{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T23:17:08Z","timestamp":1791328628096,"version":"4.3.1"},"reference-count":21,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5500","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[2000,12,22]]},"abstract":"<jats:p>\n            Recent studies suggest that insulin-degrading enzyme (IDE) in neurons and microglia degrades A\u03b2, the principal component of \u03b2-amyloid and one of the neuropathological hallmarks of Alzheimer's disease (AD). We performed parametric and nonparametric linkage analyses of seven genetic markers on chromosome 10q, six of which map near the\n            <jats:italic>IDE<\/jats:italic>\n            gene, in 435 multiplex AD families. These analyses revealed significant evidence of linkage for adjacent markers (D10S1671, D10S583, D10S1710, and D10S566), which was most pronounced in late-onset families. Furthermore, we found evidence for allele-specific association between the putative disease locus and marker D10S583, which has recently been located within 195 kilobases of the\n            <jats:italic>IDE<\/jats:italic>\n            gene.\n          <\/jats:p>","DOI":"10.1126\/science.290.5500.2302","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T09:47:44Z","timestamp":1027763264000},"page":"2302-2303","source":"Crossref","is-referenced-by-count":398,"title":["Evidence for Genetic Linkage of Alzheimer's Disease to Chromosome 10q"],"prefix":"10.1126","volume":"290","author":[{"given":"Lars","family":"Bertram","sequence":"first","affiliation":[{"name":"Genetics and Aging Unit, Department of Neurology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Blacker","sequence":"additional","affiliation":[{"name":"Gerontology Research Unit, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA."},{"name":"Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Mullin","sequence":"additional","affiliation":[{"name":"Genetics and Aging Unit, Department of Neurology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devon","family":"Keeney","sequence":"additional","affiliation":[{"name":"Genetics and Aging Unit, Department of Neurology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Jones","sequence":"additional","affiliation":[{"name":"Genetics and Aging Unit, Department of Neurology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Basu","sequence":"additional","affiliation":[{"name":"Genetics and Aging Unit, Department of Neurology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Yhu","sequence":"additional","affiliation":[{"name":"Genetics and Aging Unit, Department of Neurology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melvin G.","family":"McInnis","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Johns Hopkins University Medical Institutions, Baltimore, MD 21287, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodney C. P.","family":"Go","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, School of Public Health, University of Alabama, Birmingham, AL 35294, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Vekrellis","sequence":"additional","affiliation":[{"name":"Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis J.","family":"Selkoe","sequence":"additional","affiliation":[{"name":"Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleister J.","family":"Saunders","sequence":"additional","affiliation":[{"name":"Genetics and Aging Unit, Department of Neurology,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolph E.","family":"Tanzi","sequence":"additional","affiliation":[{"name":"Genetics and Aging Unit, Department of Neurology,"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","reference":[{"key":"e_1_3_1_2_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.20-05-01657.2000"},{"key":"e_1_3_1_3_2","unstructured":"Subjects were collected as part of the NIMH Genetics Initiative following a standardized protocol applying NINCDS\/ADRDA (National Institute of Neurological and Communicative Disorders and Stroke\/Alzheimer's Disease and Related Disorders Association) criteria for the diagnosis of AD (3). Only families in which all sampled affected individuals had onset ages \u226550 years were included ( n = 435 families n = 1426 subjects mean age of onset = 72.5 \u00b1 7.7 years range 50 to 97 years). Additional information on the procedures is available as supplemental material (12)."},{"key":"e_1_3_1_4_2","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1212\/WNL.48.1.139","volume":"48","author":"Blacker D.","year":"1997","unstructured":"Blacker D., et al., Neurology 48, 139 (1997).","journal-title":"Neurology"},{"key":"e_1_3_1_5_2","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1093\/hmg\/8.2.237","volume":"8","author":"Kehoe P.","year":"1999","unstructured":"Kehoe P., et al., Hum. Mol. Genet. 8, 237 (1999).","journal-title":"Hum. Mol. Genet."},{"key":"e_1_3_1_6_2","unstructured":"A. J. Myers et al. Neurobiol. Aging 21 (suppl.) S103 (2000)."},{"key":"e_1_3_1_7_2","first-page":"252","volume":"53","author":"Cottingham R. W.","year":"1993","unstructured":"Cottingham R. W., Idury R. M., Schaffer A. A., Am. J. Hum. Genet. 53, 252 (1993).","journal-title":"Am. J. Hum. Genet."},{"key":"e_1_3_1_8_2","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1159\/000154222","volume":"44","author":"Schaffer A. A.","year":"1994","unstructured":"Schaffer A. A., Gupta S. K., Shriram K., Cottingham R. W., Hum. Hered. 44, 225 (1994).","journal-title":"Hum. Hered."},{"key":"e_1_3_1_9_2","first-page":"1347","volume":"58","author":"Kruglyak L.","year":"1996","unstructured":"Kruglyak L., Daly M. J., Reeve-Daly M. P., Lander E. S., Am. J. Hum. Genet. 58, 1347 (1996).","journal-title":"Am. J. Hum. Genet."},{"key":"e_1_3_1_10_2","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1086\/301592","volume":"61","author":"Kong A.","year":"1997","unstructured":"Kong A., Cox N. J., Am. J. Hum. Genet. 61, 1179 (1997).","journal-title":"Am. J. Hum. Genet."},{"key":"e_1_3_1_11_2","unstructured":"Version 1.0 applying the exponential model."},{"key":"e_1_3_1_12_2","unstructured":"Disease gene frequencies were set to 0.01 in the dominant model and to 0.05 in the recessive model. Penetrance in affected individuals corresponded to phenocopy rates of 5% for definite AD ( n = 278) 10% for probable AD ( n = 645) and 14% for possible AD ( n = 65). Families were classified as \u201clate-onset\u201d when all sampled affected individuals had onset ages \u226565 years as \u201c APOE \u03b54\/4-positive\u201d if at least one affected individual had the \u03b54\/4 genotype and as \u201c APOE \u03b54\/4-negative\u201d otherwise. Parametric analyses were performed on affected individuals only."},{"key":"e_1_3_1_13_2","unstructured":"Supplementary data are available at Science Online at www.sciencemag.org\/cgi\/content\/full\/290\/5500\/2302\/DC1."},{"key":"e_1_3_1_14_2","unstructured":"Intermarker distances are according to marker locations from Marshfield except for interval D10S566 to D10S1671 where 0.7 cM was used according to the MAP-O-MAT program ()."},{"key":"e_1_3_1_15_2","unstructured":"The list of individuals included in Myers et al. (5) was supplied by P. Holmans."},{"key":"e_1_3_1_16_2","unstructured":"GenBank accession number ."},{"key":"e_1_3_1_17_2","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1159\/000022918","volume":"50","author":"Rabinowitz D.","year":"2000","unstructured":"Rabinowitz D., Laird N., Hum. Hered. 50, 211 (2000).","journal-title":"Hum. Hered."},{"key":"e_1_3_1_18_2","unstructured":"Analyses are based on estimated empirical variances (to account for the presence of linkage) (20) as implemented in FBAT (version 1.0 1999) under an additive disease model."},{"key":"e_1_3_1_19_2","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1086\/302528","volume":"65","author":"Roberts S. B.","year":"1999","unstructured":"Roberts S. B., MacLean C. J., Neale M. C., Eaves L. J., Kendler K. S., Am. J. Hum. Genet. 65, 876 (1999).","journal-title":"Am. J. Hum. Genet."},{"key":"e_1_3_1_20_2","first-page":"A278","volume":"61","author":"Hauser E. R.","year":"1997","unstructured":"Hauser E. R., Boehnke M., Am. J. Hum. Genet. 61, A278 (1997).","journal-title":"Am. J. Hum. Genet."},{"key":"e_1_3_1_21_2","doi-asserted-by":"crossref","first-page":"1515","DOI":"10.1086\/316895","volume":"67","author":"Lake S. L.","year":"2000","unstructured":"Lake S. L., Blacker D., Laird N. M., Am. J. Hum. Genet. 67, 1515 (2000).","journal-title":"Am. J. Hum. Genet."},{"key":"e_1_3_1_22_2","unstructured":"We thank T. Moscarillo for analytical assistance. We thank all families for their participation and the staff at NIMH and at all three sites for assistance with all aspects of the project. The NIMH study involves three research teams in collaboration with NIMH extramural staff. The principal investigators (PIs) and co-PIs at each site are as follows: Massachusetts General Hospital: M. S. Albert R.E.T. and D.B.; Johns Hopkins University: S. Bassett G. A. Chase and M. F. Folstein; and the University of Alabama: R.C.P.G. and L. E. Harrell. This work was sponsored by grants from the NIMH and National Institute on Aging (NIA) (Alzheimer's Disease Research Center). L.B. is a fellow of the Deutsche Forschungsgemeinschaft. A.J.S. is an NIA\u2013National Research Service Awards recipient."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.290.5500.2302","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T09:55:33Z","timestamp":1705139733000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.290.5500.2302"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2000,12,22]]},"references-count":21,"journal-issue":{"issue":"5500","published-print":{"date-parts":[[2000,12,22]]}},"alternative-id":["10.1126\/science.290.5500.2302"],"URL":"https:\/\/doi.org\/10.1126\/science.290.5500.2302","relation":{},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2000,12,22]]}}}