American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 135B:24–32 (2005) Genome Screen for Loci Influencing Age at Onset and Rate of Decline in Late Onset Alzheimer’s Disease Peter Holmans, 1 * Marian Hamshere, 2 Paul Hollingworth, 2 Frances Rice, 2 Nigel Tunstall, 3 Sue Jones, 2 Pamela Moore, 2 Fabienne Wavrant DeVrieze, 4 Amanda Myers, 4 Richard Crook, 6 Danielle Compton, 6 Helen Marshall, 5 David Meyer, 5 Shantia Shears, 5 Jeremy Booth, 5 Dzanan Ramic, 5 Nigel Williams, 2 Nadine Norton, 2 Richard Abraham, 2 Pat Kehoe, 2 Hywel Williams, 2 Varuni Rudrasingham, 2 Mick O’Donovan, 2 Lesley Jones, 2 John Hardy, 4 Alison Goate, 5 Simon Lovestone, 3 Michael Owen, 2 and Julie Williams 1,2 1 Biostatistics and Bioinformatics Unit, Wales College of Medicine, Heath Park, Cardiff, United Kingdom 2 Department of Psychological Medicine, University of Wales College of Medicine, Heath Park, Cardiff, United Kingdom 3 Institute of Psychiatry, De Crespigny Park, Denmark Hill, London, United Kingdom 4 Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 5 Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri 6 Laboratory of Neurogenetics, Birdsall Building, Mayo Clinic Jacksonville, Jacksonville, Florida We performed an affected sib-pair (ASP) linkage analysis to test for the effects of age at onset (AAO), rate of decline (ROD), and Apolipoprotein E (APOE) genotype on linkage to late-onset Alzheimer’s disease (AD) in a sample comprising 428 sib-pairs. We observed linkage of mean AAO to chromosome 21 in the whole sample (max LOD ¼ 2.57). This came entirely from the NIMH sample (max LOD ¼ 3.62), and was strongest in pairs with high mean AAO (>80). A similar effect was observed on chromosome 2q in the NIMH sample (max LOD ¼ 2.73); this region was not typed in the IADC/UK sample. Suggestive evi- dence was observed in the combined sample of linkage of AAO difference to chromosome 19q (max LOD ¼ 2.33) in the vicinity of APOE and 12p (max LOD ¼ 2.22), with linkage strongest in sib- pairs with similar AAO. Mean ROD showed sug- gestive evidence of linkage to chromosome 9q in the whole sample (max LOD ¼ 2.29), with the effect strongest in the NIMH sample (max LOD ¼ 3.58), and in pairs with high mean ROD. Additional suggestive evidence was also observed in the NIMH sample with AAO difference on chromo- some 6p (max LOD ¼ 2.44) and 15p (max LOD ¼ 1.87), with linkage strongest in pairs with similar AAO, and in the UK sample with mean ROD on chromosome 1p (max LOD ¼ 2.73, linkage stron- gest in pairs with high mean ROD). We also observed suggestive evidence of increased iden- tical by descent (IBD) in APOE e4 homozygotes on chromosome 1 (max LOD ¼ 3.08) and chromosome 9 (max LOD ¼ 3.34). The previously reported gen- ome-wide linkage of AD to chromosome 10 was not influenced by any of the covariates studied. ß 2005 Wiley-Liss, Inc. KEY WORDS: Alzheimer’s Disease; age at onset; rate of decline; genome screen; linkage INTRODUCTION Alzheimer’s disease (AD) is a common debilitating disorder with a prevalence that rises steeply with age from below 1% at 65 years to as high as 40% after the age of 90 [Bachman et al., 1992]. Genes are known to play a role in the development of AD. Twin studies show heritabilities of around 60% [Bergem et al., 1997; Gatz et al., 1997]. Indeed, variation in four genes has already been shown to cause rare forms of early-onset AD [the Amyloid Precursor Protein Gene (APP); Goate et al., 1991; Presenilin 1 (PS1); Sherrington et al., 1995; Presenilin 2 (PS2); Levy Lahad et al., 1995, Rogaev et al., 1995] or increase the general risk of disease development [Apolipoprotein E (APOE), Corder et al., 1993]. As well as increasing disease suscept- ibility, APOE e4 alleles are associated with reduced age at onset (AAO) and appear to show their strongest effect below 70 years [Farrer et al., 1997]. There is also evidence from both twin [Pedersen et al., 2001] and family studies [Tunstall et al., 2000; Li et al., 2002] that AAO in AD is heritable. Daw et al. [2000] have estimated that in addition to APOE, there are at least four loci with similar effect sizes, which contribute to AAO in AD. Recently, a number of studies [Olson et al., 2001, 2002; Li et al., 2002] have attempted to map loci contributing to AAO in AD. Using genotypes generated by the UK/US AD Consortium [Kehoe et al., 1999] on affected sibling pairs (ASPs) collectedas part of the National Institute of Mental Health (NIMH) AD Genetics Initiative, Olson et al. [2001, 2002] observed sugges- tive evidence that the mean AAO of an affected sib-pair (ASP) influenced linkage to markers on chromosome 21, in close proximity to the APP gene, and chromosome 14. However, their strongest findings were observed with mean current age (i.e., age at most recent interview or death), with significant evidence of linkage to markers on chromosome 21, again in the APP region, and markers on chromosome 20. Li et al. treated AAO as a quantitative trait, including AD patients and unaffected family members (where age at entry was used). Variance components analysis on a large sample of AD families showed suggestive linkage (LOD > 2) to APOE, and regions on chromosomes 4, 8, and 10. They also observed weaker evidence of linkage (LOD > 1) to chromosomes 6, 13, and 18. It is noteworthy that relationships with AAO have been characterized in different ways. Olson and colleagues studied Grant sponsor: Medical Research Council; Grant sponsor: Alzheimer’s Research Trust. *Correspondence to: Prof. Peter Holmans, Biostatistics and Bioinformatics Unit, Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK. E-mail: holmanspa@cardiff.ac.uk Received 31 October 2003; Accepted 9 August 2004 DOI 10.1002/ajmg.b.30114 ß 2005 Wiley-Liss, Inc.