. doi: 10.1212/wnl.56.2.194. [DOI] [PubMed] [Google Scholar]
  12. Ganguli M., Chandra V., Kamboh M. I., Johnston J. M., Dodge H. H., Thelma B. K., Juyal R. C., Pandav R., Belle S. H., DeKosky S. T. Apolipoprotein E polymorphism and Alzheimer disease: The Indo-US Cross-National Dementia Study. Arch Neurol. 2000 Jun;57(6):824–830. doi: 10.1001/archneur.57.6.824. [DOI] [PubMed] [Google Scholar]
  13. Ghebremedhin E., Schultz C., Thal D. R., Rüb U., Ohm T. G., Braak E., Braak H. Gender and age modify the association between APOE and AD-related neuropathology. Neurology. 2001 Jun 26;56(12):1696–1701. doi: 10.1212/wnl.56.12.1696. [DOI] [PubMed] [Google Scholar]
  14. Guo Z., Fratiglioni L., Viitanen M., Lannfelt L., Basun H., Fastbom J., Winblad B. Apolipoprotein E genotypes and the incidence of Alzheimer's disease among persons aged 75 years and older: variation by use of antihypertensive medication? Am J Epidemiol. 2001 Feb 1;153(3):225–231. doi: 10.1093/aje/153.3.225. [DOI] [PubMed] [Google Scholar]
  15. Heald A., Connolly S., Hudgson P. Neurosyphilis presenting as complex partial status epilepticus. Eur Neurol. 1996;36(2):111–112. doi: 10.1159/000117223. [DOI] [PubMed] [Google Scholar]
  16. Hofman A., Ott A., Breteler M. M., Bots M. L., Slooter A. J., van Harskamp F., van Duijn C. N., Van Broeckhoven C., Grobbee D. E. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study. Lancet. 1997 Jan 18;349(9046):151–154. doi: 10.1016/S0140-6736(96)09328-2. [DOI] [PubMed] [Google Scholar]
  17. Hyman B. T., Gomez-Isla T., Briggs M., Chung H., Nichols S., Kohout F., Wallace R. Apolipoprotein E and cognitive change in an elderly population. Ann Neurol. 1996 Jul;40(1):55–66. doi: 10.1002/ana.410400111. [DOI] [PubMed] [Google Scholar]
  18. Juva K., Verkkoniemi A., Viramo P., Polvikoski T., Kainulainen K., Kontula K., Sulkava R. APOE epsilon4 does not predict mortality, cognitive decline, or dementia in the oldest old. Neurology. 2000 Jan 25;54(2):412–415. doi: 10.1212/wnl.54.2.412. [DOI] [PubMed] [Google Scholar]
  19. Katzman R., Zhang M. Y., Chen P. J., Gu N., Jiang S., Saitoh T., Chen X., Klauber M., Thomas R. G., Liu W. T. Effects of apolipoprotein E on dementia and aging in the Shanghai Survey of Dementia. Neurology. 1997 Sep;49(3):779–785. doi: 10.1212/wnl.49.3.779. [DOI] [PubMed] [Google Scholar]
  20. Kivipelto Miia, Helkala Eeva-Liisa, Laakso Mikko P., Hänninen Tuomo, Hallikainen Merja, Alhainen Kari, Iivonen Susan, Mannermaa Arto, Tuomilehto Jaakko, Nissinen Aulikki. Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med. 2002 Aug 6;137(3):149–155. doi: 10.7326/0003-4819-137-3-200208060-00006. [DOI] [PubMed] [Google Scholar]
  21. Kukull Walter A., Higdon Roger, Bowen James D., McCormick Wayne C., Teri Linda, Schellenberg Gerard D., van Belle Gerald, Jolley Lance, Larson Eric B. Dementia and Alzheimer disease incidence: a prospective cohort study. Arch Neurol. 2002 Nov;59(11):1737–1746. doi: 10.1001/archneur.59.11.1737. [DOI] [PubMed] [Google Scholar]
  22. Lahoz C., Schaefer E. J., Cupples L. A., Wilson P. W., Levy D., Osgood D., Parpos S., Pedro-Botet J., Daly J. A., Ordovas J. M. Apolipoprotein E genotype and cardiovascular disease in the Framingham Heart Study. Atherosclerosis. 2001 Feb 15;154(3):529–537. doi: 10.1016/s0021-9150(00)00570-0. [DOI] [PubMed] [Google Scholar]
  23. Lippa C. F., Smith T. W., Saunders A. M., Hulette C., Pulaski-Salo D., Roses A. D. Apolipoprotein E-epsilon 2 and Alzheimer's disease: genotype influences pathologic phenotype. Neurology. 1997 Feb;48(2):515–519. doi: 10.1212/wnl.48.2.515. [DOI] [PubMed] [Google Scholar]
  24. McKhann G., Drachman D., Folstein M., Katzman R., Price D., Stadlan E. M. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939–944. doi: 10.1212/wnl.34.7.939. [DOI] [PubMed] [Google Scholar]
  25. Meyer M. R., Tschanz J. T., Norton M. C., Welsh-Bohmer K. A., Steffens D. C., Wyse B. W., Breitner J. C. APOE genotype predicts when--not whether--one is predisposed to develop Alzheimer disease. Nat Genet. 1998 Aug;19(4):321–322. doi: 10.1038/1206. [DOI] [PubMed] [Google Scholar]
  26. Miech R. A., Breitner J. C. S., Zandi P. P., Khachaturian A. S., Anthony J. C., Mayer L. Incidence of AD may decline in the early 90s for men, later for women: The Cache County study. Neurology. 2002 Jan 22;58(2):209–218. doi: 10.1212/wnl.58.2.209. [DOI] [PubMed] [Google Scholar]
  27. Molero A. E., Pino-Ramírez G., Maestre G. E. Modulation by age and gender of risk for Alzheimer's disease and vascular dementia associated with the apolipoprotein E-epsilon4 allele in Latin Americans: findings from the Maracaibo Aging Study. Neurosci Lett. 2001 Jul 6;307(1):5–8. doi: 10.1016/s0304-3940(01)01911-5. [DOI] [PubMed] [Google Scholar]
  28. Mortensen E. L., Høgh P. A gender difference in the association between APOE genotype and age-related cognitive decline. Neurology. 2001 Jul 10;57(1):89–95. doi: 10.1212/wnl.57.1.89. [DOI] [PubMed] [Google Scholar]
  29. Nussbaum Robert L., Ellis Christopher E. Alzheimer's disease and Parkinson's disease. N Engl J Med. 2003 Apr 3;348(14):1356–1364. doi: 10.1056/NEJM2003ra020003. [DOI] [PubMed] [Google Scholar]
  30. Payami H., Zareparsi S., Montee K. R., Sexton G. J., Kaye J. A., Bird T. D., Yu C. E., Wijsman E. M., Heston L. L., Litt M. Gender difference in apolipoprotein E-associated risk for familial Alzheimer disease: a possible clue to the higher incidence of Alzheimer disease in women. Am J Hum Genet. 1996 Apr;58(4):803–811. [PMC free article] [PubMed] [Google Scholar]
  31. Polvikoski T., Sulkava R., Haltia M., Kainulainen K., Vuorio A., Verkkoniemi A., Niinistö L., Halonen P., Kontula K. Apolipoprotein E, dementia, and cortical deposition of beta-amyloid protein. N Engl J Med. 1995 Nov 9;333(19):1242–1247. doi: 10.1056/NEJM199511093331902. [DOI] [PubMed] [Google Scholar]
  32. Qiu C., Bäckman L., Winblad B., Agüero-Torres H., Fratiglioni L. The influence of education on clinically diagnosed dementia incidence and mortality data from the Kungsholmen Project. Arch Neurol. 2001 Dec;58(12):2034–2039. doi: 10.1001/archneur.58.12.2034. [DOI] [PubMed] [Google Scholar]
  33. Reilly S. L., Ferrell R. E., Kottke B. A., Sing C. F. The gender-specific apolipoprotein E genotype influence on the distribution of plasma lipids and apolipoproteins in the population of Rochester, Minnesota. II. Regression relationships with concomitants. Am J Hum Genet. 1992 Dec;51(6):1311–1324. [PMC free article] [PubMed] [Google Scholar]
  34. Slooter A. J., Cruts M., Kalmijn S., Hofman A., Breteler M. M., Van Broeckhoven C., van Duijn C. M. Risk estimates of dementia by apolipoprotein E genotypes from a population-based incidence study: the Rotterdam Study. Arch Neurol. 1998 Jul;55(7):964–968. doi: 10.1001/archneur.55.7.964. [DOI] [PubMed] [Google Scholar]
  35. Tang M. X., Stern Y., Marder K., Bell K., Gurland B., Lantigua R., Andrews H., Feng L., Tycko B., Mayeux R. The APOE-epsilon4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics. JAMA. 1998 Mar 11;279(10):751–755. doi: 10.1001/jama.279.10.751. [DOI] [PubMed] [Google Scholar]
  36. Wilson R. S., Bienias J. L., Berry-Kravis E., Evans D. A., Bennett D. A. The apolipoprotein E epsilon 2 allele and decline in episodic memory. J Neurol Neurosurg Psychiatry. 2002 Dec;73(6):672–677. doi: 10.1136/jnnp.73.6.672. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Yip A. G., Brayne C., Easton D., Rubinsztein D. C., Medical Research Council Cognitive Function Ageing Study (MRC CFAS) Apolipoprotein E4 is only a weak predictor of dementia and cognitive decline in the general population. J Med Genet. 2002 Sep;39(9):639–643. doi: 10.1136/jmg.39.9.639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Zhu L., Fratiglioni L., Guo Z., Basun H., Corder E. H., Winblad B., Viitanen M. Incidence of dementia in relation to stroke and the apolipoprotein E epsilon4 allele in the very old. Findings from a population-based longitudinal study. Stroke. 2000 Jan;31(1):53–60. doi: 10.1161/01.str.31.1.53. [DOI] [PubMed] [Google Scholar]
  39. van Duijn C. M., de Knijff P., Wehnert A., De Voecht J., Bronzova J. B., Havekes L. M., Hofman A., Van Broeckhoven C. The apolipoprotein E epsilon 2 allele is associated with an increased risk of early-onset Alzheimer's disease and a reduced survival. Ann Neurol. 1995 May;37(5):605–610. doi: 10.1002/ana.410370510. [DOI] [PubMed] [Google Scholar]

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