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Apolipoprotein E (ApoE) is a major cholesterol carrier and plays an important role in maintaining lipid homeostasis. <jats:italic>APOE<\/jats:italic>-\u03b54 constitutes the most important known genetic risk factor for late-onset AD. It has been proposed that the <jats:italic>BCHE-K<\/jats:italic> allele (Ala539Thr) acts in synergy with the <jats:italic>APOE<\/jats:italic>-\u03b54 allele to promote risk for AD. However, there is insufficient evidence to support a correlation. Most studies focused only on the coding regions of the genes. In this study, we analyzed sequence regions beyond the <jats:italic>BCHE<\/jats:italic> coding sequence. We found synergy between <jats:italic>APOE<\/jats:italic>-\u03b54 and SNPs localized in 5\u2032UTR (rs1126680) and in intron 2 (rs55781031) of the <jats:italic>BCHE-K<\/jats:italic> allele (rs1803274) in 18% of patients with late-onset AD (n\u2009=\u200955). The results show that the coexistence of the <jats:italic>APOE<\/jats:italic>-\u03b54 allele and 3 SNPs in the <jats:italic>BCHE<\/jats:italic> gene is associated with a highly elevated risk of late-onset AD. SNP (rs1126680) in 5\u2032UTR of the <jats:italic>BCHE<\/jats:italic> gene is located 32 nucleotides upstream of the 28 amino acid signal peptide. Mass spectrometry analysis of the BChE protein produced by SNP (rs1126680) showed that the mutation caused an in frame N-terminal extension of 41 amino acids of the BChE signal peptide. The resultant variant with a 69 amino acid signal peptide, designated N-BChE, may play a role in development of AD.<\/jats:p>","DOI":"10.1038\/s41598-019-41578-3","type":"journal-article","created":{"date-parts":[[2019,3,26]],"date-time":"2019-03-26T11:03:26Z","timestamp":1553598206000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Synergy between the alteration in the N-terminal region of butyrylcholinesterase K variant and apolipoprotein E4 in late-onset Alzheimer\u2019s disease"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8192-6486","authenticated-orcid":false,"given":"Jacek","family":"Jasiecki","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Limon-Sztencel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3600-5578","authenticated-orcid":false,"given":"Monika","family":"\u017buk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1430-8367","authenticated-orcid":false,"given":"Magdalena","family":"Chmara","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6206-0672","authenticated-orcid":false,"given":"Dominik","family":"Cysewski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Janusz","family":"Limon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3634-7562","authenticated-orcid":false,"given":"Bartosz","family":"Was\u0105g","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,3,26]]},"reference":[{"key":"41578_CR1","unstructured":"Alzheimer\u2019s Disease International (ADI), London, World Alzheimer Report Available at: https:\/\/www.alz.co.uk\/research\/world-report-2018 (2018)."},{"key":"41578_CR2","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1016\/S0140-6736(15)01124-1","volume":"388","author":"P Scheltens","year":"2016","unstructured":"Scheltens, P. et al. 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