Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 71, Issue 1, Pages 154-161Publisher
UNIV CHICAGO PRESS
DOI: 10.1086/341034
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Funding
- NCRR NIH HHS [RR03655, P41 RR003655] Funding Source: Medline
- NHGRI NIH HHS [R01 HG001577, R29 HG001577, HG01577] Funding Source: Medline
- NIMH NIH HHS [U01 MH046373, U01 MH046281, U01 MH046290] Funding Source: Medline
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We used a covariate-based linkage method to reanalyze genome scan data from affected sibships collected by the Alzheimer Disease (AD) Genetics Initiative of the National Institute of Mental Health. As reported in an earlier article, the amyloid-beta precursor protein (APP) region is strongly linked to affected sib pairs of the oldest current age (i.e., age either at last exam or at death) who lack E4 alleles at the apolipoprotein E (ApoE) locus. We now report that a region on 20p shows the same pattern. A model that includes current age and the number of E2 alleles as covariates gives a LOD score of 4.1. The signal on 20p is near the location of the gene coding for cystatin-C, previously shown to be associated with late-onset AD and to codeposit with APP in the brains of patients with AD. Two-locus analysis provides evidence of strong epistasis between 20p and the APP region, limited to the oldest age group and to those lacking ApoE4 alleles. We speculate that high-risk polymorphisms in both regions produce a biological interaction between these two proteins that increases susceptibility to a very-late-onset form of AD.
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