ORIGINAL ARTICLE Apolipoprotein E polymorphism, homocysteine serum levels and hippocampal volume in patients with alcoholism: an investigation of a gene–environment interaction J Wilhelm 1,3 , H Frieling 1,3 , N von Ahsen 2 , T Hillemacher 1 , J Kornhuber 1 and S Bleich 1 1 Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany and 2 Department of Clinical Chemistry, University of Go ¨ttingen, Erlangen, Germany Correspondence: Dr J Wilhelm, Department of Psychiatry and Psychotherapy, University of Erlangen- Nuremberg, Schwabachanlage 6, D-91054 Erlangen, Germany. E-mail: julia.wilhelm@uk-erlangen.de 3 These authors contributed equally to this work Received 13 September 2006; revised 19 February 2007; accepted 1 March 2007; published online 10 April 2007 There is growing evidence that disadvantageous influences of the apolipo- protein E4 allele in the central nervous system are modified by environmental and dietary conditions. The present study investigated the gene–environ- ment interaction of apolipoprotein E4 with homocysteine serum levels in patients with alcohol dependence with regard to alcohol-related hippo- campal volume loss using volumetric high-resolution magnetic resonance imaging. We included 52 patients with alcohol-dependence. ApoE geno- types, homocysteine serum levels and hippocampal volumes were deter- mined. We found a significant impact of homocysteine (F ¼ 13.2; df ¼ 1; Po0.001; 1b ¼ 0.95), not for ApoE4 genotype (F ¼ 0.482; df ¼ 1; P ¼ 0.49; 1b ¼ 0.05) on hippocampal volume. There was a significant interaction between both factors (ApoE4  Hcy; F ¼ 8.8; df ¼ 1; P ¼ 0.005; 1b ¼ 0.80). The ApoE4 allele constitutes a risk factor for hippocampal volume loss in patients with alcohol dependence under the conditions of hyperhomocys- teinemia. We suggest that the disadvantageous effects of apolipoprotein E4 on alcohol-related brain volume loss are based on certain gene–environment interactions. The Pharmacogenomics Journal (2008) 8, 117–121; doi:10.1038/sj.tpj.6500453; published online 10 April 2007 Keywords: apolipoprotein E; homocysteine; brain atrophy; hippocampal volume loss; alcoholism; gene–environment interactions Introduction Neurodegenerative and neuroregenerative processes in the human central nervous system and their underlying pathophysiological mechanisms including genetic, environmental or dietary influencing factors have been the subject of recent research. The apolipoprotein E gene (ApoE gene) and its alleles (ApoE2, ApoE3, ApoE4) show specific influences on metabolism, growth, degenerative and regenerative processes in nerve tissue and are involved in the development of certain pathological conditions. Clinical studies suggest that the ApoE4 gene variant constitutes a major susceptibility factor for the development of the familial ‘late onset’ 1,2 and sporadic form 3–5 of Alzheimer’s disease (AD) as well as for the so- called tauopathy group of diseases. 6,7 Moreover, the ApoE4 allele predicts a poor outcome after both intracerebral haemmorrhage 8 and traumatic brain injury. 9 The Pharmacogenomics Journal (2008) 8, 117–121 & 2008 Nature Publishing Group All rights reserved 1470-269X/08 $30.00 www.nature.com/tpj