Skip to main content
Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 1998 Jan;64(1):37–43. doi: 10.1136/jnnp.64.1.37

A population study of apoE genotype at the age of 85: relation to dementia, cerebrovascular disease, and mortality

I Skoog 1, C Hesse 1, O Aevarsson 1, S Landahl 1, J Wahlstrom 1, P Fredman 1, K Blennow 1
PMCID: PMC2169928  PMID: 9436725

Abstract

OBJECTIVES—To study the association of apoE genotypes with dementia and cerebrovascular disorders in a population based sample of 85year old people.
METHODS—A representative sample of 85 year old people (303 non-demented, 109 demented) were given a neuropsychiatric and a medical examination and head CT. The apoE isoforms were determined. Dementia was diagnosed according to DSM-III-R.
RESULTS—At the age of 85, carriers of the apoE ε4 allele had an increased odds ratio (OR) for dementia (1.9; p<0.01) and its subtypes Alzheimer's disease (1.9; p<0.05) and vascular dementia (2.0; p<0.05). Among those categorised as having vascular dementia, the apoE ε4 allele was associated with mixed Alzheimer's disease-multi-infarct dementia (OR 6.5; p<0.05), but not with pure multi-infarct dementia (OR 1.5; NS). Only carriers of the apoE ε4 allele who also had ischaemic white matter lesions on CT of the head had an increased OR for dementia (OR 6.1; p=0.00003), and its main subtypes Alzheimer's disease (OR 6.8; p=0.002) and vascular dementia (OR 5.6; p=0.0007), whereas carriers of the apoE ε4 allele without white matter lesions had an OR for dementia of 1.0 (OR for Alzheimer's disease 1.8; NS and for vascular dementia 0.6; NS) and non-carriers of the apoE ε4 allele with white matter lesions had an OR for dementia of 2.2; NS (OR for Alzheimer's disease 2.7; NS and for vascular dementia 1.6; NS). The apoE allele variants were not related to mortality or incidence of dementia between the ages of 85 and 88. The ε2 allele was related to a higher prevalence of stroke or transient ischaemic attack at the age of 85 (OR 2.1; p<0.05) and a higher incidence of multi-infarct dementia during the follow up (OR 2.9; p<0.05).
CONCLUSIONS—Neither the apoE ε4 allele nor white matter lesions are sufficient risk factors by themselves for dementia at very old ages, whereas possession of both these entities increases the risk for Alzheimer's disease and vascular dementia substantially.



Full Text

The Full Text of this article is available as a PDF (144.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aevarsson O., Skoog I. A population-based study on the incidence of dementia disorders between 85 and 88 years of age. J Am Geriatr Soc. 1996 Dec;44(12):1455–1460. doi: 10.1111/j.1532-5415.1996.tb04070.x. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Blacker D., Haines J. L., Rodes L., Terwedow H., Go R. C., Harrell L. E., Perry R. T., Bassett S. S., Chase G., Meyers D. ApoE-4 and age at onset of Alzheimer's disease: the NIMH genetics initiative. Neurology. 1997 Jan;48(1):139–147. doi: 10.1212/wnl.48.1.139. [DOI] [PubMed] [Google Scholar]
  4. Blennow K., Wallin A. Clinical heterogeneity of probable Alzheimer's disease. J Geriatr Psychiatry Neurol. 1992 Apr-Jun;5(2):106–113. doi: 10.1177/002383099200500208. [DOI] [PubMed] [Google Scholar]
  5. Brun A., Englund E. A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study. Ann Neurol. 1986 Mar;19(3):253–262. doi: 10.1002/ana.410190306. [DOI] [PubMed] [Google Scholar]
  6. Corder E. H., Lannfelt L., Viitanen M., Corder L. S., Manton K. G., Winblad B., Basun H. Apolipoprotein E genotype determines survival in the oldest old (85 years or older) who have good cognition. Arch Neurol. 1996 May;53(5):418–422. doi: 10.1001/archneur.1996.00550050048022. [DOI] [PubMed] [Google Scholar]
  7. Corder E. H., Saunders A. M., Risch N. J., Strittmatter W. J., Schmechel D. E., Gaskell P. C., Jr, Rimmler J. B., Locke P. A., Conneally P. M., Schmader K. E. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet. 1994 Jun;7(2):180–184. doi: 10.1038/ng0694-180. [DOI] [PubMed] [Google Scholar]
  8. Corder E. H., Saunders A. M., Strittmatter W. J., Schmechel D. E., Gaskell P. C., Small G. W., Roses A. D., Haines J. L., Pericak-Vance M. A. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science. 1993 Aug 13;261(5123):921–923. doi: 10.1126/science.8346443. [DOI] [PubMed] [Google Scholar]
  9. Corder E., Basun H., Lannfelt L., Viitanen M., Winblad B. Apolipoprotein E-epsilon 4 gene dose. Lancet. 1995 Oct 7;346(8980):967–968. doi: 10.1016/s0140-6736(95)91588-5. [DOI] [PubMed] [Google Scholar]
  10. Couderc R., Mahieux F., Bailleul S., Fenelon G., Mary R., Fermanian J. Prevalence of apolipoprotein E phenotypes in ischemic cerebrovascular disease. A case-control study. Stroke. 1993 May;24(5):661–664. doi: 10.1161/01.str.24.5.661. [DOI] [PubMed] [Google Scholar]
  11. Davignon J., Gregg R. E., Sing C. F. Apolipoprotein E polymorphism and atherosclerosis. Arteriosclerosis. 1988 Jan-Feb;8(1):1–21. doi: 10.1161/01.atv.8.1.1. [DOI] [PubMed] [Google Scholar]
  12. Diaz J. F., Merskey H., Hachinski V. C., Lee D. H., Boniferro M., Wong C. J., Mirsen T. R., Fox H. Improved recognition of leukoaraiosis and cognitive impairment in Alzheimer's disease. Arch Neurol. 1991 Oct;48(10):1022–1025. doi: 10.1001/archneur.1991.00530220038016. [DOI] [PubMed] [Google Scholar]
  13. Eggertsen G., Tegelman R., Ericsson S., Angelin B., Berglund L. Apolipoprotein E polymorphism in a healthy Swedish population: variation of allele frequency with age and relation to serum lipid concentrations. Clin Chem. 1993 Oct;39(10):2125–2129. [PubMed] [Google Scholar]
  14. Erkinjuntti T., Haltia M., Palo J., Sulkava R., Paetau A. Accuracy of the clinical diagnosis of vascular dementia: a prospective clinical and post-mortem neuropathological study. J Neurol Neurosurg Psychiatry. 1988 Aug;51(8):1037–1044. doi: 10.1136/jnnp.51.8.1037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Evans D. A., Beckett L. A., Field T. S., Feng L., Albert M. S., Bennett D. A., Tycko B., Mayeux R. Apolipoprotein E epsilon4 and incidence of Alzheimer disease in a community population of older persons. JAMA. 1997 Mar 12;277(10):822–824. [PubMed] [Google Scholar]
  16. Feskens E. J., Havekes L. M., Kalmijn S., de Knijff P., Launer L. J., Kromhout D. Apolipoprotein e4 allele and cognitive decline in elderly men. BMJ. 1994 Nov 5;309(6963):1202–1206. doi: 10.1136/bmj.309.6963.1202. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Frisoni G. B., Bianchetti A., Govoni S., Trabucchi M., Calabresi L., Franceschini G. Association of apolipoprotein E E4 with vascular dementia. JAMA. 1994 May 4;271(17):1317–1317. [PubMed] [Google Scholar]
  18. Henderson A. S., Easteal S., Jorm A. F., Mackinnon A. J., Korten A. E., Christensen H., Croft L., Jacomb P. A. Apolipoprotein E allele epsilon 4, dementia, and cognitive decline in a population sample. Lancet. 1995 Nov 25;346(8987):1387–1390. doi: 10.1016/s0140-6736(95)92405-1. [DOI] [PubMed] [Google Scholar]
  19. 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]
  20. Jellinger K., Danielczyk W., Fischer P., Gabriel E. Clinicopathological analysis of dementia disorders in the elderly. J Neurol Sci. 1990 Mar;95(3):239–258. doi: 10.1016/0022-510x(90)90072-u. [DOI] [PubMed] [Google Scholar]
  21. Kane J. W., Gowland E. A method for the identification of apolipoprotein E isoforms employing chemical precipitation and flat bed isoelectric focusing in agarose. Ann Clin Biochem. 1986 Sep;23(Pt 5):509–513. doi: 10.1177/000456328602300504. [DOI] [PubMed] [Google Scholar]
  22. Kuusisto J., Koivisto K., Kervinen K., Mykkänen L., Helkala E. L., Vanhanen M., Hänninen T., Pyörälä K., Kesäniemi Y. A., Riekkinen P. Association of apolipoprotein E phenotypes with late onset Alzheimer's disease: population based study. BMJ. 1994 Sep 10;309(6955):636–638. doi: 10.1136/bmj.309.6955.636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Landén M., Thorsell A., Wallin A., Blennow K. The apolipoprotein E allele epsilon 4 does not correlate with the number of senile plaques or neurofibrillary tangles in patients with Alzheimer's disease. J Neurol Neurosurg Psychiatry. 1996 Oct;61(4):352–356. doi: 10.1136/jnnp.61.4.352. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mahley R. W. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988 Apr 29;240(4852):622–630. doi: 10.1126/science.3283935. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Myers R. H., Schaefer E. J., Wilson P. W., D'Agostino R., Ordovas J. M., Espino A., Au R., White R. F., Knoefel J. E., Cobb J. L. Apolipoprotein E epsilon4 association with dementia in a population-based study: The Framingham study. Neurology. 1996 Mar;46(3):673–677. doi: 10.1212/wnl.46.3.673. [DOI] [PubMed] [Google Scholar]
  27. Noguchi S., Murakami K., Yamada N. Apolipoprotein E genotype and Alzheimer's disease. Lancet. 1993 Sep 18;342(8873):737–737. doi: 10.1016/0140-6736(93)91728-5. [DOI] [PubMed] [Google Scholar]
  28. Pedro-Botet J., Sentí M., Nogués X., Rubiés-Prat J., Roquer J., D'Olhaberriague L., Olivé J. Lipoprotein and apolipoprotein profile in men with ischemic stroke. Role of lipoprotein(a), triglyceride-rich lipoproteins, and apolipoprotein E polymorphism. Stroke. 1992 Nov;23(11):1556–1562. doi: 10.1161/01.str.23.11.1556. [DOI] [PubMed] [Google Scholar]
  29. Poirier J., Davignon J., Bouthillier D., Kogan S., Bertrand P., Gauthier S. Apolipoprotein E polymorphism and Alzheimer's disease. Lancet. 1993 Sep 18;342(8873):697–699. doi: 10.1016/0140-6736(93)91705-q. [DOI] [PubMed] [Google Scholar]
  30. Poirier J., Minnich A., Davignon J. Apolipoprotein E, synaptic plasticity and Alzheimer's disease. Ann Med. 1995 Dec;27(6):663–670. doi: 10.3109/07853899509019253. [DOI] [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. Rebeck G. W., Perls T. T., West H. L., Sodhi P., Lipsitz L. A., Hyman B. T. Reduced apolipoprotein epsilon 4 allele frequency in the oldest old Alzheimer's patients and cognitively normal individuals. Neurology. 1994 Aug;44(8):1513–1516. doi: 10.1212/wnl.44.8.1513. [DOI] [PubMed] [Google Scholar]
  33. Rinder L., Roupe S., Steen B., Svanborg A. Seventy-year-old people in Gothenburg. A population study in an industrialized Swedish city. Acta Med Scand. 1975 Nov;198(5):397–407. doi: 10.1111/j.0954-6820.1975.tb19563.x. [DOI] [PubMed] [Google Scholar]
  34. Saunders A. M., Schmader K., Breitner J. C., Benson M. D., Brown W. T., Goldfarb L., Goldgaber D., Manwaring M. G., Szymanski M. H., McCown N. Apolipoprotein E epsilon 4 allele distributions in late-onset Alzheimer's disease and in other amyloid-forming diseases. Lancet. 1993 Sep 18;342(8873):710–711. doi: 10.1016/0140-6736(93)91709-u. [DOI] [PubMed] [Google Scholar]
  35. Saunders A. M., Strittmatter W. J., Schmechel D., George-Hyslop P. H., Pericak-Vance M. A., Joo S. H., Rosi B. L., Gusella J. F., Crapper-MacLachlan D. R., Alberts M. J. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 1993 Aug;43(8):1467–1472. doi: 10.1212/wnl.43.8.1467. [DOI] [PubMed] [Google Scholar]
  36. Schächter F., Faure-Delanef L., Guénot F., Rouger H., Froguel P., Lesueur-Ginot L., Cohen D. Genetic associations with human longevity at the APOE and ACE loci. Nat Genet. 1994 Jan;6(1):29–32. doi: 10.1038/ng0194-29. [DOI] [PubMed] [Google Scholar]
  37. Shimano H., Ishibashi S., Murase T., Gotohda T., Yamada N., Takaku F., Ohtomo E. Plasma apolipoproteins in patients with multi-infarct dementia. Atherosclerosis. 1989 Oct;79(2-3):257–260. doi: 10.1016/0021-9150(89)90132-9. [DOI] [PubMed] [Google Scholar]
  38. Skoog I., Lernfelt B., Landahl S., Palmertz B., Andreasson L. A., Nilsson L., Persson G., Odén A., Svanborg A. 15-year longitudinal study of blood pressure and dementia. Lancet. 1996 Apr 27;347(9009):1141–1145. doi: 10.1016/s0140-6736(96)90608-x. [DOI] [PubMed] [Google Scholar]
  39. Skoog I., Nilsson L., Palmertz B., Andreasson L. A., Svanborg A. A population-based study of dementia in 85-year-olds. N Engl J Med. 1993 Jan 21;328(3):153–158. doi: 10.1056/NEJM199301213280301. [DOI] [PubMed] [Google Scholar]
  40. Skoog I., Palmertz B., Andreasson L. A. The prevalence of white-matter lesions on computed tomography of the brain in demented and nondemented 85-year-olds. J Geriatr Psychiatry Neurol. 1994 Jul-Sep;7(3):169–175. doi: 10.1177/089198879400700308. [DOI] [PubMed] [Google Scholar]
  41. Slooter A. J., Tang M. X., van Duijn C. M., Stern Y., Ott A., Bell K., Breteler M. M., Van Broeckhoven C., Tatemichi T. K., Tycko B. Apolipoprotein E epsilon4 and the risk of dementia with stroke. A population-based investigation. JAMA. 1997 Mar 12;277(10):818–821. doi: 10.1001/jama.277.10.818. [DOI] [PubMed] [Google Scholar]
  42. Sobel E., Louhija J., Sulkava R., Davanipour Z., Kontula K., Miettinen H., Tikkanen M., Kainulainen K., Tilvis R. Lack of association of apolipoprotein E allele epsilon 4 with late-onset Alzheimer's disease among Finnish centenarians. Neurology. 1995 May;45(5):903–907. doi: 10.1212/wnl.45.5.903. [DOI] [PubMed] [Google Scholar]
  43. Stengård J. H., Pekkanen J., Sulkava R., Ehnholm C., Erkinjuntti T., Nissinen A. Apolipoprotein E polymorphism, Alzheimer's disease and vascular dementia among elderly Finnish men. Acta Neurol Scand. 1995 Oct;92(4):297–298. doi: 10.1111/j.1600-0404.1995.tb00132.x. [DOI] [PubMed] [Google Scholar]
  44. Strittmatter W. J., Saunders A. M., Schmechel D., Pericak-Vance M., Enghild J., Salvesen G. S., Roses A. D. 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 Mar 1;90(5):1977–1981. doi: 10.1073/pnas.90.5.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Wade J. P., Mirsen T. R., Hachinski V. C., Fisman M., Lau C., Merskey H. The clinical diagnosis of Alzheimer's disease. Arch Neurol. 1987 Jan;44(1):24–29. doi: 10.1001/archneur.1987.00520130016010. [DOI] [PubMed] [Google Scholar]
  46. Willott J. F., Bross L. S., McFadden S. L. Morphology of the inferior colliculus in C57BL/6J and CBA/J mice across the life span. Neurobiol Aging. 1994 Mar-Apr;15(2):175–183. doi: 10.1016/0197-4580(94)90109-0. [DOI] [PubMed] [Google Scholar]
  47. de la Monte S. M. Quantitation of cerebral atrophy in preclinical and end-stage Alzheimer's disease. Ann Neurol. 1989 May;25(5):450–459. doi: 10.1002/ana.410250506. [DOI] [PubMed] [Google Scholar]
  48. van Bockxmeer F. M., Mamotte C. D. Apolipoprotein epsilon 4 homozygosity in young men with coronary heart disease. Lancet. 1992 Oct 10;340(8824):879–880. doi: 10.1016/0140-6736(92)93288-x. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Neurology, Neurosurgery, and Psychiatry are provided here courtesy of BMJ Publishing Group

RESOURCES