Alzheimer Disease 5
For a phenotypic description and a discussion of genetic heterogeneity of Alzheimer disease (AD), see 104300.
MappingIn a late-onset form of familial Alzheimer disease (AD), Pericak-Vance et al. (1997) identified linkage to a locus on chromosome 12. From a series of multiplex families affected with late-onset AD (at least 60 years) ascertained during the previous 14 years and for which DNA had been obtained, Pericak-Vance et al. (1997) selected a subset of 16 families (with 52 AD patients) to use for a genomewide screen. A second subset of 38 families (with 89 AD patients) was used for a follow-up analysis. Linkage analysis was performed using both genetic model-dependent (lod score) and model-independent methods. Fifteen chromosome regions warranted initial follow up. This analysis revealed 4 regions of continued interest on chromosomes 4, 6, 12, and 20, with the strongest results observed for chromosome 12. The combined data of 54 families showed a maximum lod score of 3.5 at a point between D12S1042 and D12S390. (On the cytogenetic map, this interval corresponds to the region 12p11.23-q13.12.) The finding was of particular interest because the LRP gene (107770), which encodes a brain-expressed APOE receptor, is located on chromosome 12.
Rogaeva et al. (1998) presented data they interpreted as indicating independent confirmation of the existence of an AD susceptibility locus on chromosome 12 as well as of susceptibility genes on other chromosomes. On the other hand, Wu et al. (1998) were unable to confirm the existence of a locus on 12p12-p11, although they recognized that an effect smaller than that of the APOE locus could not be excluded.
In a follow-up study of the 54 families reported by Pericak-Vance et al. (1997), Scott et al. (2000) found evidence from conditional linkage analysis indicating linkage to chromosome 12 that was stronger in families with affected individuals lacking an APOE allele; much of the evidence came from families with affected members with a diagnosis of dementia with Lewy bodies (127750).
To investigate further the inconsistent linkage results for a form of familial Alzheimer disease determined by a gene on 12p, Mayeux et al. (2002) used 35 markers near the centromere of chromosome 12 to study 79 Caribbean Hispanic families with AD. Their results extended and provided modest evidence of linkage to loci on 12p. Linkage varied by age at onset of AD and by the presence or absence of the APOE epsilon-4 allele. Lod scores were lower when the E4 allele (107741.0016) was present; the lod score was reduced in families with onset after 65 years of age.
Lambert et al. (2000) reported an association between a noncoding polymorphism (G-A) in the 3-prime untranslated region of transcription factor CP2 (TCFP2; 189889) and sporadic AD in French and British populations and a similar trend in a North American population. The combined analysis of the 3 independent populations suggested a protective effect of the A allele (OR = 0.58, 95% CI 0.44-0.75). The A allele demonstrated reduced binding to nuclear protein(s) from a neuroblastoma cell line, and absence of the A allele was associated with lower gene expression in lymphocytes from AD cases compared with controls. The authors suggested that polymorphic variation in TFCP2 may be important for the pathogenesis of AD, particularly since the gene product interacts with proteins such as GSK3B (605004), Fe65 (602709), and certain factors involved in the inflammatory response.
Taylor et al. (2001) reported an analysis of 216 necropsy-confirmed Alzheimer disease cases and 301 nondemented controls greater than 73 years. The frequency of the A allele of the TCFP2 gene was reduced in the Alzheimer disease cases compared to the controls (odds ratio = 0.59, 95% CI, 0.35-1.00). However, the genotype frequencies of the Alzheimer disease cases when compared to controls were not significantly different. No significant effects were found when the data were adjusted for age, sex, or the presence of the apoE E4 allele.
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 in which approximately 850 persons were 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 12 yielded a maximum lod score of 4.8. Allelic frequency distributions narrowed the susceptibility gene to a 14-cM interval on chromosome 12 distal to the LRP1 locus (107770). 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.