Poster Presentations P4 P461

P4-101 UREA CYCLE AND ALZHEIMER’S DISEASE

Franck Hansmannel1, David Mann2, Corinne Lendon3,

Jean Jacques Hauw4, Geoffroy Laumet1, Anne Marie Ayral1,

Julien Chapuis1, Didier Hannequin5, Steven DeKosky6, Florence Pasquier7,

Claudine Berr8, Daniela Galimberti9, Elio Scarpini9, Ilyas Kamboh6,

Dominique Campion5, Philippe Amouyel1, Jean Charles Lambert1, 1InstitutPasteur de Lille - INSERM U744, Lille, France; 2Greater Manchester

Neurosciences Centre, University of Manchester, Manchester, United

Kingdom; 3Molecular Psychiatry Group, Queensland Institute of Medical

Research, Brisbane, Australia; 4APHP, GH Pıtie-Salpetriere, Laboratoirede Neuropathologie R Escourolle, INSERM, IFR 70, Paris, France; 5IN-

SERM U614, Faculty of Medicine of Rouen, Rouen, France; 6Department of

Human Genetics and Alzheimer’s Disease Research Centre, University ofPittsburgh, Pittsburgh, PA, USA; 7EA2391, Department of Neurology,

Memory Clinic, University Hospital of Lille, Lille, France; 8INSERM, U888,

Universite de Montpellier I, Hopital La Colombiere, Montpellier, France;9Department of Neurological Sciences, University of Milan, FondazioneOspedale Maggiore Policlinico, Milan, Italy. Contact e-mail: franck.

hansmannel@pasteur-lille.fr

Background: The urea cycle is an hepatic metabolic pathway, essential for

ammonia detoxification and it normally takes place only in liver. In the brain

of controls, we consistently observed that this cycle can not be active since

ornithine transcarbamylase (OTC), - the key-enzyme of the urea cycle-, is

not expressed. However, this cycle seems to be induced in the brain of

AD cases: OTC is expressed as well as all the different enzymes of the

urea cycle in the pathological brain tissue. This result suggests that the

urea cycle may play a role in the AD pathological process. Methods: We

compared the level of expression of the different genes involved in the

urea cycle using total RNA extracted from the brain of 38 AD cases and

37 controls. We also selected 86 Tag-Single nucleotide polymorphisms

(SNP) within these genes and studied their associations with the risk of de-

veloping AD in two French and American independent sub-populations

(n¼945). Following this first screening, the most interesting SNP were

then genotyped in four independent case-control studies (n¼3200). Results:

In addition to OTC, we observed that the Arginase 2 (Arg2) gene was over-

expressed in the brain of AD cases compared to the one of controls (þ50%,

p¼0.01). Similarly, in addition to a SNP within the OTC promoter

(rs5963409), we noticed that a polymorphism (rs742869) within the Arg2

gene was also associated with an increase in risk of developing AD in

men when all the case-control studies were analysed altogether (recessive

model, Mantel-Haentzel fixed odds ratio ¼ 1.8, CI 95% [1.3-2.5],

p¼0.0002). Conclusions: Our results highlight a potential role of the urea

cycle pin the AD process.

P4-102 A STUDY ON THE ASSOCIATION OF THE

CHROMOSOME 12P13 LOCUS WITH SPORADIC

LATE-ONSETALZHEIMER’S DISEASE IN CHINESE

You-Qiang Song, Yan Li, Leung Wing Chu, Ping-Yiu Yik, The University

of Hong Kong, Hong Kong, Hong Kong. Contact e-mail: songy@hku.hk

Background: Recent linkage and association studies have implicated the

chromosome 12p13 locus as possibly harboring genetic variants predisposed

to Alzheimer disease (AD). Further association analysis have now pointed to

a smaller region of the chromosome 12p13 locus, thus narrowing down late-

onset AD association to single genes as shown by the two recent studies. In

an effort to replicate this finding, we selected the same panel of polymor-

phism markers and conducted genotyping in our Chinese data set. Methods:

We attempted to replicate this association in a Chinese data set comprised of

260 AD cases and 264 age-matched normal controls. A total of 14 previous

published single nucleotide polymorphisms (SNPs) were examined. Re-

sults: Single marker association revealed the two SNPs in NCAPD2

(rs7311174 and rs2072374) as showing nominal significant p-values

(p¼0.0491 and 0.0116, respectively). Haplotype analysis found LD block

one to be significantly associated with AD (global p¼0.0250). The haplo-

types CGGATG and CAGTCG were also significantly associated with AD

(p¼0.0498 and p¼0.0482, respectively). Conclusions: The association of

chromosome 12p13 multiple loci with AD was confirmed in a Chinese

data set. Both single marker and haplotypic associations were significant.

Nonetheless, future genetic studies to verify this association will need to con-

duct studies with a larger data set and with other ethnic groups.

P4-103 SYNERGISM BETWEEN THE CCR5D32

DELETION AND APOE4 POLYMORPHISMS

IN VASCULAR AND MIXED DEMENTIA

OF THE VERY OLD

Dina Zekry1, Yosuke Kameoka2, Jean Pierre Michel1, Gabriel Gold1,

Francois R. Herrmann1, Karl Heinz Krause1, 1Geneva Medical Faculty andUniversity Hospitals, Geneva, Switzerland; 2National Institute of Biomedi-

cal Innovation, Laboratory of Genetic Resources, Osaka, Japan. Contact

e-mail: dina.zekry@hcuge.ch

Background: A role of chemokine receptors in the central nervous system is

increasingly recognised. We investigated the influence of CCR5 deletion

alone or combined with ApoE4 polymorphisms as a risk factor for various

types of dementia. Methods: We carried out a prospective study of inpatients

from the Geneva University geriatric hospital. Genomic DNA from periph-

eral-blood was screened by PCR for the presence of the CCR5 32bp deletion

(CCR5D32) and ApoEe4 alleles. Logistic regression models with CCR5 and

ApoE polymorphisms as independent variables, were used to assess the ge-

netic risk for different types of dementia. Results: 394 patients were included

(mean age 85): 205 were cognitively normal and 189 were demented (73 AD,

82 mixed dementia, 20 vascular dementia and 14 other). The CCR5D32 al-

lele was not an independent predictor of dementia, however, CCR5D32

strongly sinergized with ApoE4 as risk factor. Subgroup analysis suggest

that this was true for dementia with a vascular component, but not for pure

AD. Carriers of APOEe4 and CCR5D32 had a seven-fold greater risk of

vascular or mixed dementia. The combination of CCR5D32 and APOEe4

confered a significantly (p ¼ 0.002) higher dementia risk (OR ¼ 7.27,

95% CI ¼ 2.09-25.27) than APOEe4 alone (OR ¼ 2.81, 95% CI ¼ 1.40-

5.63). Conclusions: Carriage of CCR5D32 markedly enhanced the risk of

developing vascular or mixed dementia in ApoEe4-positive geriatric pa-

tients. Our results also suggest that enhancement of CCR5 signaling might

be a strategy to intefere with dementia development in ApoEe4 carriers.

P4-104 ESTROGEN RECEPTOR ALPHA (ESR1) GENE

VARIANTS ARE ASSOCIATED TO ALZHEIMER’S

DISEASE IN SPANISH POPULATION

Merce Boada1,2, Carmen Antunez3,4, J. Lopez-Arrieta5, Isabel Hernandez1,

Pablo Martinez-Lage1, Ana Mauleon1, Maitee Rosende-Roca1,

Carmen Echavarri1, Montserrat Alegret1, Reposo Ramirez-Lorca6,

Concepcion Moreno6, Francisco J. Moron6, J. Marin3, Lluıs Tarraga1,

Luis Miguel Real6, Javier Gayan6, Antonio Gonzalez-Perez6,

J. Jorge Galan6, Agustın Ruiz6, 1Fundacio ACE. Institut Catala de Neuro-

ciencies Aplicades., Barcelona, Spain; 2Neurology Service. UniversityHospital Vall d’Hebron, Barcelona, Spain; 3University Hospital Virgen de

Arrixaca, Murcia, Spain; 4Alzheimur Foundation, Murcia, Spain; 5Memory

Unit. University Hospital La Paz-Cantoblanco, Madrid, Spain; 6Departmentof Structural Genomics. NeoCodex., Sevilla, Spain. Contact e-mail:

mboada@fundacioace.com

Background: The genetic basis of Alzheimer Disease (AD) is being ana-

lyzed using candidate gene and Whole genome association approaches.

ESR1 gene has been proposed as a genetic risk factor for AD in several

low-scale population-based genetic association studies. Methods: We

have genotyped ESR1 (rs3844508, rs2234693/PvuII, NCD1/EU579440 ele-

tion) and APOE rs429358 (SNP112)/rs7412 (SNP158) in 2343 Spanish

individuals. Specifically, we analyzed 1113 AD patients, 1109 controls

from the general population and 121 neurological healthy elderly controls

(NHEC) using real time-PCR and pyrosequencing technologies. Results:

As previously reported in Spain, APOE e4 allele was strongly associated

to AD in our series (OR¼3.18, p¼3.80E-37). Next, we explored ESR1

rs3844508, rs2234693/PvuII, NCD1/EU579440 markers association using

different genetic models and comparing AD versus controls or NHECs.

We found evidence of association to AD in all ESR1 markers studied