Please cite this article in press as: Espeseth, T. et al., Accelerated age-related cortical thinning in healthy carriers of apolipoprotein E 4, Neurobiol Aging (2006), doi:10.1016/j.neurobiolaging.2006.10.030 ARTICLE IN PRESS NBA-6689; No. of Pages 12 Neurobiology of Aging xxx (2006) xxx–xxx Accelerated age-related cortical thinning in healthy carriers of apolipoprotein E 4 Thomas Espeseth a,∗ , Lars T. Westlye a , Anders M. Fjell a , Kristine B. Walhovd a , Helge Rootwelt b , Ivar Reinvang a a Department of Psychology, University of Oslo, P.O. Box 1094, Blindern, N-0317 Oslo, Norway b Department of Medical Biochemistry, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway Received 19 May 2006; received in revised form 24 October 2006; accepted 30 October 2006 Abstract Effects of APOE genotype on age-related slopes of cortical thinning was estimated by measuring the thickness of the cerebral cortex on a point-by-point basis across the cortical mantle in 96 healthy non-demented volunteers aged 48–75 years. Fifty nine were APOE 4- (no 4 allele) and 37 were 4+ (1 or 2 4 alleles). The genotype groups had similar age, sex and IQ. Two T 1 -weighted MP-RAGE sequences were averaged for each participant to yield images with high signal-to-noise ratio, and quantified using semi-automated analysis tools. 4 carriers had thicker cortex than non-carriers in several frontal and temporal areas in both hemispheres, but showed a steeper age-related decline in adjacent areas. Upon comparison of the 4-specific age-related thinning with previously published patterns of thinning in normal aging and Alzheimer’s disease (AD), we conclude that APOE 4 may function to accelerate thinning in areas found to decline in aging (medial prefrontal and pericentral cortex), but also to initiate thinning in areas associated with AD and amyloid- aggregation (occipitotemporal and basal temporal cortex). © 2006 Published by Elsevier Inc. Keywords: Apolipoprotein E; Cortical morphometry; Brain aging; Individual differences; Alzheimer’s disease 1. Introduction Gray and white matter volumes shrink with age (Bartzokis et al., 2003; Resnick et al., 2003) and the efficiency of many perceptual and cognitive functions decline in adult aging (e.g. Dobbs and Rule, 1989; Salthouse, 1996). Despite this general trend, there is considerable individual variation, and although many environmental factors modulate brain aging (Raz et al., 2005) genes also play a major role. Twin studies have shown that genetic factors contribute substantially to normal variation in brain volume (Toga and Thompson, 2005) and that heritability is generally high also in old age, but differs between structures (Pfefferbaum et al., 2001, 2000; Sullivan et al., 2001). Candidate gene allelic association methods have been used to address the issue of ∗ Corresponding author. Tel.: +47 22845135; fax: +47 22845096. E-mail address: thomas.espeseth@psykologi.uio.no (T. Espeseth). specific genes involved in individual variation, and one of the most widely studied genes is the apolipoprotein E gene (APOE). The three APOE alleles, 2, 3 and 4, produce three isoforms of a protein (ApoE) that delivers lipids to neurons in the service of synaptogenesis (Mauch et al., 2001). Inheritance of 4 is associated with increased risk of AD in a gene dose dependent manner (Corder et al., 1993). In animals, the 4 allele has been associated with impaired repair mechanisms following lesions (Teter et al., 2002). In humans, the 4 is associated with reduced brain integrity following many kinds of neural insult (Fazekas et al., 2001; Sundstrom et al., 2004) and 4 is also associated with reduc- tion in cerebral glucose metabolism (Reiman et al., 1996) and reduced cognitive functioning in healthy middle-aged adults (Flory et al., 2000; Greenwood et al., 2000). It has been suggested that APOE may be primarily characterized as a gene involved in neuronal plasticity and repair, and only secondarily as an AD susceptibility gene (Greenwood and 0197-4580/$ – see front matter © 2006 Published by Elsevier Inc. doi:10.1016/j.neurobiolaging.2006.10.030