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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 APOEɛ4 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 APOEɛ4 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-ɛ4 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-ɛ4, 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.

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-ɛ4.

Keywords

PDD DLB APOE Parkinson’s disease

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-ɛ2, APOE-ɛ3, and APOE-ɛ4 [7]. APOE and TOMM40 are in linkage disequilibrium (LD); the APOE-ɛ4 allele has been linked to the L allele of TOMM40 poly-T repeat and the APOE-ɛ3 allele has been linked to the S and VL alleles, whereas the APOE-ɛ2 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 general cognitive function in middle-aged and older adults [9].

It is now widely acknowledged that APOE-ɛ4 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-ɛ2/ɛ3 genotype may confer protection [10]. Studies on PD have shown that APOE-ɛ2 might be a risk allele for PD, whereas the APOE-ɛ4 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 SNPs [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-ɛ4 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-ɛ4 allele exhibit lower CSF Aβ₄₂ levels [19]. There are yet 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-ɛ4 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-ɛ4 allele carrier status or not. Moreover, we wanted to test the relationship between TOMM40 poly-T repeat and CSF levels of Aβ₄₂ and Aβ₄₂/Tau ratio, once again adjusting for APOE-ɛ4 allele carrier status.

MATERIALS AND METHODS

Ethical considerations

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 ɛ2/ɛ3/ɛ4 haplotypes, with rs429358 T-allele and rs7412 C-allele indicating APOE-ɛ3, rs429358 T and rs7412 T indicating APOE-ɛ2 and rs429358C and rs7412C indicating APOE-ɛ4. 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 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 TOMM40L allele is almost without exception linked to theAPOE-ɛ4 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-ɛ4 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 Aβ_42, 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 2000 g 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-amyloid_1 - 42 ELISA and EUROIMMUN Total Tau ELISA. CSF alpha-synuclein was analyzed with luminex assays as previously described [29].

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 Aβ_42/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-ɛ4 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 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-ɛ4, i.e. 99% of those with the L allele also carried the APOE-ɛ4 allele. APOE-ɛ4 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.

Associations between the APOE4 allele and PDD/DLB status

Forty-six % of the PDD/DLB subjects were APOE-ɛ4 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 allele length group 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), 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-ɛ4 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 Figs. 1 and 2 (in all subjects and in PDND subjectsonly).

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 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 allele length group 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-synuclein and TOMM40 poly-T alleles or between CSF alpha-synuclein and APOE-ɛ4 (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-ɛ4 allele, and this allelic variant was strongly inter-correlated with the L allele. When the sample was re-analyzed additionally adjusting for APOE-ɛ4 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-ɛ4 allele carrier status may have driven the results. However, when we adjusted for APOE-ɛ4 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 after 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-ɛ4, although this needs to be replicated in independent cohorts.

We replicate previous studies of a link between the APOE-ɛ4 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 of TOMM40 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-ɛ4 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.

There are only a few previous studies investigating the relationship between 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-ɛ4 may also be involved in mitochondrial dysfunction and neurotoxicity, which are potential pathophysiological mechanisms underlying dementia and PD [3 , 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-ɛ4, 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-ɛ4 into account.

Few studies have investigated TOMM40 genetic variants in relation to PD. Peplonska 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 TOMM40L 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 APOEɛ4 remains the strongest risk factor for LOAD [27].

The mechanisms behind the association between dementia in PD and APOE-ɛ4 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-ɛ4 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].

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 , 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 APOEɛ4 in the PDD/DLB group. The link between dementia in PD and the L allele of TOMM40 poly-T repeat and/or APOEɛ4 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 CSF Aβ42/Tau levels need to be replicated in independent patient cohorts.

CONFLICT OF INTEREST

Each of the authors declares no conflict of interest in the work reported.

Footnotes

ACKNOWLEDGMENTS

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.

Appendix

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Associations between TOMM40 Poly-T Repeat Variants and Dementia in Cases with Parkinsonism

Abstract

Keywords

INTRODUCTION

MATERIALS AND METHODS

Ethical considerations

Study participants

Genotyping

CSF Samples

Statistical analyses

RESULTS

Demographic characteristics

Associations between the APOE4 allele and PDD/DLB status

Associations between allelic variants of TOMM40 poly-T repeat and PDD/DLB status

Associations between allelic variants of TOMM40 poly-T repeat and CSF levels of Aβ42 and Tau

DISCUSSION

CONFLICT OF INTEREST

Footnotes

ACKNOWLEDGMENTS

Appendix

References

Associations between allelic variants of TOMM40 poly-T repeat and CSF levels of Aβ₄₂ and Tau