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From the Department of Psychology (M.R.S., M.J.L., M.D.G.), Boston University, MA; Department of Psychiatry (C.E.F., W.S.K.) and Center for Behavioral Genomics (W.S.K.), University of California, San Diego; The Institute for Rehabilitation and Research (C.B.), Houston, TX; Department of Psychiatry (K.C.J.), University of Chicago, IL; Research Service (H.X., S.A.E.) and Medical Service (S.A.E.), St. Louis VA Medical Center, MO; Departments of Internal Medicine (H.X., S.A.E.) and Psychiatry (S.A.E.), Washington University School of Medicine, St. Louis, MO; VA Puget Sound Healthcare System (G.D.S.); and Division of Gerontology and Geriatric Medicine (G.D.S.), Department of Medicine, and Departments of Neurology and Pharmacology (G.D.S.), University of Washington, Seattle.
Address correspondence and reprint requests to Dr. William S. Kremen, Department of Psychiatry, Center for Behavioral Genomics, University of California, San Diego, 9500 Gilman Drive (MC 0738), La Jolla, CA 92093-0738 wkremen{at}ucsd.edu
Background: Virtually all adult studies of APOE genotypes and cognition have included individuals over 60. In older adults, 
4 carriers may manifest greater cognitive asymmetries than non-4 carriers even in the absence of overall mean differences. General cognitive ability may also be affected by aging and APOE genotype, but most studies have inadequately addressed this potential confound. The goals of this study were to examine, in middle age, the relationship of APOE genotype with episodic memory and verbal-visuospatial episodic memory asymmetries, after accounting for prior general cognitive ability.
Method: We compared 4+ and 4– individuals in 626 male twins in their 50s. We examined verbal and visuospatial episodic memory and verbal-visual asymmetry scores after adjusting for cognitive ability at age 20. Analyses corrected for correlations between twin pair members.
Results: Compared with 4– individuals, 4 carriers performed significantly more poorly on verbal, but not visuospatial memory, manifested significantly greater cognitive asymmetry, and also had significantly more concerns about memory. At age 20, 4 carriers had higher general cognitive ability than 4– individuals, and current memory differences were enhanced after adjusting for age 20 cognitive ability.
Conclusions: Small, but significant, APOE-4-related memory deficits appear in the sixth decade of life in individuals who show no signs of preclinical dementia. The results partially support studies of older adults that suggest that increased cognitive asymmetries reflect risk for dementia and are associated with the APOE-4 genotype. The results also highlight the potential problems of not having accurate data on prior cognitive ability.
Abbreviations: AD = Alzheimer disease; AFQT = Armed Forces Qualification Test; CES-D = Center for Epidemiologic Studies Depression Scale; VETSA = Vietnam Era Twin Study of Aging; WMS-III = Wechsler Memory Scale.
e-Pub ahead of print on January 30, 2008, at www.neurology.org.
Disclosure: The authors report no conflicts of interest.
Received March 20, 2007. Accepted in final form August 14, 2007.
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