Analysis of association between Alzheimer disease and the K variant of butyrylcholinesterase (BCHE-K) Janet M. Grubber a , Ann M. Saunders a , Alison R. Crane-Gatherum a, b , William K. Scott a , Eden R. Martin a , Carol S. Haynes a , P.M. Conneally c , Gary W. Small d , Allen D. Roses a, b , Jonathan L. Haines e , Margaret A. Pericak-Vance a, * a Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA b Genetics Directorate, GlaxoWellcome R&D, Research Triangle Park, North Carolina, NC 27709, USA c Department of Medical and Molecular Genetics, Indiana University, Indianapolis, IN 46202, USA d Department of Psychiatry, UCLA School of Medicine, Los Angeles, CA 90024, USA e Program in Human Genetics, Vanderbilt University, Nashville, TN 37232, USA Received 5 April 1999; received in revised form 10 May 1999; accepted 10 May 1999 Abstract Butyrylcholinesterase (BCHE) is an enzyme expressed in most human tissues. Recently, an increased odds of carrying the K variant of BCHE (BCHE-K) was reported among Alzheimer disease (AD) cases as compared with controls. We tested our data set of 245 sporadic AD cases and 241 controls for an association between BCHE-K, APOE4, and AD using logistic regression and chi-square analyses. The sib transmission disequilibrium test (S-TDT) was also used to test for differ- ences in BCHE-K allele frequencies between 163 discordant sib-pairs selected from multiplex AD families. No statistically signi®cant differences were noted between BCHE-K case and control allele frequencies even after stratifying by APOE4 status. S-TDT analysis between the BCHE-K variant and AD was also not signi®cant (P  0:52). We conclude that BCHE-K is not a major genetic risk factor for AD in our study population. q 1999 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Butyrylcholinesterase gene; Apolipoprotein E; Alzheimer disease; Transmission disequilibrium test; Association; Linkage disequilibrium Alzheimer disease (AD), the leading cause of dementia in Americans aged 65 and older, is a progressive brain disor- der, which occurs gradually and results in memory loss, unusual behavior, personality changes, and an irreversible decline in thinking abilities [11]. To date, four genes which account for approximately half of the genetic risk of AD [5] have been identi®ed: amyloid precursor protein (APP) [6]; presenilin 1 (PS1) [18]; presenilin 2 (PS2) [9,13]; and apoli- poprotein E (APOE) [17]. Mutations in APP, PS1, and PS2 cause the early-onset Mendelian form of AD while APOE is considered a susceptibility gene, where the APOE4 allele increases risk of AD in a dose-dependent fashion [3]. Although a number of additional genes have been examined as possible AD risk factors, ®ndings have been inconsistent, leaving the remaining genetic effect in AD unexplained. Two recent case-control studies [8,15] reported an increased odds of late-onset AD cases carrying the K variant of the butyrylcholinesterase gene (BCHE-K) when compared to control subjects. The association was strongest (OR  15.00, OR  14.40, respectively) among subjects who were carriers of the APOE4 allele. Another study [4] identi®ed a statistically signi®cant association (OR  1.89) between BCHE-K and AD among subjects who did not carry the APOE4 allele. Additional studies [2,7,14,20] failed to con®rm a positive association between BCHE-K and AD. The purpose of the present study was to determine if an association between BCHE-K and AD exists in our data set using two different analysis methods: the traditional unmatched case-control study design and a newly devel- oped family-based association method, the sib transmission disequilibrium test (S-TDT) [21]. The study population for the case-control analyses consisted of 245 AD cases with no reported family history of AD or dementia and 241 unrelated controls. Cases were Neuroscience Letters 269 (1999) 115±119 0304-3940/99/$ - see front matter q 1999 Elsevier Science Ireland Ltd. All rights reserved. PII: S0304-3940(99)00426-7 * Corresponding author. Center for Human Genetics, Duke University Medical Center, DUMC Box 3445, Durham, NC 27710, USA. Tel.: 11-919-684-2063. E-mail address: mpv@chg.mc.duke.edu (M.A. Pericak-Vance)