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TOMM40 ‘523’ poly-T repeat length is a determinant of longitudinal cognitive decline in Parkinson’s disease

Bakeberg, M.C., Gorecki, A.M., Pfaff, A.L.ORCID: 0000-0002-2231-9800, Hoes, M.E., Kõks, S., Akkari, P.A., Mastaglia, F.L. and Anderton, R.S. (2021) TOMM40 ‘523’ poly-T repeat length is a determinant of longitudinal cognitive decline in Parkinson’s disease. npj Parkinson's Disease, 7 . Article 56.

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Abstract

The translocase of outer mitochondrial membrane 40 (TOMM40) ‘523’ polymorphism has previously been associated with age of Alzheimer’s disease onset and cognitive functioning in non-pathological ageing, but has not been explored as a candidate risk marker for cognitive decline in Parkinson’s disease (PD). Therefore, this longitudinal study investigated the role of the ‘523’ variant in cognitive decline in a patient cohort from the Parkinson’s Progression Markers Initiative. As such, a group of 368 people with PD were assessed annually for cognitive performance using multiple neuropsychological protocols, and were genotyped for the TOMM40 ‘523’ variant using whole-genome sequencing data. Covariate-adjusted generalised linear mixed models were utilised to examine the relationship between TOMM40 ‘523’ allele lengths and cognitive scores, while taking into account the APOE ε genotype. Cognitive scores declined over the 5-year study period and were lower in males than in females. When accounting for APOE ε4, the TOMM40 ‘523’ variant was not robustly associated with overall cognitive performance. However, in APOE ε3/ε3 carriers, who accounted for ~60% of the whole cohort, carriage of shorter ‘523’ alleles was associated with more severe cognitive decline in both sexes, while carriage of the longer alleles in females were associated with better preservation of global cognition and a number of cognitive sub-domains, and with a delay in progression to dementia. The findings indicate that when taken in conjunction with the APOE genotype, TOMM40 ‘523’ allele length is a significant independent determinant and marker for the trajectory of cognitive decline and risk of dementia in PD.

Item Type: Journal Article
Murdoch Affiliation(s): Centre for Molecular Medicine and Innovative Therapeutics (CMMIT)
Publisher: Nature Publishing Group
Copyright: © The Author(s) 2021
United Nations SDGs: Goal 3: Good Health and Well-Being
URI: http://researchrepository.murdoch.edu.au/id/eprint/61497
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