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APOE genotype and cognitive decline in a middle-aged cohort

From the Division of Epidemiology (Dr. Folsom, C.K. Blair), School of Public Health, University of Minnesota, Minneapolis; Department of Neurology (Dr. Knopman), Mayo Clinic, Rochester, MN; Children’s Nutrition Research Center (Dr. Bray), Department of Pediatrics, Baylor College of Medicine, Houston; Department of Medicine (Geriatrics) (Dr. Mosley), University of Mississippi Medical Center, Jackson; and Human Genetics Center and Institute of Molecular Medicine (Dr. Boerwinkle), Houston Health Sciences Center, University of Texas, Houston.

Address correspondence and reprint requests to Dr. A.R. Folsom, Division of Epidemiology, University of Minnesota, 1300 S. Second St., Suite 300, Minneapolis, MN 55454; e-mail: folsom{at}epi.umn.edu

Background: Most longitudinal studies of nondemented persons have reported greater cognitive decline among APOE 4 carriers vs noncarriers. However, most studies involved elderly samples (aged 65+) and were not large enough to examine the three APOE alleles separately.

Methods: Change in cognitive function was examined over a 6-year period using three neuropsychological tests among four APOE genotype groups (2/2 + 2/3, 3/3 (referent), 4/2 + 4/3, 4/4). The population-based sample included 1,693 African Americans and 6,202 Caucasians initially ages 47 to 68.

Results: There was increasingly greater cognitive decline from the 2 group to the 4/4 group in Caucasians for two of the three tests. The combination of APOE 4 with hypercholesterolemia or diabetes showed the greatest cognitive decline. Among African Americans, only the test measuring psychomotor speed showed associations with APOE genotype.

Conclusions: APOE 4 is associated with greater cognitive decline in middle-aged Caucasian individuals, with a reduced decline among 2 carriers. This suggests that the processes by which APOE genotype mediates dementia risk are operative well in advance of overt dementia.

Supported by contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022 from the National Heart, Lung, and Blood Institute, NIH, as well as by contracts UR6/CCU617218 and HL073366.

Received May 10, 2004. Accepted in final form October 8, 2004.

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