Associations between TOMM40 poly-T repeat variants and
dementia in cases with parkinsonism
Daniel Lindqvist, MD, PhD 1,2*, Inga Prokopenko PhD 3, Elisabet Londos, MD, PhD 4,5,
Lefkos Middleton, MD 3, Oskar Hansson, MD, PhD 4,5
1 Department of Clinical Sciences, Section for Psychiatry, Lund University, Lund,
Sweden 2 Psychiatry Skåne, Lund, Sweden 3 Neuroepidemiology and Ageing
Research, School of Public Health, Imperial College London, UK 4 Clinical Memory
Research Unit, Department of Clinical Sciences, Lund University, Malmö, Sweden
5Memory Clinic, Skåne University Hospital, Lund, Sweden.
* Correspondence to: Daniel Lindqvist, Department of Clinical Sciences, Section for
Psychiatry, Lund University, Lund, Sweden. Email: [email protected].
Adress: Baravägen 1, SE-221 85, Lund, Sweden; phone: +46-46 174474; fax: +46-
46-176048
Running title: TOMM40 poly-T repeat variants in PDD and DLB
1
Abstract
Background: Mitochondrial dysfunction has been implicated in the pathophysiology of
Parkinson’s disease (PD)-related pathologies.
Objective: To investigate the role of the Translocase of the Outer Mitochondrial
Membrane 40 homolog (TOMM40) variants in PD without dementia (PDND), PD with
dementia (PDD) and in Dementia with Lewy bodies (DLB).
Methods: 248 individuals, including 92 PDND, 55 PDD, and 101 DLB, were included.
The rs10524523 locus in the TOMM40 gene (TOMM40 poly-T repeat) is
characterized by a variable number of T residues that were classified into three
groups based on length; short (S), long (L), and very long (VL). We tested log-
additive genetic model of association with dementia and adjusted for age, sex, and
APOE ε4 carrier status. We analyzed cerebrospinal fluid (CSF) levels of Aβ42 and
Tau, biomarkers related to Alzheimer's disease (AD).
Results: PDD/DBL status and abnormal CSF AD biomarkers (Aβ42 and Aβ42/Tau ratio)
were both associated with the APOE ε4 allele (p<0.014) and the L allele of TOMM40
poly-T repeat (p<0.008). The VL allele was less frequently observed in the PDD/DLB
group (p=0.013). In APOE-ε4 adjusted analyses, the relationships between the L and
VL alleles and dementia status as well as CSF AD biomarkers were not significant.
When adjusting for APOE-ε4, however, there were associations between S carrier
status and PDD/DLB (p=0.019) and abnormal CSF levels of Aβ42/Tau ratio (p=0.037)
although these were not significant after adjustment for multiple comparisons.
2
Conclusion: Our results do not support the notion that TOMM40 poly-T repeat
variants have independent effects on PDD and DLB pathology. This relationship
seems to be driven by APOE-ε4.
Key words: PDD, DLB, TOMM40, APOE, Parkinson’s disease
3
Introduction
Alzheimer´s disease (AD), Parkinson´s disease (PD) and associated phenotypes
have been conceptualized as a complex continuum of late onset neurodegenerative
conditions potentially sharing common underlying pathophysiological mechanisms
[1]. The two PD associated dementia forms, Parkinson’s disease with dementia
(PDD) and Dementia with Lewy Bodies (DLB) share common clinical and
pathological findings, their main distinctive feature being the timing of dementia onset
with respect to the onset of motor parkinsonian signs [2].
Mitochondrial dysfunction has been implicated in the pathophysiology of AD- and PD-
related pathologies [3, 4]. The encoded product of the Translocase of the Outer
Mitochondrial Membrane 40 homolog (TOMM40) gene is involved in protein
transportation into mitochondria. The rs10524523 locus in the TOMM40 gene
(TOMM40 poly-T repeat) is characterized by a variable number of T residues that
have been classified into three groups, based on length; short (S), long (L), and very
long (VL) [5]. Adjacent to TOMM40 (on chromosome 19q13.2) is the apolipoprotein E
(APOE) gene, which encodes a protein known to play an important role in cholesterol
metabolism, in particular, in the central nervous system [6]. There are three APOE
allelic variants that have been well-described in the literature: APOE-ε2, APOE-ε3,
and APOE-ε4 [7]. APOE and TOMM40 are in linkage disequilibrium (LD); the APOE-
ε4 allele has been linked to the L allele of TOMM40 poly-T repeat and the APOE-ε3
allele has been linked to the S and VL alleles, whereas the APOE-ε2 allele has been
linked mostly to the S allele [5, 8]. Interestingly, a recent meta-analysis of genome-
wide association studies showed that both APOE and TOMM40 were associated with
4
general cognitive function in middle-aged and older adults [9].
It is now widely acknowledged that APOE-ε4 is a major risk factor for the non- familial
common late-onset form of AD. A meta-analysis has confirmed this and concluded
that the APOE-ε2/ε3 genotype may confer protection[10]. Studies on PD have shown
that APOE-ε2 might be a risk allele for PD, whereas the APOE-ε4 allele is associated
with increased risk for PDD [11, 12]. Contrarily, another large-scale study, did not
report a significant association between APOE and PD diagnosis, or between APOE
and MMSE scores within the PD group. In this study, however, the MMSE range was
26-30, thus the relationship between APOE and PD-related dementia was not tested
[13]. In a recent multi-center study, Bras et al. found that APOE is a strong genetic
risk factor also for DLB, and several SNPs associated with DLB were located within
the TOMM40 gene[14]. In a recently published review, Gottschalk et al., reported
unpublished data from a small case-control study and a post-mortem investigation in
support of an association between Lewy body pathology and TOMM40 poly-T repeat
[15].
Lower levels of β-amyloid42 (Aβ42) and higher levels of Tau in cerebrospinal fluid
(CSF) are strongly associated with presence of Aβ-containing neuritic plaques and
tau-containing neurofibrillary tangles, respectively, in subjects with AD [16, 17].
Carrier status of the APOE-ε4 allele has been associated with lower CSF Aβ4 levels
in elderly controls and in cases with AD, although the association with CSF Tau is
less robust [18]. The relationship between APOE genotype and CSF Aβ42 and Tau
has been less studied in patients with PD-related disorders, but there is evidence that
PD subjects with the APOE-ε4 allele exhibit lower CSF Aβ42 levels [19]. There are yet
5
few studies evaluating the relationship between TOMM40 poly-T repeat and CSF AD
biomarkers. Cruchaga and colleagues found a strong association between TOMM40
poly T repeat and CSF Aβ42 levels in subjects with AD, although this association was
not significant when APOE genotype was added as a covariate in the model [20].
Alpha-synuclein is a protein that contribute to the pathophysiology of PD-related
conditions such as DLB [21], and some experimental studies suggest that it might
also be involved in mitochondrial dysfunction [15, 22].
No previously published studies have investigated TOMM40 common genetic
variants in PDD or DLB. Peplonska et al. did not find any associations between PD
risk and TOMM40 genotype or allele frequencies, but did not investigate specific
effects on PDD or DLB [23]. Even though previous studies have shown that the
APOE-ε4 allele is associated with AD, as well as PDD and DLB, the role of TOMM40
common genetic variants in PDD and DLB is yet to be elucidated. In this study, we
aimed at testing the relationship between DLB/PDD and allelic variants of TOMM40
poly-T repeat and whether these associations are independent of APOE-ε4 allele
carrier status or not. Moreover, we wanted to test the relationship betweenTOMM40
poly-T repeat and CSF levels of Aβ42 and Aβ42/Tau ratio, once again adjusting for
APOE-ε4 allele carrier status.
Materials and methods
Ethical considerations
6
The Ethics Committee of Lund University approved this study. Study participants
gave informed consent to research. The study was conducted in accordance with the
provisions of the Helsinki Declaration.
Study participants
Between 2008 and 2012, 248 subjects (89 women and 159 men, mean age 72±5
years) were recruited at the Neurology Clinic and the Memory Clinic at the Skåne
University Hospital in Lund/Malmö, Sweden. Ninety-two were diagnosed with PD - no
dementia (PDND), 55 with PDD and 101 with DLB. PD diagnosis was verified
according to the NINDS Diagnostic Criteria [24]. A diagnosis of PDD was determined
according to the Clinical Diagnostic Criteria for Dementia Associated with PD [25]. A
diagnosis of probable DLB was made according to the DLB consensus criteria [2].
Genotyping
APOE genotypes were determined by genotyping the two haplotype tagging SNPs
rs429358 (hg19 chr19:g.4541194T>C) and rs7412 (hg19 chr19:45412079C>T),
whose combination uniquely identifies the ε2/ε3/ε4 haplotypes, with rs429358 T-allele
and rs7412 C-allele indicating APOE-ε3, rs429358 T and rs7412 T indicating APOE-
ε2 and rs429358 C and rs7412 C indicating APOE-ε4. APOE genotype was missing
for one PDD/DLB subject. The TOMM40 poly T repeat rs10524523 (hg19
chr19:45403049-45403067-> polyT) was genotyped directly through PCR, obtaining
a direct read of the poly T length, which were then thus grouped as follows: length of
fewer than 20 thymine bases was classified as Short (S), length in range 20 to 30
bases was classified as Long (L) and length of 31 or more bases was classified as
7
Very Long (VL) [26]. The distinction between the L and VL alleles of TOMM40 poly-T
repeat has varied across previous studies, with some defining the L allele as <31 [26,
27] and other as <30 [28]. As noted by Roses et al. [8], this decision may be guided
by APOE genotype since the TOMM40 L allele is almost without exception linked to
the APOE-ε4 allele in whites. In our sample, all subjects with a poly T length of 30 (6
PDD/DLB subjects and 2 PDND subjects) were APOE-ε4 carriers, thus supporting
our classification of the L allele of TOMM40 poly-T repeat >31. In addition to this
approach, we also classified TOMM40 poly-T alleles based on tertiles, and re-tested
the relationship between dementia status and TOMM40 poly-T alleles using this
classification (see supplementary information). Genotyping was carried out by
Polymorphic DNA, Alameda, California, using standard PCR procedures.
CSF Samples
CSF levels of Aβ42, alpha-synuclein, and Tau were measured in CSF samples
obtained from 115 subjects (36 PDD/DLB subjects and 79 PDND subjects). Lumbar
punctures were performed between 11 am and 1 pm in the L3/L4 or L4/L5 interspace
with the patient sitting and non-fasting. The samples were collected in polypropylene
tubes and gently mixed to avoid gradient effects. All samples were centrifuged within
30 minutes at +4°C at 2000g for 10 min to remove cells and debris, and then stored
in aliquots at −80°C pending biochemical analysis. The CSF levels of Aβ42 and Tau
were quantified using EUROIMMUN Beta-amyloid1-42 ELISA and EUROIMMUN Total
Tau ELISA. CSF alpha-synuclein was analyzed with luminex assays as previously
described [29].
8
Statistical analyses
The Statistical Package for the Social Sciences (SPSS) was used for statistical
analyses. Student´s T-tests were used for group-wise comparisons. Aβ42 levels and
the Aβ42/Tau ratio were normally distributed, hence raw data was used. Pearson’s
chi-square test was used to compare proportions. Logistic regression was used to
analyze binary outcome, having PDD/DLB status as dependent variable, and allelic
variants of TOMM40 poly-T repeat as independent variables. Linear regression
models were used to test the relationship between CSF levels of Aβ42 and Tau
(dependent variable) and allelic variants of TOMM40 poly-T repeat (independent
variables). Regression models were adjusted for age, sex and APOE-ε4 allele carrier
status.
Given that we did three separate analyses (S, L, and VL allelic variants versus
PDD/DLB status, Aβ42 levels and Aβ42/Tau), p-values of <0.017 (0.05/3) were
considered significant. All tests were two-sided.
Results
Demographic characteristics
The demographics of the PDD/DLB and PDND subjects are given in Table 1. Groups
differed significantly with regards to age and CSF levels of CSF Aβ42 and Aβ42/Tau,
but not with regards to disease duration and sex distribution. The L allele of TOMM40
poly-T repeat was strongly correlated with APOE-ε4, i.e. 99% of those with the L
allele also carried the APOE-ε4 allele. APOE-ε4 allele carriers had significantly lower
levels CSF Aβ42 (P-value<0.001, t=6.6) and Aβ42/Tau (P-value<0.001, t=7.3) than
non-carriers.
9
Associations between the APOE4 allele and PDD/DLB status
Forty-six % of the PDD/DLB subjects were APOE-ε4 carriers compared to 28 % of
the PDND subjects (P-value=0.014, odds ratio (OR)=2.26, 95% confidence interval
(CI)=1.18-4.34).
Associations between allelic variants of TOMM40 poly-T repeat and PDD/DLB status
The distribution of TOMM40 poly-T alleles in the non-demented PD patients
compared to the PDD/DLB group is given in Table 2 (adjusted for age and sex). In
our series, 48% of the subjects with PDD or DLB were L carriers compared to 28% of
the PDND subjects (P-value=0.007, OR=2.43, 95% CI=1.27-4.65). Contrarily, the VL
allele was less frequently observed in the PDD/DLB group compared to PDND
subjects (P-value=0.013, OR=0.44, 95% CI=0.23-0.84). When adjusting for APOE4
allele carrier status these changes were no longer significant at the level of p<0.017,
however, there was a trend for an association between the TOMM40 poly-T S allele
and PDD/DLB status (Table 2). The main analyses were also performed with
TOMM40 poly-T alleles determined based on tertiles, and results were very similar
(see supplementary material).
To increase the likelihood that the non-demented PD sample actually represented a
“non-demented endophenotype” (as opposed to non-demented PD subjects that
would later on convert to PDD) we re-performed these group comparisons including
only those non-demented PD subjects with disease duration >5 years (n=61). In
these sub-analyses adjusting for age and sex, PDD/DLB subjects were more likely to
be TOMM40 poly-T L allele carriers (P-value=0.003, OR=3.23, 95% CI=1.51-6.92),
10
although the difference in distribution of VL (P-value=0.061, OR=0.51, 95% CI=0.25-
1.03), and S (P-value=0.535, OR=1.27, 95% CI=0.60-2.72) allele carrier status did
not differ significantly between groups.
Again, when we additionally adjusted for APOE-ε4 carrier status, the relationship
between PDD/DLB status and TOMM40 poly-T L allele carrier status was no longer
significant when comparing PDD/DLB subjects and those PDND subjects with
disease duration of more than 5 years (P-value>0.05).
Associations between allelic variants of TOMM40 poly-T repeat and CSF levels of
Aβ42 and Tau
In order to test whether the associations between allelic variants of TOMM40 poly-T
repeat and dementia in PD might be mediated via increased AD-related pathology
we also measured CSF levels of Aβ42, and tau in a subpopulation (n=115).
Associations between allelic variants of TOMM40 poly-T repeat and CSF Aβ42 and
Aβ42/Tau were tested using linear regression models in all subjects and in PDND
subjects only, adjusted for age and sex. Results are summarized in Table 3
(supplementary material). CSF levels of Aβ42 and Tau per genotype group are shown
in Figures 1 and 2 (in all subjects and in PDND subjects only).
L allele carrier status was significantly associated with lower Aβ42 (all subjects: P-
value<0.001, β=-0.49; PDND subjects only: P-value<0.001, β=-0.56), and lower
Aβ42/Tau (all subjects: P-value<0.001, β=-0.49; PDND subjects only: P-value<0.001,
β=-0.49). In all subjects, but not in PDND only, VL allele carrier status was
associated with higher Aβ42 (all subjects: P-value=0.006, β=0.25; PDND subjects
11
only: P-value=0.090, β=0.19), as well as higher Aβ42/Tau (all subjects: P-
value=0.019, β=0.20; PDND subjects only: P-value=0.120, β=0.17).
When additionally adjusting for APOE4 allele carrier status these changes were no
longer significant at the level of p<0.017, however, there was a trend for an
association between the TOMM40 poly-T S allele and CSF Aβ42/Tau (Table 4,
supplementary material). These analyses were also performed with TOMM40 poly-T
alleles determined based on tertiles, and results were very similar (see
supplementary material).
In all subjects (or in PDND subjects only), there were no significant association
between CSF alpha-syn and TOMM40 poly-T alleles or between CSF alpha-syn and
APOE4 (all p>0.18).
Discussion
We here show, in a clinical sample of PD (with and without dementia) and DLB, that
those with dementia were more likely to carry the L allele of TOMM40 poly-T repeat.
Moreover, we show that the L allele of TOMM40 poly-T repeat is associated with
lower Aβ42 and Aβ42/Tau levels in CSF, indicating possible presence of AD-related
pathology. Interestingly this association was also observed in PDND subjects.
PDD/DLB patients were more likely to carry the APOE-ε4 allele, and this allelic
variant was strongly inter-correlated with the L allele. When the sample was re-
analyzed additionally adjusting for APOE-ε4 allele carrier status, the associations
between the L allele and PDD/DLB status as well as CSF biomarker levels did not
remain significant, suggesting that APOE-ε4 allele carrier status may have driven the
12
results. However, when we adjusted for APOE-ε4 carrier-status, we observed
nominally significant associations between the S allele of TOMM40 poly-T repeat
and DLB/PDD status as well as lower CSF levels of CSF Aβ42/Tau, although these
did not reach statistical significance adjustment for multiple comparisons. Our
findings suggest that there may be an effect of TOMM40 on PDD/DLB and AD-
related pathology that is independent of APOE-ε4, although this needs to be
replicated in independent cohorts.
We replicate previous studies of a link between APOE-ε4 allele and PDD/DLB [30,
31], but also show an association between TOMM40 allelic variants and PDD/DLB.
The TOMM40 gene product plays an important role in mitochondrial function, which
is key to almost all aspects of cellular metabolism [15]. The TOMM complex is the
main entry portal for proteins synthesized in the cytoplasm to enter the mitochondria,
and TOMM40 is the key subunit of this protein transport complex [15]. Results from
genetic knock-out studies have emphasized the importance ofTOMM40 for the
viability of eukaryotic organisms [32, 33]. TOMM40 and APOE are both located on
chromosome 19 in the tight gene cluster TOMM40-APOE-APOC1-APOC4-APOC2
that forms a strong LD block [34]. Late-onset Alzheimer´s disease (LOAD) has been
strongly associated with the APOE LD region (specifically the APOE-ε4 haplotype)
[35, 36]. However, other genetic factors within this LD block may also be linked to
cognitive decline. As reviewed by Gottschalk et al., several studies have found that
TOMM40 SNPs are associated with LOAD [15] and there is evidence that this effect
may be independent of APOE [37].
There are only a few previous studies investigating the relationship between
13
TOMM40 and PDD/DLB. In a large-scale association study of 54 genomic region
previously implicated in PD or AD, Bras et al. found several SNPs associated with
DLB located within the TOMM40 gene [38]. There are also unpublished clinical and
post-mortem data recently reported in a review by Gottschalk et al. supporting the
link between DLB and the TOMM40 gene [15]. Moreover, TOMM40 polymorphisms
have been shown to predict cerebrospinal fluid levels of apoE in non-demented
individuals [39] and APOE expression in the AD brain [40]. APOE-ε4 may also be
involved in mitochondrial dysfunction and neurotoxicity, which are potential
pathophysiological mechanisms underlying dementia and PD [3, 4, 41]. Indeed,
some authors have speculated that changes in APOE expression is a secondary
consequence, and that TOMM40 variants affecting mitochondrial function are the
actual primary effecters for AD risk [40]. In line with this notion and partly in line with
our own findings, Roses et al. showed the L allele of TOMM40 poly-T repeat is most
commonly linked with APOE-ε4, and that the longer length of the allele of TOMM40
poly-T repeat was associated with a higher risk for late-onset AD [5]. However,
several studies have failed to show an independent effect of TOMM40 on AD-related
pathology and cognitive decline. Cruchaga et al. found an association between
TOMM40 poly T repeat and low CSF Aβ42 levels in AD, although this was no longer
significant after taking into account the effects of APOE [20]. Similarly, Jun et al. did
not find a significant association between TOMM40 and AD risk or age of onset after
adjusting for APOE genotype [42]. In line with these studies, we found that APOE
and TOMM40 shared a significant amount of variance, and the association between
dementia and L allele was no longer significant after taking APOE-ε4 into account.
Few studies have investigated TOMM40 genetic variants in relation to PD. Peplonska
14
et al. found no significant difference in the distribution of TOMM40 poly-T alleles or
APOE genotypes between 407 PD subjects and 305 healthy controls [23]. However,
the authors did not specify the exact number of dementia cases in their sample, but
noted that it was low and that this may have been one of the reasons for their
negative findings [23]. Based on our findings, we hypothesize that TOMM40-L may
be more strongly associated with dementia in PD rather than PD per se. In support of
a link between the TOMM40 L allele and dementia, Maruszak et al. showed that the
L allele of TOMM40 poly-T repeat was significantly associated with LOAD compared
to controls, even though the APOE ε4 remains the strongest risk factor for LOAD
[27].
The mechanisms behind the association between dementia in PD and APOE-ε4
and/or the L allele of TOMM40 poly-T repeat are not yet fully understood.
Consequently, we quantified the CSF levels of Aβ42 and Tau in a subpopulation of the
study participants. Decreased CSF Aβ42 is an independent marker of cerebral
accumulation of Aβ fibrils, and increased CSF tau is a marker of tau-pathology and
neurodegeneration [18]. In the present study we found that the L allele of TOMM40
poly-T repeat was associated both with lower CSF-Aβ42 and Aβ42/Tau in PD,
suggesting that the increased risk of dementia in PD associated with these
genotypes is mediated via possible induction of AD-related pathologies. Once again,
these findings did not remain significant after adjusting for APOE-ε4 carrier status,
thus this latter known risk factor for AD-related pathology may have been driving
these correlations. While these associations have not been tested, to the best of our
knowledge, in PDD/DLB specifically, our findings are generally in line with studies on
AD dementia [18], [43], [20].
15
As this is cross-sectional study, our findings do not infer causality. Furthermore, in
the absence of a healthy control group, our data cannot establish whether the
distributions of TOMM40 poly-T repeat variants differ between PD patients and
healthy controls. . Also, this is one of the first studies exploring the association
between TOMM40 and PDD and DLB. Therefore our results should be considered as
preliminary and need to be replicated in an independent sample. Moreover, this is the
first study to simultaneously investigate CSF biomarkers and APOE or TOMM40
genetic variants in a clinical PDD/DLB sample. A potential limitation of the present
investigation is that it comprised a smaller sample size compared to some other
previously published studies in the field [23, 27, 28]. Our study did, however, have
some distinct advantages in the thorough clinical characterization of subjects,
including CSF data. The latter feature may provide important clues in interpreting the
genetic data. Moreover, we are the first to investigate TOMM40 in PDD/DLB versus
non-demented PD subjects. In light of this, we believe that our study is important in
formulating new hypotheses regarding TOMM40 versus PDD/DLB that should be
confirmed, or refuted, in future larger trials.
In conclusion, our investigation suggests that the L allele of TOMM40 poly-T repeat
(a gene involved in mitochondrial function) is more common in PDD/DLB subjects
than in non-demented PD. Based on our results, these findings may, however, be
accounted for by an increased frequency of APOE ε4 in the PDD/DLB group. The link
between dementia in PD and the L allele ofTOMM40 poly-T repeat and/or APOE ε4
alleles seem to be mediated via Aβ and Tau pathology. However, the associations
between the S allele of TOMM40 poly-T repeat and PDD/DLB status and abnormal
16
CSF Aβ42/Tau levels need to be replicated in independent patient cohorts.
Acknowledgements
Helene Jacobsson is acknowledged for statistical advice. The study was supported
by the Swedish Research Council, The Parkinson Foundation of Sweden, the
European Research Council, the Crafoord Foundation, the Swedish Brain
Foundation, the Swedish Federal Government under the ALF Agreement, Multipark,
and the Knut and Alice Wallenberg Foundation. The Imperial College London
investigators were supported by grants from Parkinson’s UK, the Michael J Fox
Foundation and UCB. The funding sources had no role in the design and conduct of
the study; in the collection, analysis, interpretation of the data; or in the preparation,
review, or approval of the manuscript.
Conflict of Interest
Each of the authors declares no conflict of interest in the work reported.
17
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25
Tables
Table 1. Demographic characteristics of subjects
DLB/PDD
subjects
Non-demented
PD patients
Statistical
test
P-value
N 156 92 N/A N/A
Age (mean + SD) 76.1 + 6.3 66.5 + 10.3 t=9.2 <0.001
Proportion female
(%)
32.7 41.3 c2=1.9 0.17
Disease duration
in years (mean +
SD)
8.4 + 6.2 9.4 + 6.3 t=1.2 0.21
CSF Aβ42 in ng/L
(mean + SD)
544.7 + 193.6
(n=36)
622.9 + 156.3
(n=79)
t=2.3 0.023
CSF- Aβ42/Tau
(mean + SD)
1.99 + 0.94
(n=36)
2.64 + 0.88
(n=79)
t=3.7 <0.001
26
Table 2. Distribution of TOMM40 poly-T alleles in the non-demented PD patients (n=92)
compared to the PDD/DLB group (n=156). The proportion of subjects within each group
having a specific allele is given in parenthesis. OR was calculated for the indicated allele vs.
all other alleles. P-values were calculated using logistic regression, with PDD/DLB status as
dependent variable and TOMM40 poly-T allele carrier status for each of S/L/VL alleles as
independent variable. P-values<0.017 (0.05/3) were considered statistically significant.
Alleles Dementia status Model 1 Model 2
DLB/PDD,
allele carriers
vs non-
carriers, n
(%)
Non-
demented
PD, allele
carriers vs
non-carriers
n (%)
OR
(95% CI)
P-
value
OR
(95% CI)
P-
value
TOMM40-S 108 (69.2%)
vs 48
(30.8%)
58 (63.0%)
vs 34
(37.0%)
1.75
(0.90-3.39)
0.10 2.36
(1.15-4.82)
0.02
TOMM40-L 75 (48.1%)
vs 81
(51.9%)
26 (28.3%)
vs 66
(71.7%)
2.43
(1.27-4.65)
<0.01 3.89
(0.31-
48.81)
0.29
TOMM40-
VL
84 (53.8%)
vs 72
(46.2%)
57 (62.0%)
vs 35 (38%)
0.44
(0.23-0.84)
0.01 0.44
(0.27-1.06)
0.07
Model 1 = adjustment for age and sex
Model 2= adjustment for age, sex, and APOE4 carrier status
27
Levels of CSF Aβ42 and CSF-TAU byTOMM40 genotype in all subjects (n=115) and
in non-demented Parkinson´s disease (PDND) subjects (n=79) only. The box
represents the interquartile range, with the median indicated in the middle. The error
bars represent the lowest and highest normal values (max 1.5 box lengths from the
lower and upper quartiles, respectively).
After Bonferroni corrections, the following group differences were significant for CSF
Aβ42: S/S vs S/L (p=0.003 for all subjects; p=0.009 for PDND only), S/S vs L/L
(p=0.003 for all subjects; p=0.007 for PDND only), S/S vs L/VL (p=0.104 (NS) for all
subjects, p=0.029 for PDND only), S/L vs S/VL (p=0.001 for all subjects; p=0.012 for
PDND only), S/L vs VL/VL (p<0.001 for all subjects; p<0.001 for PDND only), S/VL vs
L/L (p=0.001 for all subjects; p=0.009 for PDND only), S/VL vs L/VL (p=0.032 for all
subjects; p=0.041 for PDND only), L/L vs VL/VL (p<0.001 for all subjects; p=0.001 for
PDND only), and L/VL vs VL/VL (p=0.001 for all subjects; p=0.001 for PDND only).
The following group differences were significant for CSF Tau: S/S vs S/L (p=0.001),
S/L vs S/VL (p=0.016), and S/L vs VL/VL (p=0.033). None of these group differences
were significant in the PDND group only (all p-values>0.19).
Legend Figure 2
30
Levels of CSF Aβ42 and CSF-TAU by APOE genotype in all subjects (n=115) and in
non-demented Parkinson´s disease (PDND) subjects (n=79) only. The box
represents the interquartile range, with the median indicated in the middle. The error
bars represent the lowest and highest normal values (max 1.5 box lengths from the
lower and upper quartiles, respectively).
After Bonferroni corrections, the following group differences were significant for CSF
Aβ42: e2/e3 vs e2/e4 (p=0.048 for all subjects; p=0.883 (NS) for PDND only), e2/e3 vs
e3/e4 (p=0.013 for all subjects; p=0.076 (NS) for PDND only), e2/e3 vs e4/e4
(p=0.001 for all subjects; p=0.003 for PDND only), e2/e4 vs e3/e3 (p=0.009 for all
subjects; p=0.356 (NS) for PDND only), e3/e3 vs e3/e4 (p<0.001 for all subjects;
p<0.001 for PDND only), e3/e3 vs e4/e4 (p<0.001 for all subjects; p<0.001 for PDND
only).
In all subjects, the following group differences were significant for CSF Tau: e2/e3 vs
e3/e4 (p=0.027) and e3/e3 vs e3/e4 (p=0.001), but none of these differences were
significant in the PDND only (all p-values>0.11)
31
Supplementary material
Legend: Table 3. Associations between TOMM40 poly-T allele carrier status and CSF levels
of Aβ42 and Aβ42/Tau. Linear regression models, adjusted for age and sex, were used,
standardized beta (β) and p-values are given. Data is given for all subjects with available
CSF samples (n=115) and for PDND subjects only (n=79) in parenthesis. Significant values
are marked in bold. P-values<0.017 (0.05/3) were considered statistically significant
Alleles CSF Aβ42 CSF Aβ42/Tau
β (ng/L) p-value β (ng/L / ng/L) p-value
TOMM40-S 0.04 (0.08) 0.70 (0.46) 0.02 (0.11) 0.78 (0.32)
TOMM40-L -0.49 (-0.56) <0.001 (<0.001) -0.49 (-0.49) <0.001 (<0.001)
TOMM40-VL 0.25 (0.09) <0.01 (0.19) 0.20 (0.17) 0.02 (0.12)
32
Legend: Table 4. Associations between TOMM40 poly-T allele carrier status and CSF levels
of Aβ42 and Aβ42/Tau. Linear regression models, adjusted for age sex, and APOE4 carrier
status were used, standardized beta (β) and p-values are given. Data is given for all subjects
with available CSF samples (n=115) and for PDND subjects only (n=79) in parenthesis. P-
values<0.017 (0.05/3) were considered statistically significant
Alleles CSF Aβ42 CSF Aβ42/Tau
β p-value β p-value
TOMM40-S -0.13 (-0.16) 0.10 (0.13) -0.15 (-0.11) 0.04 (0.25)
TOMM40-L -0.13 (-0.38) 0.59 (0.18) 0.02 (-0.13) 0.91 (0.61)
TOMM40-VL 0.15 (0.13) 0.06 (0.18) 0.10 (0.11) 0.17 (0.24)
Legend: Supplementary analyses of TOMM40 poly-T repeat vs dementia status
using tertiles in order to assign TOMM40 poly-T repeat length to categories.
Since 43% of the alleles are 16 in length (and this is the shortest allele length
measured in this dataset), this was set as the cut-off for the S allele in these new
analyses.
S allele: 16 or less
L allele: 17-31
VL allele: 32-39
Associations between allelic variants of TOMM40 poly-T repeat and PDD/DLB status
33
Forty-eight% of the subjects with PDD or DLB were L carriers compared to 29% of
the PDND subjects (P-value=0.011, OR=2.31, 95% CI=1.21-4.39). Fifty-four% of the
PDD/DLB subjects were VL allele carriers compared to 62% of the PDND subjects
(P-value=0.013, OR=0.44, 95% CI=0.23-0.84). Sixty-nine% of the subjects with PDD
or DLB were S carriers compared to 63% of the PDND subjects (P-value=0.098,
OR=1.75, 95% CI=0.90-3.39).
When additionally adjusting for APOE4 allele carrier status, none of these differences
were significant at the level of p<0.017 (data not shown).
Associations between allelic variants of TOMM40 poly-T repeat and CSF levels of
Aβ42 and Tau
In order to test whether the associations between allelic variants of TOMM40 poly-T
repeat and dementia in PD might be mediated via increased AD-related pathology
we also measured CSF levels of Aβ42, and tau in a subpopulation (n=115).
Associations between allelic variants of TOMM40 poly-T repeat and CSF Aβ42 and
Aβ42/Tau were tested using linear regression models in all subjects and in PDND
subjects only, adjusted for age and sex.
L allele carrier status was significantly associated with lower Aβ42 (all subjects: P-
value<0.001, β=-0.48; PDND subjects only: P-value<0.001, β=-0.54), and lower
Aβ42/Tau (all subjects: P-value<0.001, β=-0.46; PDND subjects only: P-value<0.001,
β=-0.44). In all subjects, but not in PDND only, VL allele carrier status was
associated with higher Aβ42 (all subjects: P-value=0.006, β=0.25; PDND subjects
only: P-value=0.090, β=0.19), as well as higher Aβ42/Tau (all subjects: P-
value=0.019, β=0.20; PDND subjects only: P-value=0.120, β=0.17). There were no
34