olfaction identification in older adults: a genome-wide association study
TRANSCRIPT
Poster Presentations: P4 P671
AD subjects or animal models of AD is not limited to the hippocampus and
other brain regions classically believed to be involved in learning and mem-
ory, but also include themidbrain nigrostriatal pathway involved in the mod-
ulation of motor functions. Our recent study has shown that there is
a decrease of Nissl-stained neurons, TH-positive neurons in substantia nigra
in a triple transgenicmousemodel (3xTgAD) carrying early onset mutations
in two human familial AD genes (APPSwe, PS1M146V) and one frontal tem-
poral dementia-linked tau mutation (tauP301L). Methods: In this study, we
compared general locomotion among non-Tg, 3xTgAD, and 4xTgAD
(3xTgAD plus the human apoE4 gene, a late onset risk factor) mice. Loco-
motor activity was tested in tracking chambers and in a Y-maze. Results:
Our results show an AD gene dependent decrease in total locomotion
with a consistent trend (NonTG>3xTG>4xTG) in both tests. Distance trav-
elled in locomotor activity chamber was analyzed over 10 1 min blocks us-
ing Repeated Measures ANOVA and revealed a main effect of genotype (P
¼ 0.001); Arm average entries in 5mins in Y-Maze were 19.561.76,
16.2564.73, 10.6762.40 for NonTG, 3xTG, 4xTG, respectively (P ¼0.028). Conclusions: Our preliminary results provide further support for
the hypothesis that these early onset mutations and late onset risk factor
of AD are important genetic contributors for Parkinson-like motor deficits
seen in Alzheimer’s disease.
P4-111 OLFACTION IDENTIFICATION IN OLDER
ADULTS: AGENOME-WIDEASSOCIATION STUDY
Karen Mather1, Nicola Armstrong2, Arezoo Assareh3, John Kwok4,
John Crawford5, Simone Reppermund6, Julian Trollor1, Nicole Kochan7,
Kristan Kang5, Melissa Slavin5, Brian Draper8, Henry Brodaty9,
Peter Schofield4, Perminder Sachdev10, 1University of New South Wales,
Randwick, Australia; 2Garvan Institute of Medical Research, Sydney,
Australia; 3Neuroscience Research Australia, Sydney, Australia;4Neuroscience Research Australia, Randwick-Sydney, Australia;5University of New South Wales, Sydney, Australia; 6University of New
South Wales, Sydney, Australia; 7Neuropsychiatric Institute, University of
New South Wales, Sydney, Australia; 8Academic Department for Old Age
Psychiatry, Randwick, Australia; 9Dementia Collaborative Research
Centre, Sydney, Australia; 10University of New South Wales,
Randwick-Sydney, Australia.
Background: The ability to identify odours decreases with normal ageing.
Olfactory identification deficits have also been associated with the prede-
mentia syndrome, mild cognitive impairment (MCI) and Alzheimer’s dis-
ease (AD). Studies on heritability suggest low to moderate heritability for
olfaction. Unravelling the role genetics plays in olfactory impairment may
elucidate the biological pathways involved in olfaction and olfactory im-
pairment and may shed light on the relationship between olfaction and
age-related cognitive decline and the development of AD. This study seeks
to identify genetic variants associated with olfactory identification in older
adults using a non-hypothesis driven approach.Methods: Participants were
community-dwelling non-demented adults from the Sydney Memory and
Ageing Study, who were aged 70-90 years at baseline. Genome-wide geno-
typingwas undertaken using the Affymetrix SNP 6.0 array and APOEE 2/3/
4 genotyping was performed using Taqman assays. Genome-wide analyses
were undertaken to identify single-nucleotide polymorphisms that were as-
sociated with baseline performance on the 12-item Brief Smell Identifica-
tion Test (BSIT). Analyses were conducted controlling for (i) age and sex
and (ii) age, sex and current smoking. Results: In this sample, younger
age, female sex and non-current smokers were associated with better olfac-
tory identification scores using BSIT. However, APOE E 4 carrier status was
not associated with BSIT scores. Genome-wide genotyping data were avail-
able for 925 individuals and 734,550 SNPs remained in the analysis after
quality control checks. One intergenic SNP located on chromosome 5 ap-
proached genome-wide significance (P ¼ 5.5 x 10 -8) when the analyses
were adjusted for age and sex. When controlling for all covariates, this
SNP remained suggestive (P ¼1.48 x 10 -7). Other suggestive hits were
also observed (P<1 x 10 -5) when controlling for (i) age and sex and (ii)
for all covariates. Conclusions: This study identified suggestive SNPs for
odour identification in a population study of older adults. These results
will require confirmation and further investigation in independent cohorts.
P4-112 GENETIC ASSOCIATION AND INTERACTION OF
ALZHEIMER’S RISK GENES CLU, CR1, BIN1,
PICALM AND MS4A IN A FLANDERS-BELGIAN
COHORT
Karolien Bettens1, Caroline Van Cauwenberghe1, Elise Cuyvers1,
Nathalie Le Bastard2, Sebastiaan Engelborghs3, Rik Vandenberghe4,
Peter De Deyn5, Christine Van Broeckhoven1, Kristel Sleegers1, 1VIB and
Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; 2Institute
Born-Bunge, University of Antwerp, Antwerp, Belgium; 3Department of
Neurology and Memory Clinic, Hospital Network Antwerp (ZNA)
Middelheim and Hoge Beuken, and Institute Born-Bunge, University of
Antwerp, Antwerp, Belgium; 4Department of Neurology, University
Hospitals Leuven and University of Leuven (KULeuven), Leuven, Belgium;5Department of Neurology and Memory Clinic, Hospital Network Antwerp
(ZNA) Middelheim and Hoge Beuken, and Institute Born-Bunge, University
of Antwerp, Antwerp, Belgium.
Background: Large-scale genome wide association (GWA) studies on Alz-
heimer’s disease (AD) have led to substantial breakthroughs in deciphering
its genetic architecture. Compelling evidence of association was shown for
variations in 9 risk genes (CLU, CR1, PICALM, BIN1, CD2AP, EPHA1,
ABCA7, MS4A gene cluster and CD33). We aimed at evaluating the contri-
bution of these 9 genes to AD risk association in an extended Flanders-Bel-
gian AD-control cohort. Further, we tested for significant variant interaction
between the 9 genes and APOE. Finally, we investigated whether the asso-
ciated variants correlated with cerebrospinal fluid biomarker profiles.
Methods: We genotyped GWA top SNPs in ABCA7, CD2AP, EPHA1,
CD33 and MS4A cluster and fine-mapped the genomic CLU (15 SNPs),
CR1 (28 SNPs), BIN1 (24 SNPs) and PICALM (19 SNPs) loci in 1173
AD patients and 983 control individuals. Coding CLU exons were se-
quenced and copy number variants in CR1 were quantified. CSF levels of
Ab1–42, T-tau and P-tau181P were available for 347 patients.Results: Signif-
icant associations were replicated for GWA top SNPs in CLU, CR1, BIN1,
PICALM andMS4A (p-values ranging between 0.001 and 0.042). Fine-map-
ping of CLU, CR1 and PICALM loci showed additional common and rare
variant associations. Associations for CLU and CR1 were predominantly
found in APOE-ε4 carriers, while MS4A and ABCA7 were associated in
APOE-ε4 negative individuals only. No interaction was observed between
associated SNPs and APOE-ε4 status. We observed interaction between
CR1 and BIN1 and CLU and BIN1, and borderline interaction for BIN1
and PICALM (P ¼ 0.05). Interestingly, variants in CD2AP, PICALM,
BIN1 were associated with levels of T-tau or P-tau181P while variants in
CLU, CR1 and ABCA7 were associated with levels of Ab1–42 in CSF (p-
values <0.05). Conclusions: We confirmed that genetic variations in
CLU, CR1, PICALM, BIN1 and MS4A are increasing risk for AD in the
Flanders-Belgian cohort. Further, we report for the first time evidence for
epistatic interaction between CR1 and BIN1 and between CLU and BIN1
variants. Correlation with AD biomarker profiles highlights possible impli-
cation in amyloid (CLU, CR1, ABCA7) and tau biology (CD2AP, PICALM,
BIN1).
P4-113 ASSOCIATION BETWEEN PROMOTER
POLYMORPHISMS OF THE GRP78 GENE AND
RISK OFALZHEIMER’S DISEASE IN A CHINESE
HAN POPULATION
Keshen Li, Affiliated Hospital of Guangdong Medical College, Zhanjiang,
China.
Background: GRP78 (78-kiloDalton glucose-regulated protein), also re-
ferred to as BiP (immunglobulin heavy-chain binding protein), belongs to
the heat-shock protein 70 family that resides primarily in the endoplasmic
reticulum (ER). As a major ER chaperone, interaction of GRP78 with am-
yloid precursor protein (APP) in the ER modulates intracellular APP matu-
ration and processing and may facilitate its correct folding. Recently,
polymorphisms in promoter region of GRP78, which were known to be