Linkage to chromosome 14q in Alzheimer's disease (AD) patients without psychotic symptoms

Abstract

Cases of early onset AD have been attributed to three genes, PSEN1, PSEN2, and APP, while the only gene consistently associated with late onset AD (LOAD) is APOE. Several genome scans have now been performed for LOAD with inconsistent findings in several genomic regions, possibly reflecting the underlying genetic heterogeneity. Many lines of evidence suggest that the absence or presence of psychotic symptoms, common in AD, might delineate distinct etiologic disease subtypes. We have performed a genome scan of 148 AD pedigrees (ages of onset more than 50 years) including the presence or absence of delusions and hallucinations as covariates. This approach identified linkage to a locus on chromosome 14q24.3, close to the PSEN1 locus (LOD score 3.91; genome-wide empirical P = 0.052), derived from individuals that do not have co-morbid hallucinations. The finding appears stronger (LOD score 5.74; genome-wide empirical P = 0.048) in families that include younger affected members (AAO between 50 and 65 years), however it is not present without the inclusion of the covariate and we observe no correlation between the presence of hallucinations and the age of onset. A mutation screen of PSEN1 did not detect any coding region or splice site mutations. This linkage finding suggests the presence of a gene causing AD without co-morbid hallucinations and with an earlier (yet not early) age at onset (AAO) in the 14q24 region. This region requires further study to replicate the finding and identify the genetic variant responsible for the linkage.

Age-at-onset linkage analysis in Caribbean Hispanics with familial late-onset Alzheimer’s disease

“…Avramopoulos and colleagues [41] reported significant evidence for linkage near PSEN1 at 14q24 related to a phenotype that included psychosis. Although 14q32.12 is some distance away (~33 cM) from 14q24 and the PSEN1 gene, we as others [16] observed significant linkage at this locus.…”

Neurobiology of Delusions in Alzheimer’s Disease

“…Familial aggregation studies of probands and siblings with AD have shown a higher chance of concordance for AD+D in siblings and probands than by chance alone [33]. Using genome scans of 148 AD pedigrees, Avramopoulos and colleagues [34] identified a locus on chromosome 2p that is linked with AD+D and a locus on 14q that predisposes individuals to a form of dementia without comorbid psychotic features.…”

Genetics of Alzheimer's Disease: A Centennial Review

“…Most studies with both late and early/mixed age at onset datasets showed separate results for these different age groups [ 126,129,132,133 ]. Where applicable, the age subsets for the results are shown in Tables 3 -8. Many of the studies performed subset analyses based on ApoE genotypes [ 117,124,126,127,136 ], though their definitions of E4+ (ApoE ε4 +) or E4− subsets varied between the studies.…”

“…The autopsy confirmed subset also had another downstream region on chromosome 9q with evidence of linkage. In the substantially overlapping dataset analyzed by Myers et 3) Alternative analytical methods to detect risk loci for LOAD-In addition to the 9 whole genome linkage or association analyses in predominantly non-overlapping samples [ 117,119,121,123,126,127,129,130,132,135,136 ], seven linkage studies are presented here, which utilized alternative analytical strategies to re-assess the data in overlapping datasets [ 122,124,125,128,131,133,134 ]. We will briefly discuss their approaches and results, as they bring potential new understanding and evidence to the LOAD risk loci.…”

“…Several groups included a number of variables as covariates in linkage analyses [ 128,133,134 ]. Olson et al studied 272 sibpairs from the NIMH Genetics Initiative with complete covariate information on age-at-onset, current age and ApoE genotype, to determine the effects of these covariates on linkage [ 128 ].…”