Increased familial risk and genomewide significant linkage for Alzheimer's disease with psychosis.
Hollingworth P., Hamshere ML., Holmans PA., O'Donovan MC., Sims R., Powell J., Lovestone S., Myers A., DeVrieze FW., Hardy J., Goate A., Owen M., Williams J.
Psychotic symptoms are common in Alzheimer's disease (AD) and are associated with increased cognitive impairment and earlier institutionalization. One study has suggested that they are genetically modified and two genome screens have been performed to search for susceptibility loci for AD with psychosis (AD + P). The aim of this study was to further investigate the familial aggregation of AD + P and perform a genome screen for AD, conditioning on the presence or absence of psychotic symptoms. Samples from the UK and US were combined, providing data from 374 families in which at least two members met criteria for AD and had complete data regarding psychotic symptoms. Generalized estimating equations (GEE) were used to assess the relationship of psychotic symptoms between siblings. A total of 321 affected relative pairs (ARPs) were genotyped for linkage. There was a significant association between proband psychosis status and the occurrence of AD + P in siblings in the UK (OR = 4.17, P = 0.002) and US (OR = 3.2, P < 0.001) samples. Chromosomewide and genomewide significant linkage peaks were observed on chromosomes 7 (LOD = 2.84) and 15 (LOD = 3.16), respectively, with the strongest evidence coming from pairs concordant for AD without psychosis. A LOD score of 2.98 was observed close to a previously reported AD + P linkage region on chromosome 6, however the increase in LOD attributable to psychosis was not significant. These findings support the hypothesis that psychotic symptoms in AD are genetically modified and that a gene/s implicated in their aetiology may be located on chromosome 7 and 15.