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


Apolipoprotein E ε 4 allele was associated with dementia and stroke

ACP J Club. 1997 Sep-Oct;127:48. doi:10.7326/ACPJC-1997-127-2-048

Related Content in this Issue
• Companion Abstract and Commentary: Apolipoprotein E ε 4 allele was a risk factor for Alzheimer disease

Source Citation

Slooter AJ, Tang MX, van Duijn CM, et al. Apolipoprotein E ε 4 and the risk of dementia with stroke. A population-based investigation. JAMA. 1997 Mar 12;277:818-21.



To determine the association between the apolipoprotein E (APOE) genotypes and dementia in patients with stroke.


2 population-based case-control studies (Rotterdam Study and Washington Heights Study).


The Netherlands and New York, USA.


6315 patients were screened for inclusion. 187 patients (mean age 81 y, 73% women, 52% white) with stroke (World Health Organization criteria plus interviews, neurologic examination, and brain imaging) and dementia (Diagnostic and Statistical Manual of Mental Disorders, 3d edition, Revised (DSM-III-R)) were included. The diagnosis of Alzheimer disease was based on the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association. Exclusion criteria were Alzheimer disease alone or dementia from other causes. The 507 control patients (mean age 77 y, 60% women, 58% white) did not have dementia and were matched for age and ethnic group (3 per patient).

Assessment of risk factors

APOE genotypes (ε 3/ε 3, ε 2/ε 2, ε 2/ε 3, ε 2/ε 4, ε 3/ε 4, ε 4/ε 4) were ascertained in a blinded fashion using a polymerase chain reaction assay. The ε 3/ε 3 genotype was used as the reference standard.

Main outcome measures

Dementia with stroke (n = 187). Dementia was defined as vascular dementia (n = 90), Alzheimer disease with cardiovascular disease (n = 70), or unclassified dementia (n = 27).

Main results

The data from the sites were similar and therefore were pooled. Adjustment was made for age, sex, residency, and education. Dementia with stroke was associated with the APOE ε 3/ε 4 genotype (odds ratio [OR] 1.8, 95% CI 1.2 to 2.7, P < 0.05) and the APOE ε 4/ε 4 genotype (OR 6.9, CI 1.6 to 29.4, P < 0.005). Vascular dementia with stroke was associated with the APOE ε 4/ε 4 genotype (OR 10.5, CI 2.4 to 46.6). Alzheimer disease with cardiovascular disease was associated with the ε 3/ε 4 genotype (OR 22, CI 1.2 to 3.8). The APOE ε 4/ε 4 allele was associated with dementia for African Americans and Hispanics (OR 10.7, CI 1.1 to 80.4, P < 0.002) and whites (OR 2.2, CI 1.8 to 3.9, P < 0.007). Associations were similar in men and women and did not vary for increasing age.


The apolipoprotein E ε 4 allele was associated with dementia with stroke, including either vascular dementia or Alzheimer disease with cardiovascular disease. Sex and age did not change the association.

Sources of funding: The Rotterdam Study: NESTOR Stimulation Program for Geriatric Research in the Netherlands; the Netherlands Prevention Fund; Municipality of Rotterdam; The Washington Heights Study: National Institutes of Health; Charles S. Robertson Memorial Gift; Blanchette Hooker Rockefeller Fund.

For article reprint: Dr. R. Mayeux, Gertrude H. Sergievsky Center, Columbia University, 630 West 168th Street, New York, NY 10032, USA. FAX 212-305-2515.


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 APOEε 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.