Alzheimer Disease 11
For a general phenotypic description and a discussion of genetic heterogeneity of Alzheimer disease (AD), see 104300.Mapping
By genomewide linkage analysis of 466 families with late-onset AD, including 730 affected sib pairs, Pericak-Vance et al. (2000) identified a candidate disease locus on chromosome 9p22.1 (nonparametric maximum lod score of 2.97 at marker D9S741). Analysis of a subset of 199 families in which there was at least 1 autopsy-confirmed AD case yielded a higher lod score of 4.31 at the same marker.
Scott et al. (2003) reexamined 437 white AD families included in the original report by Pericak-Vance et al. (2000) by considering age of onset as a covariate. Ordered-subsets analysis included continuous covariates in linkage analysis by rank ordering families by a covariate and summing lod scores. The lod score in the 9p22 region previously linked to AD increased to 4.6 at D9S741 in 334 families with minimum age at onset between 60 and 75 years. The analysis also identified linkage to 2q34, with a peak nonparametric multipoint lod score of 3.2 at D2S2944 in 31 families with a minimum age at onset between 50 and 60 years. The findings indicated that linkage to 9p was strongest in late-onset AD and that regions on 2q34 and 15q22 were linked to early-onset AD and very-late-onset AD, respectively.
Farrer et al. (2003) observed an unusually high prevalence of dementia of the Alzheimer type in Wadi Ara, an inbred Arab community in northern Israel comprising approximately 850 persons over the age of 60 years. A 10-cM genomic scan revealed significant allelic association with AD (p less than 0.05) at locations on chromosomes 2, 9, 10, and 12. The location on chromosome 9 yielded a maximum lod score of 5.5. Allelic frequency distributions narrowed the susceptibility gene to a 13-cM interval on chromosome 9 between D9S157 and D9S259, and a 14-cM interval on chromosome 12 distal to the LRP1 (107770) locus. Evidence for linkage on chromosome 9 stemmed primarily from excess homozygosity of marker alleles in cases compared with controls, suggesting that a gene at this location may behave in either a recessive or additive fashion. Farrer et al. (2003) noted that there was no neuropathologic evidence for AD in any patient from this community because religious customs prevented brain autopsy.
Zuchner et al. (2008) performed detailed linkage analysis using SNPs spanning the AD11 locus in 674 families of European descent with late-onset Alzheimer disease ascertained from 3 different study groups. Although positive lod scores were found in all 3 groups, the highest linkage was found for chromosome 9p21.3 when analyzing a subset of 166 families with autopsy confirmation (HLOD of 4.95 at D9S741 and 2.81 at rs2772577). Zuchner et al. (2008) noted that the CDKN2A gene (600160) is located 2.7-Mb upstream of D9S741, and may be a candidate gene.