Alzheimer Disease 9, Susceptibility To

A number sign (#) is used with this entry because of evidence that susceptibility to late-onset Alzheimer disease-9 (AD9) is conferred by heterozygous variation in the ABCA7 gene (605414) on chromosome 19p13.

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

Clinical Features

Van den Bossche et al. (2016) characterized the phenotype of 22 Belgian patients with AD9 who carried putative pathogenic variants in the ABCA7 gene. The mean age at onset was 73 years, with a wide age range between 54 and 90 years. The phenotype was classic for AD, mainly including progressive memory loss. About half of patients developed frontal signs, including disinhibition or behavioral changes. Other manifestations included language difficulties, depression, and delusions. One patient presented with parkinsonism, and a few showed mild extrapyramidal symptoms. Brain imaging tended to show atrophy of various brain regions, and many patients had chronic microvascular lesions. Cerebrospinal fluid examination of 2 patients showed decreased beta-amyloid(1-42) and increased total tau, consistent with AD. Neuropathologic examination of 4 patients showed cortical atrophy and neuronal loss in the hippocampus. Senile plaques and neurofibrillary tangles were also apparent. The patients had previously been reported by Cuyvers et al. (2015) and included a family with autosomal dominant inheritance (DR170).

Inheritance

The transmission pattern of AD9 the family reported by Van den Bossche et al. (2016) was consistent with autosomal dominant inheritance.

Mapping

Late-onset familial Alzheimer disease is a genetically heterogeneous and complex disease. The Bayesian Markov chain-Monte Carlo (MCMC) linkage analysis methods provide a computationally tractable approach for complex trait analysis. These methods are particularly suitable for multilocus trait models. Wijsman et al. (2004) applied this approach to an analysis of late-onset AD on 5 chromosomes with previous reports of linkage. They identified strong evidence of a late-onset AD locus on 19p13.2. They also obtained weak evidence of linkage to chromosome 10 at the same location as a previous report of linkage (AD6; 605526) but found no evidence for linkage of late-onset AD age-at-onset loci on chromosomes 9, 12 (see 103950), or 21 (AD1; 104760).

By linkage analysis of 5 Amish families from the midwestern U.S. in which 49 individuals had late-onset dementia or mild cognitive impairment, Hahs et al. (2006) obtained 2-point lod scores greater than 1.5 at marker D19S586 on 19p13 (lod scores of 2.06 and 1.82). The results were obtained under a model assuming autosomal dominant inheritance.

Molecular Genetics

Hollingworth et al. (2011) undertook a combined analysis of 4 genomewide association datasets of patients with late-onset Alzheimer disease (stage 1) and identified 10 newly associated variants with p = 1 x 10(-5) or less. They tested these variants for association in an independent sample (stage 2). Three SNPs at 2 loci replicated and showed evidence for association in a further sample (stage 3). One of these SNPs was in the ABCA7 gene, and metaanalyses of all data provided compelling evidence for ABCA7 (rs3764650, meta p = 4.5 x 10(-17); including the Alzheimer's Disease Genetic Consortium (ADGC) data, meta p = 5.0 x 10(-21)).

Among 3,419 Icelanders with Alzheimer disease and 151,805 controls, Steinberg et al. (2015) found a significant association between loss-of-function variants in the ABCA7 gene (see, e.g., 605414.0001) (odds ratio (OR) 2.12, p = 2.2 x 10(-13)). A significant association was also found for a splice site variant (c.5570+5G-C; rs200538373) that was shown to cause premature termination (OR 1.91, p = 3.8 x 10(-6)). The association with loss-of-function variants was replicated in study groups from Europe and the United States (OR 2.03, p = 6.8 x 10(-15)).

Cuyvers et al. (2015) found an association between variation in the ABCA7 gene and susceptibility to late-onset Alzheimer disease (AD9). Targeted resequencing of the ABCA7 gene found an increased frequency of predicted loss-of-function variants (7 variants) among 772 unrelated Belgian patients compared to 757 controls (relative risk 4.03, p = 0.0002). One of these was a frameshift mutation (Glu709fs; 605414.0001) that segregated with the disorder in a family and showed a founder effect in the population. Expression of ABCA7 was reduced in brain tissue from 2 carriers of loss-of-function mutations, including Glu709fs and W1214X (605414.0002). The strongest association with AD was for an intronic variant (rs78117248), which showed minor allele frequencies of 3.8% in 58 patients and 1.8% in 28 controls (OR 2.07, p = 0.0016). The variant occurred in a transcription factor binding region; however, no difference in expression of ABCA7 was noted in cells derived from carriers of the variant compared to controls. The SNP rs78117248 was in linkage disequilibrium with GWAS SNPs rs3764650, rs4147929, and rs3752246; regression analysis removed the association between the GWAS SNPs and disease. In the Belgian study, the c.5570+5G-C variant identified by Steinberg et al. (2015) occurred at a frequency of more than 1% in both patients and controls, and was not associated with AD.

By targeted resequencing of the ABCA7 gene in 2 Caucasian cohorts totaling 330 patients with late-onset AD and in the ExAC database, Vardarajan et al. (2015) found a significant association between an E1769X variant and AD (p = 5.3 x 10(-4)).

Among 484 French patients with onset of AD before 65 years and 590 controls, Le Guennec et al. (2016) found a significant association between loss-of-function and missense ABCA7 variants and AD (OR 3.40, p = 0.0002). Variants were found in 6.6% of patients and in 2.0% of controls. A metaanalysis using previously reported data (Steinberg et al., 2015; Cuyvers et al., 2015) in a combined sample of 1,256 patients and 1,347 controls yielded an OR of 2.81 (p = 3.60 x 10(-7)). No functional studies of the variants were performed.

Exclusion Studies

Klein et al. (2013) found no mutations in exons 20 and 21 of the DNMT1 gene (126375) on chromosome 19p13 in 364 patients with autopsy-confirmed late-onset Alzheimer disease, thus likely excluding a role for this gene in AD9.