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While <jats:italic>APOE<\/jats:italic> is known to be an age\u2010at\u2010onset modifier, it does not explain all of this variation. We performed a genome scan within nine such families for loci influencing age\u2010at\u2010onset, while simultaneously controlling for variation in the primary <jats:italic>PSEN2<\/jats:italic> mutation (N141I) and <jats:italic>APOE<\/jats:italic>. We found significant evidence of linkage between age\u2010at\u2010onset and chromosome 1q23.3 (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001) when analysis included all families, and to chromosomes 1q23.3 (<jats:italic>P<\/jats:italic>\u2009&lt;\u20090.001), 17p13.2 (<jats:italic>P<\/jats:italic>\u2009=\u20090.0002), 7q33 (<jats:italic>P<\/jats:italic>\u2009=\u20090.017), and 11p14.2 (<jats:italic>P<\/jats:italic>\u2009=\u20090.017) in a single large pedigree. Simultaneous analysis of these four chromosomes maintained strong evidence of linkage to chromosomes 1q23.3 and 17p13.2 when all families were analyzed, and to chromosomes 1q23.3, 7q33, and 17p13.2 within the same single pedigree. Inclusion of major gene covariates proved essential to detect these linkage signals, as all linkage signals dissipated when <jats:italic>PSEN2<\/jats:italic> and <jats:italic>APOE<\/jats:italic> were excluded from the model. The four chromosomal regions with evidence of linkage all coincide with previous linkage signals, associated SNPs, and\/or candidate genes identified in independent AD study populations. This study establishes several candidate regions for further analysis and is consistent with an oligogenic model of AD risk and age\u2010at\u2010onset. More generally, this study also demonstrates the value of searching for modifier loci in existing datasets previously used to identify primary causal variants for complex disease traits. \u00a9 2010 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/ajmg.b.31072","type":"journal-article","created":{"date-parts":[[2010,3,23]],"date-time":"2010-03-23T15:29:50Z","timestamp":1269358190000},"page":"1031-1041","source":"Crossref","is-referenced-by-count":24,"title":["Evidence for three loci modifying age\u2010at\u2010onset of Alzheimer's disease in early\u2010onset <i>PSEN2<\/i> families"],"prefix":"10.1002","volume":"153B","author":[{"given":"Elizabeth E.","family":"Marchani","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas D.","family":"Bird","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen J.","family":"Steinbart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth","family":"Rosenthal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang\u2010En","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard D.","family":"Schellenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ellen M.","family":"Wijsman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2010,6,24]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1186\/1755-8794-1-44"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrg1916"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.12.008"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.1320600102"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1934"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2008.10.008"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410230106"},{"key":"e_1_2_6_9_1","first-page":"229","article-title":"Characteristics of familial Alzheimer's disease in nine kindreds of Volga German ancestry","volume":"317","author":"Bird TD","year":"1989","journal-title":"Prog Clin Biol Res"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410400619"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg007"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/geront\/43.2.158"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1086\/302011"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.2105\/AJPH.88.9.1337"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2009.03.013"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1086\/302553"},{"issue":"6","key":"e_1_2_6_17_1","first-page":"899","article-title":"Canadian study of health and aging: Study methods and prevalence of dementia","volume":"150","author":"Canadian Study of Health and Aging Working Group","year":"1994","journal-title":"CMAJ"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neulet.2004.01.016"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.4088\/JCP.v68n0419"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.8346443"},{"issue":"1","key":"e_1_2_6_21_1","first-page":"252","article-title":"Faster sequential genetic\u2010linkage computations","volume":"53","author":"Cottingham RW","year":"1993","journal-title":"Am J Hum Genet"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1086\/302276"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1086\/302710"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-1809.2008.00449.x"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1086\/340732"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0749-0690(05)70066-5"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.b.30689"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00688180"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb960"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.2105\/AJPH.84.8.1261"},{"issue":"18","key":"e_1_2_6_31_1","doi-asserted-by":"crossref","first-page":"2551","DOI":"10.1001\/jama.1989.03430180093036","article-title":"Prevalence of Alzheimer's disease in a community population of older persons. 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