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.

线粒体外膜 40 ( TOMM40 ) '523'多态性的转位酶先前与阿尔茨海默病的发病年龄和非病理性衰老的认知功能有关，但尚未被探索为帕金森病认知能力下降的候选风险标志物。 PD）。因此，这项纵向研究调查了“523”变体在帕金森病进展标志物倡议患者队列中认知能力下降的作用。因此，每年使用多种神经心理学协议对一组 368 名 PD 患者的认知表现进行评估，并针对TOMM40 '523'进行基因分型使用全基因组测序数据的变异。协变量调整的广义线性混合模型用于检查TOMM40 '523'等位基因长度与认知评分之间的关系，同时考虑APOE ε 基因型。在 5 年的研究期间，认知评分下降，男性低于女性。在考虑APOE ε4 时，TOMM40 '523'变体与整体认知表现没有密切关联。然而，在占整个队列约 60% 的APOE ε3/ε3 携带者中，携带较短的“523”等位基因与两性更严重的认知衰退有关，而女性携带更长的等位基因与更好地保存整体认知和许多认知子域有关，并延迟进展为痴呆症。研究结果表明，当与APOE基因型结合使用时，TOMM40 '523'等位基因长度是认知能力下降轨迹和 PD 痴呆风险的重要独立决定因素和标志物。