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 epsilon 4 carrier status. We analyzed cerebrospinal fluid (CSF) levels of A beta(42) and Tau, biomarkers related to Alzheimer's disease (AD).
Results: PDD/DBL status and abnormal CSF AD biomarkers (A beta(42) and A beta(42)/Tau ratio) were both associated with the APOE-epsilon 4 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-epsilon 4 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-epsilon 4, however, there were associations between S carrier status and PDD/DLB (p = 0.019) and abnormal CSF levels of A beta(42)/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-epsilon 4.