The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons

JAMA. 1999 Jul 7;282(1):40-6. doi: 10.1001/jama.282.1.40.


Context: Cognitive decline in elderly persons is often an early predictor of dementia. Subclinical cardiovascular disease (CVD) and diabetes mellitus may contribute to substantial decline in cognitive function in the elderly. These risks may be modified by gene-environment interactions between apolipoprotein E (APOE) genotype and CVD risk factors or subclinical CVD.

Objectives: To examine the association between subclinical CVD and decline in cognitive functioning in the elderly and to examine effect modification by the APOE genotype of the association between subclinical disease and cognitive decline.

Design: The Cardiovascular Health Study, a population-based, prospective cohort study.

Setting and population: A total of 5888 randomly selected Medicare-eligible participants from Sacramento County, California; Forsyth County, North Carolina; Washington County, Maryland; and Pittsburgh, Pa, aged 65 years or older, who were recruited in 1989-1990 (n = 5201) and in 1992-1993 (n = 687) and who were followed up for 7 and 5 years, respectively.

Main outcome measures: Change over time in scores on the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test as a function of APOE genotype, subclinical CVD, and diabetes mellitus.

Results: Seventy percent of participants had no significant decline on the Modified Mini-Mental State Examination. Systolic blood pressure, the ankle-arm brachial index, atherosclerosis of the internal carotid artery, diabetes mellitus, and several diagnoses of prevalent CVD were significantly associated with declines in scores on the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test. The rate of cognitive decline associated with peripheral vascular disease, atherosclerosis of the common and internal carotid arteries, or diabetes mellitus was increased by the presence of any APOE epsilon4 allele.

Conclusions: Most healthy elderly people did not experience cognitive decline. Measures of subclinical CVD were modest predictors of cognitive decline. Those with any APOE epsilon4 allele in combination with atherosclerosis, peripheral vascular disease, or diabetes mellitus were at substantially higher risk of cognitive decline than those without the APOE epsilon4 allele or subclinical CVD. High levels of atherosclerosis increased cognitive decline independently of APOE genotype.

MeSH terms

  • Aged
  • Aging / physiology*
  • Alleles
  • Apolipoproteins E / genetics*
  • Cardiovascular Diseases / genetics
  • Cardiovascular Diseases / physiopathology
  • Cognition Disorders / diagnosis
  • Cognition Disorders / etiology
  • Cognition Disorders / genetics*
  • Cohort Studies
  • Diabetes Mellitus / genetics
  • Diabetes Mellitus / physiopathology
  • Genotype
  • Humans
  • Mental Status Schedule
  • Prospective Studies
  • Risk Factors


  • Apolipoproteins E