and sisters) by PCR and restriction analysis using the enzyme Hha I. Age of onset was obtained from caregivers. Differences in age of onset in 33 affected sib-pairs were analyzed in relation to ApoE genotype by one-way ANOVA. Results: 78% of the AD cases were ApoE 4/3 (50%) or 4/4 (28%), while 32% were 3/3. ApoE 4/4 carriers had a younger age at onset (665 years, mean  SD) than 3/4 (697) and 3/3 carriers (716) but without statistical difference. The distribution of Apo E concordant sib- pairs (n=22) was the following: 3/3 (n=4 sib-pairs, differences in age at onset 7.26.4 years), 3/4 (n=11, 4.53.0 years), 4/4 (n=7, 6.53.4 years). ApoE discordant sib-pairs (n=12) were the following: 3/4 versus 4/4 (n=8 sib-pairs, differences in age at onset 4.22.4 years), and 3/3 versus 3/4 (n=4, 5.51.9 years). Differences in age at onset in concordant ApoE sib-pairs (5.73.9 years) were not significantly different than in discordant sib-pairs (4.62.3 years). The presence of an extra ApoE allele in discordant sib-pairs only meant a younger age at onset in half of the pairs. Conclusions: Within sib-pairs with familial AD, ApoE genotype is not a major factor influencing age at onset. Other variables should be considered to influence the great variability in age at onset among affected siblings. P1-318 A NOVEL ALZHEIMER’S DISEASE LOCUS ASSOCIATED WITH ATYPICAL ‘PLAQUE- PREDOMINANT’ NEUROPATHOLOGY Agnes A. Luty 1,2 , John B. Kwok 1,2 , Elizabeth Thompson 3 , Peter C. Blumbergs 4 , William Brooks 5 , Peter R. Schofield 1,5 , 1 Garvan Institute of Medical Research, Sydney, NSW, Australia; 2 University of New South Wales, Sydney, NSW, Australia; 3 South Australian Clinical Genetics Service, North Adelaide, SA, Australia; 4 Institute of Medical and Veterinary Science, Adelaide, SA, Australia; 5 Prince of Wales Medical Research Institute, Sydney, NSW, Australia. Contact e-mail: a.luty@garvan.org.au Background: Alzheimer’s disease is a neurodegenerative disorder typi- cally characterized by massive accumulation of senile plaques and neuro- fibrillary tangles (NFTs) in the brains of affected patients. A small pro- portion of cases have ‘plaque-predominant’ AD (PPAD), where the neuropathology is unusual in that there is marked lack of NFTs. Objective: 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. Meth- ods: 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 domi- nant model of inheritance with age dependent penetrance using the pro- gram LINKAGE. Loci of interest were defined as those achieving LOD scores over 1 and where the adjacent markers also achieved positive LOD scores. Results: 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 chromo- some 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 posi- tional candidate genes is continuing. Conclusion: 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. P1-319 PRESENILIN 2 SER130LEU MUTATION IN A CASE OF LATE-ONSET “SPORADIC” AD Carmine Tomaino 1 , Livia Bernardi 1 , Maria Anfossi 1 , Angela Costanzo 1 , Francesca Ferrise 1 , Maura Gallo 1 , Silvana Geracitano 1 , Raffaele Maletta 1 , Sabrina Anna Maria Curcio 1 , Maria Mirabelli 1 , Rosanna Colao 1 , Francesca Frangipane 1 , Gianfranco Puccio 1 , Cinzia Calignano 1 , Maria Gabriella Muraca 1 , Annamaria Paonessa 1 , Nicoletta Smirne 1 , Attilio Leotta 2 , Amalia Cecilia Bruni 1 , 1 Regional Neurogenetic Centre AS6, Lamezia Terme, Italy; 2 Pathology Department AS6, Lamezia Terme, Italy. Contact e-mail: maletta@arn.it Background: Mutations of PSEN2 gene are a rare cause of Familial Alzheimer’s Disease (FAD) displaying a large span of the age at onset (40-80 years). To date, PSEN2 mutations have never been described in sporadic late onset AD. The PSEN2 Ser130Leu mutation, signalled as pathogenic and causative in a patient from a dominant FAD family, has recently been interpreted, after in vitro experimental procedures, as a rare polymorphism or a mutation not pathogenic. Objective(s): To report the PSEN2 Ser130Leu mutation in a sporadic late onset AD case. Methods: Patient manifested his mild memory deficits, spatial disori- entation and personality changes at 81. At 83 diagnosis of AD was performed according to NINCDS-ADRDA criteria, neuropsychology, and neuroimaging. No cases of dementia were reported in his family, however, his father and one sister, both deceased at 84 without cogni- tive decline, were referred as having had a “Parkinson’s disease” (PD). Although it did not matter, the family asked for molecular screening of the known FAD genes. All available relatives were also genetically investigated. 220 unrelated subjects (110 controls and 100 AD patients) were screened for Ser130Leu mutation through PCR-RFLP and se- quence analyses respectively. Apolipoprotein E was also genotyped. Results: Sequence analysis identified a PSEN2 Ser130Leu mutation in exon 5 that was present also in two out of three of his healthy children and it was absent in all 220 subjects screened, excluding it as common polymorphism. APOE genotype was 33. Conclusions: The PSEN2 Ser130Leu mutation found in our “sporadic” AD late onset case and in the previously reported one is not a common polymorphism. For what concerns the pathogenicity of the mutation, it is obviously possible that in vivo other genetic and/or environmental factors could interact with the mutation to produce the pathological phenotype. In our patient neither a de novo nor an inherited mutation can be ruled out. Each of his parents could have transmitted it without developing AD if their death occurred before the onset. Indeed, frequency of PSEN2 mutations could be underestimated in AD general population. P1-320 GENETIC STUDY OF SARDINIAN PATIENTS WITH ALZHEIMER’S DISEASE Paola Piscopo 1 , Antonella Manfredi 1 , Lorenzo Malvezzi-Campeggi 1 , Alessio Crestini 1 , Ornella Spadoni 1 , Rossella Cherchi 2 , Emiliano Deiana 2 , Angelo Deplano 2 , Maria Rita Piras 2 , Annamaria Confaloni 1 , 1 Istituto Superiore di Sanita `, Rome, Italy; 2 University of Sassari, Sassari, Italy. Contact e-mail: paola.piscopo@iss.it Background: Alzheimer’s disease (AD) exists in two forms, charac- terized by an early onset (EOAD) and a late onset (LOAD). After age, family history of dementia is the second major risk factor for AD. Mutations in three genes, APP, presenilin 1 (PSEN1) and presenilin 2 (PSEN2) are known to be involved in the ethiology of familial AD (FAD). However, screening studies have demonstrated that these mu- tations explain only a proportion of early onset FAD, leaving an important gap with regard to factors involved in sporadic and late onset forms. Objective: Our aim was to perform an extended screening in a Sardinian cohort of genetically isolated subjects to identify additional genetic abnormalities implicated in sporadic and familial AD cases. S190 Poster Presentations P1