Longitudinal study of the effect of apolipoprotein e4 allele on the association between education and cognitive decline in elderly men

BMJ 1997; 314 doi: (Published 04 January 1997) Cite this as: BMJ 1997;314:34
  1. Sandra Kalmijn, research associate (Kalmijn{at},
  2. Edith J M Feskens, senior researchera,
  3. Lenore J Launer, assistant professora,
  4. Daan Kromhout, professor of public health researcha
  1. a Department of Chronic Diseases and Environmental Epidemiology, National Institute of Public Health and the Environment, PO Box 1, 3720 BA Bilthoven, Netherlands
  1. Correspondence and reprint requests to: Dr Kalmijn
  • Accepted 23 July 1996


Less educated people have an increased risk of cognitive decline,1 and several possible explanations for this have been suggested. The activation of nerve cells in higher educated subjects might protect these cells against degeneration,2 thereby delaying the pathological process leading to cognitive decline. Higher education might also lead to an increased brain reserve capacity, so that other neurons can take over the tasks of dead neurons.3 This would retard the onset of cognitive decline. However, the association might be due to confounding by factors related to lifestyle.

The apolipoprotein e4 allele on chromosome 19 is an important risk factor for cognitive decline.4 We examined the association between education and cognitive decline in elderly men with and without the e4 allele to see whether this genetic risk factor modified the association.

Subjects, methods, and results

The Zutphen elderly study is a longitudinal study on risk factors for chronic diseases in men living in Zutphen, the Netherlands.4 In 1990, 560 (78%) of the 718 surviving men were examined, and the examinations were repeated in 1993 on 390 (71%) of the 553 survivors. Complete information was available for 356 men participating both in 1990 and 1993. Global cognitive function was tested with the Dutch version of the 30 point mini-mental state examination. Cognitive decline was defined as a drop of more than two points (>1 standard deviation) during 1990-3, which corresponded to the 14th centile of change. Years of formal education were obtained in 1990 and categorised as ≤6 years or >6 years. Serum samples were obtained in 1990 and frozen at -20°C until 1993, when the apolipoprotein E phenotype was determined by isoelectric focusing of delipidated plasma samples followed by immunoblotting. The association between education and cognitive decline was examined by logistic regression in the total group and the carriers and non-carriers of e4, adjusting for age and baseline score for cognitive function.

The subjects' mean age in 1990 was 74.6 (SD 4.2) years. The median score for cognitive function was 27 (10th centile 23, 90th centile 29). Table 1 shows the association between education and cognitive decline. This was strong in non-carriers of e4, but in carriers of e4 it was absent (test for interaction not significant, P=0.11). Additional adjustment for history of cardiovascular diseases did not change these results. For carriers and non-carriers of e4, the subjects who did not participate in 1993 showed a similar association between education and cognitive function in 1990 as did those who participated in 1993 (results not shown).

Table 1

Adjusted odds ratios (95% confidence interval) for cognitive decline* in 356 elderly men according to level of education and presence of apolipoprotein e4 allele

View this table:


We observed a significantly increased risk of cognitive decline associated with a lower level of education in subjects without an apolipoprotein e4 allele. In contrast, there was no association between education and cognitive decline in carriers of the e4 allele.

Possible explanations for this lack of association in the subjects with an e4 allele include selective survival and non-response. However, our data do not suggest that less educated men with e4 who did not participate in 1993 had a different risk of cognitive impairment than those who participated. We do not know, though, whether the risk of cognitive decline differed between the groups. The e4 allele may be such a strong risk factor for cognitive decline that cognitive performance in carriers of an e4 allele deteriorates regardless of educational level. Alternatively, apolipoprotein e4 may play a role in inhibiting neuronal growth5 and may thus block the putative stimulating effect of education on neuronal growth. Finally, we cannot exclude the possibility that our results are a chance finding.

In conclusion our results suggest that the apolipoprotein e4 allele may modify the association between education and cognitive decline. However, our findings need to be confirmed by larger studies.


We thank the fieldwork team in Zutphen, especially Drs E B Bosschieter and B P M Bloemberg; C de Lezenne Coulander for data management; and Dr L M Havekes for determination of the apolipoprotein E polymorphism.

Funding: This study was supported by grants from the Praeventie Fonds, the Hague, Netherlands, and the National Institute on Aging, Bethesda MD, USA.

Conflict of interest: None.


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