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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.

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