Alzheimer Disease 8


For a phenotypic description and a discussion of genetic heterogeneity of Alzheimer disease (AD), see 104300.


In a linkage study of 272 affected sib pairs (ASPs) with AD who were 60 years of age or older at onset, Blacker et al. (1997) found strong evidence of linkage on chromosomes 20 (lod score = 4.09) and 21 (lod score = 5.9). Because of the large marker spacing in the initial genome scan, the candidate region on chromosome 20 spanned 25 cM, corresponding to chromosomal bands 20p12.2-q11.21. Within this candidate region, 1 gene of particular interest was that encoding cystatin-3 (CST3; 604312), because it is known to be an amyloidogenic protein and is codeposited with the amyloid-beta precursor protein (APP; 104760) in amyloid plaques in the brain of AD patients.

Using a covariate-based linkage method, Olson et al. (2001) showed that the APP region on chromosome 21q21 is strongly linked to AD-affected sib pairs of the oldest current age (i.e., age either at last exam or at death) who lacked E4 alleles at the apolipoprotein E (APOE; 107741) locus. In further use of a covariate-based linkage method to reanalyze genome scan data, Olson et al. (2002) determined that a region on chromosome 20p showed the same pattern. A model that included current age and the number of E2 alleles at the APOE locus as covariates gave a lod score of 4.1. The signal on 20p was near the location of the gene encoding cystatin C. Two-locus analysis provided evidence of strong epistasis between 20p and the APP region, limited to the oldest age group and to those lacking E4 alleles at the APOE locus. Olson et al. (2002) speculated that high-risk polymorphisms in both regions produce a biologic interaction between these 2 proteins that increases susceptibility to a very late-onset form of AD. They suggested that this type of AD is biologically independent of APOE and that its association with E2 in their data set was the result of E4-related attrition at earlier ages.

By further linkage studies of sibships originally reported by Blacker et al. (1997), Goddard et al. (2004) narrowed the AD candidate region on chromosome 20 to an 11.8-cM region between markers D20S174 and D20S471, which includes the CST3 gene. In addition, they observed association for markers located near the CST3 gene, with P values between 0.002 and 0.08 for 2-locus haplotypes. The results supported the presence of a susceptibility locus for AD in the vicinity of CST3 for very elderly subjects with AD.

Although both Finckh et al. (2000) and Crawford et al. (2000) reported associations between polymorphisms in the CST3 gene and late-onset AD, Monastero et al. (2005) and Nacmias et al. (2006) found no such associations.