Impact of SORL1 Single Nucleotide Polymorphisms on Alzheimer's Disease Cerebrospinal Fluid Markers

ArticleinDementia and Geriatric Cognitive Disorders 32(3):164-70 · December 2011with12 Reads
Impact Factor: 3.55 · DOI: 10.1159/000332017 · Source: PubMed
Abstract

Recently, genetic variants of the neuronal sortilin-related receptor with A-type repeats (SORL1, also called LR11 or sorLA) have emerged as risk factors for the development of Alzheimer's disease (AD). In this study, SORL1 gene polymorphisms, which have been shown to be related to AD, were analyzed for associations with cerebrospinal fluid (CSF) amyloid beta1-42 (Aβ(1-42)), phosphorylated tau181, and total tau levels in a non-Hispanic Caucasian sample, which encompassed 100 cognitively healthy elderly individuals, 166 patients with mild cognitive impairment, and 87 patients with probable AD. The data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu/ADNI). Moreover, the impact of gene-gene interactions between SORL1 single nucleotide polymorphisms (SNPs) and the apolipoprotein E (APOE) ε4 allele, the major genetic risk factor for sporadic AD, on Aβ(1-42) concentrations was investigated. Significant associations between CSF Aβ(1-42) levels and the SORL1 SNPs 23 (rs3824968) and 24 (rs2282649) were detected in the AD group. The latter association became marginally statistically insignificant after Bonferroni correction for multiple comparisons. Carriers of the SORL1 SNP24 T allele and the SNP23 A allele both had lower CSF Aβ(1-42) concentrations than non-carriers of these alleles. The analysis of the impact of interactions between APOE ε4 allele and SORL1 SNPs on CSF Aβ(1-42) levels unraveled significant influences of APOE. Our findings provide further support for the notion that SORL1 genetic variants are related to AD pathology, probably by regulating the amyloid cascade.

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Available from: Panagiotis Alexopoulos, Jun 08, 2015
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O r i g i n a l R e s e a r c h A r t i c l e
Dement Geriatr Cogn Disord 2011;32:164170
DOI: 10.1159/000332017
Impact of SORL1 Single Nucleotide
Polymorphisms on Alzheimers Disease
Cerebrospinal Fluid Markers
Panagiotis Alexopoulos Liang-Hao Guo Martina Kratzer
Christine Westerteicher Alexander Kurz Robert Perneczky
Alzheimer’s Disease Neuroimaging Initiative
Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technische Universität München,
Munich , Germany
ciations between CSF A
1–42
levels and the SORL1 SNPs 23
(rs3824968) and 24 (rs2282649) were detected in the AD
group. The latter association became marginally statistically
insignificant after Bonferroni correction for multiple com-
parisons. Carriers of the SORL1 SNP24 T allele and the SNP23
A allele both had lower CSF A
1–42
concentrations than non-
carriers of these alleles. The analysis of the impact of interac-
tions between APOE 4 allele and SORL1 SNPs on CSF A
1–42
levels unraveled significant influences of APOE . Conclu-
sions: Our findings provide further support for the notion
that SORL1 genetic variants are related to AD pathology,
probably by regulating the amyloid cascade.
Copyright © 2011 S. Karger AG, Basel
Key Words
Dementia Mild cognitive impairment Healthy aging
Amyloid cascade Association
Abstract
Background: Recently, genetic variants of the neuronal sor-
tilin-related receptor with A-type repeats (SORL1, also called
LR11 or sorLA) have emerged as risk factors for the develop-
ment of Alzheimer’s disease (AD). Methods: In this study,
SORL1 gene polymorphisms, which have been shown to be
related to AD, were analyzed for associations with cerebro-
spinal fluid (CSF) amyloid beta1–42 (A
1–42
), phosphorylated
tau181, and total tau levels in a non-Hispanic Caucasian sam-
ple, which encompassed 100 cognitively healthy elderly in-
dividuals, 166 patients with mild cognitive impairment, and
87 patients with probable AD. The data were obtained from
the Alzheimer’s Disease Neuroimaging Initiative (ADNI) da-
tabase (www.loni.ucla.edu/ADNI). Moreover, the impact of
gene-gene interactions between SORL1 single nucleotide
polymorphisms (SNPs) and the apolipoprotein E (APOE) 4
allele, the major genetic risk factor for sporadic AD, on A
1–42
concentrations was investigated. Results: Significant asso-
Accepted: August 3, 2011
Published online: October 13, 2011
Dr. Panagiotis Alexopoulos
Klinik und Poliklinik für Psychiatrie und Psychotherapie
Technische Universität München , Ismaninger Strasse 22
DE–81675 München (Germany)
Tel. +49 89 4140 4214, E-Mail panos.alexopoulos
@ lrz.tum.de
© 2011 S. Karger AG, Basel
1420–8008/11/0323–0164$38.00/0
Accessible online at:
www.karger.com/dem
P.A. and L.-H.G. contributed equally to this work.
Data used in preparation of this article were obtained from the Alz-
heimer’s Disease Neuroimaging Initiative (ADNI) database (www.
loni.ucla.edu/ADNI). As such, the investigators within the ADNI con-
tributed to the design and implementation of ADNI and/or provided
data, but did not participate in analysis or writing of this report. A
complete listing of ADNI investigators can be found at: http://adni.
loni.ucla.edu/research/active-investigators.
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Impact of SORL1 SNPs on AD CSF
Markers
Dement Geriatr Cogn Disord 2011;32:164–170
165
Introduction
The causes of late-onset Alzheimer’s disease (AD) are
multifactorial and complex
[1] . Twin studies suggest that
around 3778% of the variance in age at onset of clinical
AD can be explained by additive genetic effects
[1] . In re-
cent years, the gene encoding the neuronal sortilin-relat-
ed receptor with A-type repeats (SORL1, also called LR11
or sorLA) has emerged among others as a candidate ge-
netic risk factor for AD
[2] . It is located on chromosome
11q23.2–q24.2 and encodes a membrane protein which is
specifically expressed in neurons. Several studies have
replicated the initial observation of the genetic associa-
tion between SORL1 and AD
[3–13] . Nonetheless, no gen-
eral consensus on the role of SORL1 genetic variants as
risk factors for AD exists, since other investigations only
found weak or no associations between SORL1 genetic
variants and AD
[14 –19] . Furthermore, the detected al-
lelic associations varied across studies and the impact on
AD risk were only modest with odds ratios ranging from
1.4 to 2.2
[1] . However, a recent meta-analysis of all avail-
able data derived from studies including individuals of
Caucasian or Asian origin confirmed that variants in the
SORL1 gene are related to risk for AD
[20] .
SORL1 is a member of the apolipoprotein E (APOE)
and low-density lipoprotein receptor family; it is diffuse-
ly expressed throughout the brain and acts as an intracel-
lular sorting receptor that engages in the Golgi appara-
tus-endosome transport
[21] . SORL1 is thought to be cru-
cially involved in the sorting of amyloid precursor protein
(APP) and in its interactions with secretases
[22, 23] . Low
levels of SORL1 lead to overproduction of amyloid beta
(A )
[2] . Interestingly, it has been reported that in pa-
tients with AD the expression of SORL1 is decreased in
neurons
[24, 25] . Attempting to unravel possible associa-
tions between SORL1 gene variants and biomarkers [26]
of AD is a challenging task that may offer a meaningful
contribution to our understanding of AD pathogenesis.
Due to the role of SORL1 in the processing of APP, we
explored possible associations between sequence varia-
tions within SORL1 and established cerebrospinal fluid
(CSF) markers of amyloid pathology (A
1–42
) and axonal
degeneration (total tau, tTau; tau phosphorylated at thre-
onine 181, pTau
181
) in a large sample of patients with
probable AD, mild cognitive impairment (MCI), and
cognitively healthy control subjects. Additionally, the im-
pact of sequence variations within SORL1 on A
1–42
lev-
els in CSF was investigated in association with the pres-
ence of an APOE 4 allele, since APOE 4 constitutes the
major genetic predisposition factor for the development
of late-onset AD
[27] and since SORL1 levels in CSF are
particularly increased in patients with AD carrying the
APOE 4 allele
[28] .
Materials and Methods
The data used in this study were obtained on September
9, 2010, from the Alzheimer’s Disease Neuroimaging Initia-
tive (ADNI) database (www.loni.ucla.edu/ADNI). ADNI was
launched in 2003 by the National Institute on Aging, the Nation-
al Institute of Biomedical Imaging and Bioengineering, the Food
and Drug Administration, private pharmaceutical companies,
and non-profit organizations as a USD 60 million 5-year public-
private partnership. The primary goal of ADNI has been to ex-
plore whether serial MRI, PET, other biological markers, and clin-
ical and neuropsychological data can be combined to assess the
progression of MCI and early AD. The determination of sensitive
and specific markers of very early AD progression is intended to
support researchers and clinicians to develop new treatments and
monitor their effectiveness, as well as lessen the time and costs of
clinical trials. The principal investigator of this initiative is Mi-
chael W. Weiner, MD, VA Medical Center and University of Cal-
ifornia San Francisco, USA. ADNI is the result of a broad col-
laboration of academic institutions and private corporations.
Subjects have been recruited from over 50 sites across the USA
and Canada. The initial goal of ADNI was to recruit 800 adults
aged 55–90 years to participate in the research: approximately 200
cognitively normal older individuals to be followed for 3 years;
400 people with MCI to be followed for 3 years; and 200 people
with early AD to be followed for 2 years. Detailed information on
ADNI can be found in previous publications and at www.adni-
info.org. The study was approved by the institutional review
boards of all participating centers and written informed consent
was obtained from all participants or authorized representatives
after extensive description of ADNI.
Baseline CSF samples were obtained from 416 ADNI subjects
and analyzed at the ADNI biomarker core laboratory at Univer-
sity of Pennsylvania; the detailed sampling methods have been
described previously
[29] . The CSF concentrations of A
1–42
,
tTau, and pTau
181
were measured using the multiplex xMAP Lu-
minex platform (Luminex Corp, Austin, Tex., USA) with Innoge-
netics immunoassay kit-based reagents (INNO-BIA AlzBio 3;
Ghent, Belgium; for research use-only reagents). From 416 sam-
ples, 410 passed quality control and an additional subject later
failed ADNI screening, resulting in 409 valid CSF samples. This
sub-sample is comparable to the entire ADNI cohort regarding
demographic, clinical, and APOE genotyping results.
Single nucleotide polymorphism (SNP) genotyping for more
than 620,000 target SNPs was performed on all ADNI participants
according to published protocols
[29] . Genomic DNA samples
were analyzed using the Human 610-Quad BeadChip (Illumina
Inc., San Diego, Calif., USA) according to the manufacturer’s in-
structions (Inf inium HD Assay; Super Protocol Guide; rev. A, May
2008). SNP genotypes were generated in Illumina BeadStudio
software v3.2 from bead intensity data. The previously reported
most significant SORL1 SNPs for AD were selected from the lit-
erature
[1, 20] . These markers included rs661057 (SNP4), rs668387
(SNP8), rs689021 (SNP9), rs641120 (SNP10), rs2070045 (SNP19),
Page 2
Alexopoulos et al.
Dement Geriatr Cogn Disord 2011;32:164–170
166
rs1699102 (SNP22) and rs3824968 (SNP23), rs2282649 (SNP24)
and rs1010159 (SNP25). SNP23 and SNP24 are not available in the
ADNI database. Therefore, they were genotyped at Washington
University St. Louis as part of genome-wide association studies
[30] . The present analysis was restricted to non-Hispanic Cauca-
sians, who were identified in the clinical database and whose ge-
notype data of SORL1 SNPs were available. The final sample with
genotype data for the present report included 353 individuals (100
controls, 166 patients with MCI, and 87 patients with AD).
Regarding the statistical analysis, a stepwise discriminant
analysis, employing multiple linear regression models in PASW
software v17 (SPSS Inc., Chicago, Ill., USA), was used to identify
potential significant covariates for CSF tTau pTau
181
and A
1–42
levels. The potential confounding variables that were tested were
age, gender distribution, Mini Mental State Examination (MMSE)
scores and the presence of the APOE 4 allele (dichotomized into
carriers and non-carriers of the allele). Subsequently, separate lin-
ear regression analysis models with the CSF parameters as depen-
dent variables were built to assess the impact of SORL1 SNPs on
the neurodegeneration parameter concentrations after adjust-
ment for the appropriate covariates. In order to unravel the influ-
ence of possible gene-gene interactions between the aforemen-
tioned SORL1 SNPs and the APOE 4 allele on A
1–42
concentra-
tions, the interaction parameter SORL1 SNP genotype ! APOE
4 carriers/non-carriers was fed as the independent factor togeth-
er with the significant covariates detected in the first step of the
analysis into a linear regression analysis model with A
1–42
as the
dependent factor. A Bonferroni correction for multiple compari-
sons was applied to the significance threshold of p ! 0.05; this
yielded a Bonferroni corrected p ! 0.006. To compare the distri-
butions of the dependent variables with the normal distribution,
normal p-p plots of regression standardized residuals were gener-
ated, which plot the cumulative proportions of standardized re-
siduals of the dependent variable against the cumulative propor-
tions of the respective normal distribution. The normality as-
sumption was supported by these plots (results not shown).
R e s u l t s
Characteristics and SNP distributions of the sample
are given in table1 . In the AD group, APOE (p ! 0.001,
n = 87), age (p = 0.02, n = 87), and gender (p = 0.04, n =
87) were associated with A
1–42
, and age with pTau
181
(p ! 0.01, n = 87). In the MCI group, there was an asso-
ciation between APOE and pTau
181
(p ! 0.01, n = 166),
APOE and A
1–42
(p ! 0.001, n = 166), as well as APOE
(p ! 0.01, n = 166) and gender (p = 0.02, n = 166) with
tTau. In the control group, APOE was correlated with
A
1–42
(p ! 0.001, n = 100) and tTau (p = 0.02, n = 100),
as well as APOE (p ! 0.01, n = 100) and age (p = 0.02, n =
100) with pTau
181
. The separate multivariate variance
analyses yielded, after Bonferroni correction for multi-
ple comparisons, a significant association between CSF
A
1–42
and the A allele of the SORL1 SNP23 (p = 0.003,
n = 87) in the AD group. SORL1 SNP23 A allele carriers
had lower CSF A
1–42
concentrations than non-carriers
(carriers vs. non-carriers: mean 8 SD, 131.77 8 35.65 vs.
154.56 8 45.85 ng/l; fig.1 ). Interestingly, the presence of
Table 1. Characteristics of the study sample
Control group MCI group AD group
Patients, n 100 166 87
Age, years
75.7585.32 74.9887.41 74.8487.52
Men:women 50:50 114:52 50:37
MMSE score
29.0481.06 26.9381.81 23.4981.93
APOE 4 carriers, n
59258
CSF A
1–42
, ng/l
205.46855.76 162.45854.38 144.3482.90
pTau
181
, ng/l
25.27815.21 36.20818.19 42.46820.54
tTau, ng/l
69.82831.00 104.39859.78 123.01858.89
SNP4 (rs661057) TT/CT/CC 32/48/20 62/75/29 36/36/15
SNP8 (rs668389) CC/CT/TT 27/46/27 60/78/28 40/35/12
SNP9 (rs689021) GG/AG/AA 26/45/29 59/79/28 37/39/11
SNP10 (rs641120) TT/CT/CC 27/42/31 28/72/66 12/34/41
SNP19 (rs2070045) TT/GT/GG 61/34/5 110/48/8 59/26/2
SNP22 (rs1699102) TT/CT/CC 47/38/15 78/69/19 44/38/5
SNP23 (rs3824968) TT/AT/AA 49/42/9 83/70/13 48/34/5
SNP24 (rs22822649) CC/CT/TT 50/41/9 17/80/69 49/22/5
SNP25 (rs1010159) TT/CT/CC 43/43/14 69/80/17 43/39/5
Data are presented as means 8 SD, unless otherwise indicated.
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Impact of SORL1 SNPs on AD CSF
Markers
Dement Geriatr Cogn Disord 2011;32:164–170
167
the SORL1 SNP24 T allele was also significantly associ-
ated with CSF A
1–42
levels in patients with AD (p =
0.007, n = 87). However, this association marginally failed
to survive the Bonferroni correction. In carriers of the
SORL1 SNP24 T allele, lower CSF A
1–42
concentrations
were detected (carriers vs. non-carriers: 127.76 8 25.74
vs. 157.20 8 49.00 ng/l; fig.1 ). Furthermore, SORL1
SNP8 genotypes (p = 0.04, n = 87) and SNP25 genotypes
(p = 0.03, n = 87) were associated with CSF A
1–42
levels.
Nonetheless, these associations did not remain statisti-
cally significant after Bonferroni correction. Unexpect-
edly, such a trend was also observed in the group of pa-
tients with MCI between pTau
181
and SORL1 SNP24 ge-
notypes (p = 0.03, n = 166), which did not reach statistical
significance after Bonferroni correction. No further as-
sociations were detected between SORL1 SNPs and CSF
protein concentrations in any of the three study groups.
In line with the literature, the presence of the APOE 4
allele was associated with lower CSF A
1–42
concentra-
tions in all three study groups (p ! 0.001 for all groups).
The interactions between the APOE 4 allele and SORL1
SNP23 genotypes (p = 0.001, n = 87), SNP24 genotypes
(p = 0.004, n = 84), SNP25 genotypes (p = 0.009, n = 87),
SNP8 genotypes (p = 0.03, n = 87), and SNP9 genotypes
(p = 0.04, n = 87) were found to exert significant influ-
ences on CSF A
1–42
concentrations in patients suffering
from AD. The influence of the former two interaction
factors on A
1–42
remained statistically significant after
Bonferroni correction. No further significant associa-
tions were observed.
Discussion
SORL1 is listed among the top 10 AD risk genes in the
Alzgene.org database (accessed on February 6, 2011)
[31] .
In the present study, associations between variants of the
SORL1 gene and established CSF biomarkers of AD pa-
thology were investigated in patients with probable AD
and MCI, as well as healthy elderly controls. The main
finding of our study is that patients with probable AD
carrying the SORL1 SNP23 A allele had lower levels of
A
1–42
compared with non-carriers. Moreover, a margin-
al association was also detected between the presence of
the SORL1 SNP24 T allele and A
1–42
in patients with
probable AD. Other studied SORL1 SNPs tended to relate
to altered levels of A
1–42
or pTau
181
. However, these as-
sociations did not survive Bonferroni correction.
A number of studies have tried to dig up biological
evidence for a role of SORL1 in AD, suggesting an influ-
ence of SORL1 gene variants on AD endophenotypes. In
contrast to our results, a study which derived its sample
from the population-based Swedish Twin Registry
[32]
and an investigation partly using ADNI data
[30, 33]
both failed to detect associations between SORL1 SNPs
and CSF biomarkers of AD. Three possible reasons
might be responsible for this inconsistence. Firstly, the
former study significantly differed from our study in
terms of gender distribution within the AD group (
2
test, p ! 0.001). Our analysis revealed that gender influ-
enced the levels of A
1–42
in the AD group. This finding
is in line with the previously reported association be-
tween SORL1 gene variants and gender
[13] and with re-
ports from AD transgenic animal models indicating an
impact of gender on amyloid pathology
[34] Secondly,
our study was restricted to individuals with a non-His-
panic Caucasian ancestry, whereas the Swedish Twin
Registry Study comprised individuals drawn from the
multiethnic Swedish society regardless of their origin. A
recent meta-analysis on the association between vari-
ants in SORL1 and AD showed clear deviations in the
AD associated SORL1 SNPs in the different ethnic
groups
[20] Thirdly, in the referenced ADNI study [30] ,
patients with probable AD and MCI as well as healthy
controls were treated as a single group, and no separate
analyses were performed in each of the three groups. As
a consequence it is possible that the effect of SORL1 vari-
ants on A
1–42
in the group of patients with AD was
masked by the absence of such effects in the rest of the
sample. A German multicenter study, which was not re-
stricted to non-Hispanic Caucasians, identified an as-
sociation between A
1–42
and SORL1 SNP21 in 153 pa-
Non-T-carriers
0
100
200
300
Non-A-carriers
A
1–42
in CSF (ng/l)
A-carriers
SORL1 rs3824968 (SNP23) SORL1 rs2282649 (SNP24)
T-carriers
Fig. 1. CSF A
1–42
concentrations in relation to SORL1 SNPs 23
and 24 in the AS group (mean value indicated by horizontal line).
Page 4
Alexopoulos et al.
Dement Geriatr Cogn Disord 2011;32:164–170
168
tients with AD [35] . Such an association could not be
replicated in our study sample. In addition, it should be
underscored that linking gene variants with discrete
variations in biological markers is a challenging task. It
is possible that the investigated genetic variants exert a
direct influence on the biomarker levels, but it is also
plausible that the genetic variation mediates an effect
through other downstream functional change or through
the regulation of other genes
[36] . These caveats must be
borne in mind when the observed influence of SORL1
genetic variants on A
1–42
is considered or deviations in
study observations are interpreted.
The detected significant influence of SORL1 SNP23 A
allele and SNP24 T allele on A
1–42
was restricted to pa-
tients suffering from AD and no association between
SORL1 polymorphisms and CSF A
1–42
concentrations
was observed in patients with MCI. Although the clinical
entity of MCI represents in many cases a prodromal
phase of AD, it is not exclusively caused by AD and it has
a variable prognosis
[37–38] . Since the diagnosis of MCI
in our study was based on clinical criteria, the MCI group
probably did not exclusively encompass patients with in-
cipient AD in whom an association between SORL1 SNPs
and A
1–42
could be expected. As a consequence it can be
reckoned that the presence of the aforementioned alleles
may foster alterations, for instance in SORL1 shedding or
intracellular concentrations
[22, 28, 39] , which exclusive-
ly occur in patients with AD pathology.
Decreased CSF A
1–42
levels are generally found in
AD and it has been reported that A
1–42
concentrations
decrease with disease progression
[35, 40] , although not
in all published studies
[41] . Thus, it might be argued that
reduced levels of A
1–42
in patients with AD possessing
the SORL1 SNP24 T allele or the SORL1 SNP23 A allele
are attributable to differences in the severity of amyloid
pathology. However, in line with previous observations
[35] no impact of MMSE scores, mirroring clinical dis-
ease severity, on CSF concentrations of A
1–42
was ob-
served in our sample.
The revealed impact of gene-gene interactions be-
tween SORL1 genetic variants and the presence of the
APOE 4 allele on A
1–42
provides further evidence for
possible interactions between APOE and SORL1 , which
may affect the pathogenesis of AD. SORL1 binds multiple
ligands including APOE and induces the endocytosis
of APOE-containing lipoproteins
[42] . Interactions be-
tween SORL1 and APOE might interfere with the forma-
tion of the APOE-A complex, which has been detected
in the CSF, and this process may foster the deposition of
A in brain by increasing unbound A species
[28] .
The trend of SORL1 SNP24 to affect the levels of
pTau
181
in patients with MCI was unexpected since
SORL1 has been shown to be implicated in the sorting of
APP and in its interactions with the secretases
[22] and
not in the processes of hyperphosphorylation of tau.
Though it cannot be ruled out with final certainty that
this observation is due to a type I error, this finding is in-
triguing especially in the light of the absence of such an
association in patients with AD. Further investigations
are warranted, since SORL1 SNP24 may be involved in
the interrelation between the amyloid cascade and the
hyperphopshorylation processes of tau
[43] or hypothet-
ically through gene-gene interactions in the molecular
mechanisms inducing tau hyperphosphorylation in pa-
tients suffering from pathologies other than AD (e.g.
frontotemporal lobar degeneration, Lewy-body patholo-
gy), which also lead to the clinical entity of MCI.
Though relatively large for a CSF investigation, it can
be claimed that the present study sample is of limited size.
However, our findings are in line with previous publica-
tions, which reported that SORL1 exerts a relevant influ-
ence on amyloid metabolism and thus on AD risk and
pathology
[20–23] . Nonetheless, replication studies with
independent larger samples are warranted.
To conclude, our findings show that SORL1 variants
have a significant influence on brain amyloid pathology
within the framework of AD. Therefore, our results pro-
vide further in vivo validation of SORL1 as a risk gene for
AD and stress the need for subsequent studies to unveil
its pathogenic and clinical relevance
[44] .
Acknowledgments
The study was supported by the Kommission für Klinische
Forschung of the Klinikum rechts der Isar München (grant No.
B06-09, B08-10). Data collection and sharing for this project was
funded by the ADNI (National Institutes of Health grant U01
AG024904). ADNI is funded by the National Institute on Aging,
the National Institute of Biomedical Imaging and Bioengineer-
ing, and through generous contributions from the following: Ab-
bott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers
Squibb, Eisai Global Clinical Development, Elan Corporation,
Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics,
Johnson and Johnson, Eli Lilly and Co., Medpace, Inc., Merck
and Co., Inc., Novartis AG, Pfizer Inc., F. Hoffman-La Roche,
Schering-Plough, Synarc, Inc., as well as non-profit partners in-
cluding the Alzheimer’s Association and Alzheimer’s Drug Dis-
covery Foundation, with participation from the US Food and
Drug Administration. Private sector contributions to ADNI are
facilitated by the Foundation for the National Institutes of Health
(www.fnih.org). The grantee organization is the Northern Cali-
fornia Institute for Research and Education, and the study is co-
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Impact of SORL1 SNPs on AD CSF
Markers
Dement Geriatr Cogn Disord 2011;32:164–170
169
ordinated by the Alzheimer’s Disease Cooperative Study at Uni-
versity of California San Diego. ADNI data are disseminated by
the Laboratory for Neuroimaging at University of California Los
Angeles. This research was also supported by NIH grants
P30AG010129, K01 AG030514, and the Dana Foundation. The
sponsors did not have any role in the design and conduct of the
study; collection, management, analysis, and interpretation of
the data; and preparation, review, or approval of the manuscript.
The authors wish to thank John S.K. Kauwe, PhD, and Carlos
Cruchaga, PhD, from the Department of Biology at Brigham
Young University, Provo, Utah, and Alison M. Goate, DPhil,
from the Department of Psychiatry at Washington University
School of Medicine, St. Louis, Mo., for sharing some of the geno-
typing information used for this study, and for valuable discus-
sion on the manuscript.
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