Multiple SNPs Within and Surrounding the Apolipoprotein E Gene Influence Cerebrospinal Fluid Apolipoprotein E Protein Levels

Article type: Research Article

Authors: Bekris, Lynn M.^{a; b; *} | Millard, Steven P.^{a; c} | Galloway, Nichole M.^a | Vuletic, Simona^d | Albers, John J.^d | Li, Ge^e | Galasko, Douglas R.^f | DeCarli, Charles^g | Farlow, Martin R.^h | Clark, Chris M.ⁱ | Quinn, Joseph F.^{j; k} | Kaye, Jeffrey A.^j | Schellenberg, Gerard D.^{a; l} | Tsuang, Debby^{c; e} | Peskind, Elaine R.^{c; e} | Yu, Chang-En^{a; b}

Affiliations: [a] Geriatric Research, Education, and Clinical Center (GRECC) VA Puget Sound Health Care System, Seattle, WA, USA | [b] Department of Medicine, University of Washington, Seattle, WA, USA | [c] Northwest Network VISN-20 Mental Illness Research, Education and Clinical Center (MIRECC), University of Washington School of Medicine, Seattle, WA, USA | [d] Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington School of Medicine, Seattle, WA, USA | [e] Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA | [f] Department of Neurosciences, University of California at San Diego and VA Medical Center, San Diego, CA, USA | [g] Department of Neurology, University of California at Davis, Sacramento, CA, USA | [h] Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA | [i] Department of Neurology, Institute on Aging, University of Pennsylvania, Philadelphia, PA, USA | [j] Department of Neurology, Oregon Health and Science University, Portland, OR, USA | [k] Portland VA Medical Center, Portland, OR, USA | [l] Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA

Correspondence: [*] Corresponding author: Lynn M. Bekris, Ph.D., University of Washington Department of Medicine, Box 358280 VAPSHCS GRECC 182B, 1660 South Columbian Way, Seattle, Washington 98108, USA. Tel.: +1 206 277 645; Fax: +1 206 764 2569; E-mail: lbekris@u.washington.edu.

Abstract: The ε4 allele of the apolipoprotein E gene (APOE) is associated with increased risk and earlier age at onset in late onset Alzheimer's disease (AD). Other factors, such as expression level of apolipoprotein E protein (apoE), have been postulated to modify the APOE related risk of developing AD. Multiple loci in and outside of APOE are associated with a high risk of AD. The aim of this exploratory hypothesis generating investigation was to determine if some of these loci predict cerebrospinal fluid (CSF) apoE levels in healthy non-demented subjects. CSF apoE levels were measured from healthy non-demented subjects 21–87 years of age (n=134). Backward regression models were used to evaluate the influence of 21 SNPs, within and surrounding APOE, on CSF apoE levels while taking into account age, gender, APOE ε4 and correlation between SNPs (linkage disequilibrium). APOE ε4 genotype does not predict CSF apoE levels. Three SNPs within the TOMM40 gene, one APOE promoter SNP and two SNPs within distal APOE enhancer elements (ME1 and BCR) predict CSF apoE levels. Further investigation of the genetic influence of these loci on apoE expression levels in the central nervous system is likely to provide new insight into apoE regulation as well as AD pathogenesis.

Keywords: Apolipoprotein E gene, apolipoprotein E protein, cerebroshinal fluid, enhancer, promoter, SNP

DOI: 10.3233/JAD-2008-13303

Journal: Journal of Alzheimer's Disease, vol. 13, no. 3, pp. 255-266, 2008