Submitted to: Neurology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/8/2004
Publication Date: 1/25/2005
Citation: Blair, C.K., Folsom, A.R., Knopman, D.S., Bray, M.S., Mosley, T.H., Boerwinkle, E. 2005. APOE genotype and cognitive decline in a middle-aged cohort. Neurology. 64:268-276. Interpretive Summary: APOE is a gene that influences cholesterol levels, a type of fat that is found in the blood. When cholesterol levels are high, this fat can accumulate on the inside of blood vessels. Some scientists have proposed that the APOE gene may be related to diseases that are associated with accumulation of fatty deposits on vessel walls, such as heart disease (where fatty deposits accumulate in the heart) and Alzheimer’s disease (where deposits can accumulate in the brain). We investigated whether variation in the DNA sequence of the APOE gene is related to mental function in a large group of adults. We found that two particular forms of the APOE gene, called epsilon 2 and epsilon 4, were associated with poorer mental function compared to other forms of the gene. Such discoveries may help doctors and scientists to identify individuals that may be at risk for the development of diseases like Alzheimer’s disease.
Technical Abstract: BACKGROUND: Most longitudinal studies of nondemented persons have reported greater cognitive decline among APOE epsilon4 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 (epsilon2/2 + epsilon2/3, epsilon3/3 (referent), epsilon4/2 + epsilon4/3, epsilon4/4). 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 epsilon2 group to the epsilon4/4 group in Caucasians for two of the three tests. The combination of APOE epsilon4 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 epsilon4 is associated with greater cognitive decline in middle-aged Caucasian individuals, with a reduced decline among epsilon2 carriers. This suggests that the processes by which APOE genotype mediates dementia risk are operative well in advance of overt dementia.