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

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...

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Autores principales:	Megan C. Bakeberg, Anastazja M. Gorecki, Abigail L. Pfaff, Madison E. Hoes, Sulev Kõks, P. Anthony Akkari, Frank L. Mastaglia, Ryan S. Anderton
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/30375ae8dea94afcbcdd8245b45abbe4
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spelling	oai:doaj.org-article:30375ae8dea94afcbcdd8245b45abbe42021-12-02T18:34:20ZTOMM40 ‘523’ poly-T repeat length is a determinant of longitudinal cognitive decline in Parkinson’s disease10.1038/s41531-021-00200-y2373-8057https://doaj.org/article/30375ae8dea94afcbcdd8245b45abbe42021-07-01T00:00:00Zhttps://doi.org/10.1038/s41531-021-00200-yhttps://doaj.org/toc/2373-8057Abstract 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.Megan C. BakebergAnastazja M. GoreckiAbigail L. PfaffMadison E. HoesSulev KõksP. Anthony AkkariFrank L. MastagliaRyan S. AndertonNature PortfolioarticleNeurology. Diseases of the nervous systemRC346-429ENnpj Parkinson's Disease, Vol 7, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Neurology. Diseases of the nervous system RC346-429
spellingShingle	Neurology. Diseases of the nervous system RC346-429 Megan C. Bakeberg Anastazja M. Gorecki Abigail L. Pfaff Madison E. Hoes Sulev Kõks P. Anthony Akkari Frank L. Mastaglia Ryan S. Anderton TOMM40 ‘523’ poly-T repeat length is a determinant of longitudinal cognitive decline in Parkinson’s disease
description	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.
format	article
author	Megan C. Bakeberg Anastazja M. Gorecki Abigail L. Pfaff Madison E. Hoes Sulev Kõks P. Anthony Akkari Frank L. Mastaglia Ryan S. Anderton
author_facet	Megan C. Bakeberg Anastazja M. Gorecki Abigail L. Pfaff Madison E. Hoes Sulev Kõks P. Anthony Akkari Frank L. Mastaglia Ryan S. Anderton
author_sort	Megan C. Bakeberg
title	TOMM40 ‘523’ poly-T repeat length is a determinant of longitudinal cognitive decline in Parkinson’s disease
title_short	TOMM40 ‘523’ poly-T repeat length is a determinant of longitudinal cognitive decline in Parkinson’s disease
title_full	TOMM40 ‘523’ poly-T repeat length is a determinant of longitudinal cognitive decline in Parkinson’s disease
title_fullStr	TOMM40 ‘523’ poly-T repeat length is a determinant of longitudinal cognitive decline in Parkinson’s disease
title_full_unstemmed	TOMM40 ‘523’ poly-T repeat length is a determinant of longitudinal cognitive decline in Parkinson’s disease
title_sort	tomm40 ‘523’ poly-t repeat length is a determinant of longitudinal cognitive decline in parkinson’s disease
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/30375ae8dea94afcbcdd8245b45abbe4
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TOMM40 ‘523’ poly-T repeat length is a determinant of longitudinal cognitive decline in Parkinson’s disease

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