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

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; empirical genome-wide P=0.052), derived from individuals that do not have co-morbid hallucinations. The finding appears stronger (LOD score 5.74; empirical genome-wide 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. (C) 2004 Wiley-Liss, Inc.