AbstractPoster presentation: Sunday posterP1-318: A novel Alzheimer’s disease locus associated with atypical ‘plaque-predominant’ neuropathology

Alzheimer's disease is a neurodegenerative disorder typically characterized by massive accumulation of senile plaques and neurofibrillary tangles (NFTs) in the brains of affected patients. A small proportion of cases have ‘plaque–predominant’ AD (PPAD), where the neuropathology is unusual in that there is marked lack of NFTs. We have identified two large multi–generational pedigrees with PPAD. With mutations in the APP, PS1, PS2 and MAPT genes excluded, the aim was to identify a novel genetic locus involved in this form of AD. DNA from 24 individuals, of which 9 are affected, underwent a genome wide scan at the Australian Genome Research Facility using 400 microsatellite markers. The data was analyzed under an autosomal dominant model of inheritance with age dependent penetrance using the program LINKAGE. Loci of interest were defined as those achieving LOD scores over 1 and where the adjacent markers also achieved positive LOD scores. Only one region, on chromosome 9, achieved a significant two–point LOD score of 3.5. Positive LOD scores for surrounding markers defined an area which spans 30–40 cM. This region was narrowed by Multipoint Linkage Analysis, Fine Mapping and Haplotype Analysis to 25 cM and corresponds to 9p21–9q21. This region is of interest because it overlaps with several dementia loci on chromosome 9q21–22 and chromosome 9p21.1–12. Out of a total of 180 genes located in this area, 35 of these were considered as potential candidates based on biological considerations. To date, the valosine–containing protein (VCP) a gene in which mutations give rise to inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia and 16 of the candidate genes have been screened for the presence of mutations. Mutation screening of the positional candidate genes is continuing. These results suggest that a novel locus associated with PPAD is located on chromosome 9. The identification of the causal gene will aid in our understanding of the mechanisms of the onset of various forms of inherited dementia and the biology of Alzheimer's disease.