Current issues of ACP Journal Club are published in Annals of Internal Medicine


Apolipoprotein E ε 4 allele was a risk factor for Alzheimer disease

ACP J Club. 1997 Sep-Oct;127:49. doi:10.7326/ACPJC-1997-127-2-049

Related Content in this Issue
• Companion Abstract and Commentary: Apolipoprotein E ε 4 allele was associated with dementia and stroke

Source Citation

Evans DA, Beckett LA, Field TS, et al. Apolipoprotein E ε 4 and incidence of Alzheimer disease in a community population of older persons. JAMA. 1997 Mar 12;277:822-4.



To determine the association between apolipoprotein E (APOE) ε 4 allele and the development of Alzheimer disease in adults > 65 years of age.


Community-based cohort study.


Boston, Massachusetts, USA.


A cohort of 2313 persons who were free of Alzheimer disease at baseline was followed for an average period of 4.3 years and a stratified random sample of 578 persons was evaluated for Alzheimer disease. Sampling was weighted to include fewer adults with little or no decline in memory performance than persons with poor performance. The participants were predominately working class, white, and Italian American.

Assessment of risk factors

APOE genotypes and allele distribution were ascertained in a blinded manner from frozen samples (2% with ε 2/ε 2, 9% with ε 2/ε 3, 1% with ε 2/ε 4, 71% with ε 3/ε 3, 17% with ε 3/ε 4, and 1% with ε 4/ε 4). Risk factors were age, observation interval, sex (men), and APOE ε 2/ε 2 and ε 2/ε 3 genotypes. The ε 3/ε 3 genotype was taken as the reference standard.

Main outcome measures

Probable Alzheimer disease based on the criteria of the Joint Work Group of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association.

Main results

88 persons (9%) developed Alzheimer disease. Only 19 of the 88 patients (22%) who developed Alzheimer disease, however, had APOE ε 4/ε 4 (n = 2) or ε 3/ε 4 (n = 17) genotypes. Sex and APOE ε 2/ε 2 or ε 2/ε 3 genotype were not associated with Alzheimer disease. Multivariate analysis showed that age was not associated with the ε 4 allele (P = 0.89).


The apolipoprotein E ε 4 allele was a risk factor for developing Alzheimer disease.

Source of funding: National Institute on Aging.

For article reprint: Dr. D.A. Evans, Rush Institute on Aging, Suite 675, 1645 West Jackson Boulevard, Chicago, IL 60612, USA. FAX 312-942-2861.

Table. Risk factors for developing Alzheimer disease

Risk factor Odds ratio 95% CI P value
Age (per year) 1.20 1.15 to 1.25 <0.001
Time from baseline to evaluation (per year) 1.77 1.29 to 2.41 <0.001
APOE* ε 4/ε 4 or ε 3/ε 4 2.27 1.06 to 4.89 0.04

*APOE = apolipoprotein E.


The recent discovery of an association between APOE ε 4 and Alzheimer disease has important medical and social implications. Medically, we are now prepared to dissect the biological role of APOE ε 4, and by doing so, we can make hypotheses and devise mechanisms to prevent the disease. Socially, we are faced with the possibility that assessing the genotype of persons may serve as the basis for denial of health benefits or job opportunities on the basis of likely future cognitive dysfunction. A recent study by Johanssen and Bogdanovic (1) suggests that the APOE ε 4 allele is associated with an increased risk for motor vehicle accidents in older persons. Might not insurance companies reasonably insist on higher rates for persons with an unfortunate genetic endowment? The report of recognizable cognitive changes in nuns half a century before the development of frank Alzheimer disease (2) could conceivably be used as a pretext to justify genetic screening for jobs that require intellectual capacity. As it happens, APOE ε 4 is not sufficient or necessary to produce disease. The Alzheimer disease phenotype may represent a final common pathway of degenerative changes that are probably caused by many factors.

The studies by Evans and Slooter and their colleagues attempt to further delineate the risk for dementia attributable to APOE ε 4. Both studies are necessarily retrospective analyses of prospectively collected data because data collection began before the identification of the association between APOE ε 4 and Alzheimer disease (3). The complex sampling strategy for the incidence study by Evans and colleagues is being used with increasing frequency in epidemiologic research. This study shows that the risk attributable to APOE ε 4 may be overstated in the elderly population. The authors excluded patients with Alzheimer disease at baseline. It is very possible that risk attributable to APOE ε 4 was much higher in this excluded group. However, no association between age and APOE ε 4 was found.

The study by Slooter and colleagues suggests that APOE ε 4 may play a role in dementia with stroke and vascular dementias. This hypothesis is attractive because it is known that risk for both conditions is attributable to the vagaries of lipoprotein metabolism. Simultaneously, we are learning that nonsteroidal anti-inflammatory drugs may protect against both conditions, again suggesting mechanistic commonality. The potential weakness of the Slooter study is that the diagnoses of dementia were based on clinical rather than pathologic criteria. These criteria are reliable and valid but the lack of pathologic confirmation may result in imperfect classification of vascular-type dementia. The magnitude of the risk for vascular dementia attributable to homozygous APOE ε 4 was, however, quite large and was found to be greater than in those persons with Alzheimer disease alone. This therefore demands further investigation.

In summary, these 2 studies add to previous research of increased risk for Alzheimer disease associated with the APOE ε allele in large populations. They teach us that the APOE ε allele does not automatically lead to dementia and that the key to prevention of several varieties of dementia may lie in an improved understanding of lipoprotein metabolism.

John Wurzelmann, MD, MPH
ClinTrials Research, Inc.Research Triangle Park, North Carolina, USA

John Wurzelmann, MD, MPH
ClinTrials Research, Inc.
Research Triangle Park, North Carolina, USA


1. Johanssen K, Bogdanovic N. Alzheimer's disease and apolipoprotein E ε 4 in older drivers who die in automobile accidents. Lancet. 1997;349:1143.

2. Snowdon DA, Kemper SJ, Mortimer JA, et al. Linguistic ability in early life and cognitive function and Alzheimer's disease in late life. Findings from the Nun Study. JAMA. 1996;275:528-32.

3. Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology. 1993;43:1467-72.