03451nas a2200349 4500008004100000022001400041245011600055210006900171260001600240300000900256490000800265520247500273653000902748653001002757653001202767653002202779653002802801653002402829653001902853653002202872653001302894653001102907653002702918653002402945653001702969100001502986700001703001700001703018700001703035700001403052856003503066 1999 eng d a0098-748400aThe role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons.0 arole of APOE epsilon4 in modulating effects of other risk factor c1999 Jul 07 a40-60 v2823 a

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.

10aAged10aAging10aAlleles10aApolipoproteins E10aCardiovascular Diseases10aCognition Disorders10aCohort Studies10aDiabetes Mellitus10aGenotype10aHumans10aMental Status Schedule10aProspective Studies10aRisk Factors1 aHaan, M, N1 aShemanski, L1 aJagust, W, J1 aManolio, T A1 aKuller, L uhttps://chs-nhlbi.org/node/59703163nas a2200337 4500008004100000022001400041245008900055210006900144260001600213300001200229490000700241520223900248653000902487653002202496653002202518653002202540653002102562653003302583653001102616653001302627653001102640653002702651653002902678653001702707100001302724700001202737700001302749700001402762700001402776856003502790 2000 eng d a0028-387800aEstrogen use, APOE, and cognitive decline: evidence of gene-environment interaction.0 aEstrogen use APOE and cognitive decline evidence of geneenvironm c2000 May 23 a1949-540 v543 a

OBJECTIVE: APOE-epsilon4 increases the risk of cognitive decline, while elderly women who take estrogen may have less risk of cognitive decline. The authors sought to determine whether estrogen use modifies the association between APOE-epsilon4 and cognitive decline.

METHOD: - As part of the Cardiovascular Health Study, 3,393 Medicare-eligible women (> or =65 years) were randomly selected and recruited from Sacramento County, CA; Washington County, MD; Forsyth County, NC; and Pittsburgh, PA. Cognitive testing was administered annually; the authors studied the 2,716 women with cognitive testing on > or =2 visits. They analyzed change in score on the Modified Mini-Mental State Examination (3MS) as a function of estrogen use, APOE genotype, and baseline common and internal carotid artery wall thickening.

RESULTS: A total of 297 (11%) women were current estrogen users and 336 (12%) were past estrogen users. Over the 6-year average follow-up, baseline current users declined 1.5 points on the 3MS whereas never users declined 2.7 points (p = 0.023). Compared with epsilon4-negative women, epsilon4-positive women had a greater adjusted hazard ratio of cognitive impairment (3MS < 80), hazard risk [HR] = 1.47; 95% CI, 1.13 to 1.90. There was an interaction between estrogen use and epsilon4 presence (p = 0.037). Among epsilon4-negative women, current estrogen use reduced the risk of adjusted cognitive impairment compared with never users by almost half (HR = 0.59; 95% CI, 0.36 to 0.99), whereas, it did not reduce the risk among epsilon4-positive women (current use, HR = 1.33; 95% CI, 0.74 to 2.42). Compared with never use, current estrogen use was associated with less internal and common carotid wall thickening in epsilon4-negative women but not in epsilon4-positive women (p for interaction < 0.05 for both). Differences remained after adjusting for age, education, race, and stroke.

CONCLUSIONS: Estrogen use was associated with less cognitive decline among epsilon4-negative women but not epsilon4-positive women. Potential mechanisms, including carotid atherosclerosis, by which epsilon4 may interact with estrogen and cognition warrant further investigation.

10aAged10aAlzheimer Disease10aApolipoprotein E410aApolipoproteins E10aCarotid Stenosis10aEstrogen Replacement Therapy10aFemale10aGenotype10aHumans10aMental Status Schedule10aNeuropsychological Tests10aRisk Factors1 aYaffe, K1 aHaan, M1 aByers, A1 aTangen, C1 aKuller, L uhttps://chs-nhlbi.org/node/617