Association of the mitochondrial tRNAA4336G mutation with Alzheimer's and Parkinson's diseases

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Abstract
Alzheimer's and Parkinson's diseases (AD, PD) are among the most common neurodegenerative disorders in adults. Both AD and PD have a complex aetiology, and it is widely considered that genetic factors, acting independently or in concert with other genetic and/or environmental factors, modify the risk of developing them. While the apolipoprotein E (ApoE) ε4 allele represents an established risk factor for familial and sporadic late‐onset AD, it has been suggested that a common polymorphism in the α1‐antichymotrypsin gene modifies the ApoE ε4 dosage effect in AD. Moreover, it has been proposed that a mitochondrial tRNAGln sequence variant (A4336G transition) confers an increased risk for both AD and PD. This finding is of particular interest as the A4336G mutation seems to predispose to two clinically and neuropathologically distinct neurodegenerative disorders. We have examined the allelic frequencies of these putative susceptibility genes in 28 neuropathologically confirmed cases of AD, 23 cases with Lewy‐body PD and 100 age‐matched controls without clinical or histological evidence of neurodegenerative disease. The ApoE ε4 allele frequency was significantly over‐represented in AD patients vs controls (0.35 vs 0.11) but we could not find evidence for an association between the α1‐antichymotrypsin AA genotype, the ApoE ε4 allele and AD. In contrast, the mtDNAA4336G mutation was present in one of 28 AD cases and in two of 23 PD patients, whereas no mutation was found in 100 age‐matched controls (P<0.05). Our data therefore support the hypothesis that the mitochondrial A4336G mutation represents a risk factor for AD and PD.