Abstract
Mitochondrial dysfunction is implicated in neurodegenerative disorders, such as Alzheimer's disease (AD). Translocase of outer mitochondrial membrane 40 (TOMM40) may be influential in this regard by influencing mitochondrial neurotoxicity. Little is known about the influence of the TOMM40 gene on hippocampal (HC) volume and episodic memory (EM), particularly in healthy older adults. Thus, we sought to discern the influence of TOMM40 single nucleotide polymorphisms (SNPs), which have previously been associated with medial temporal lobe integrity (rs11556505 and rs2075650), on HC volume and EM. The study sample consisted of individuals from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K) who were free of dementia and known neurological disorders, and 60–87 years of age (n = 424). EM was measured by using a 16-item word list with a 2-min free recall period and delineation of the HC was performed manually. The influence of Apolipoprotein E (APOE) and TOMM40 was assessed by 2 × 2 ANOVAs and partial correlations. There was no effect of APOE and TOMM40 on EM performance and HC volume. However, partial correlations revealed that HC volume was positively associated with free recall performance (r = 0.21, p < 0.01, r2 = 0.04). When further stratified for TOMM40, the observed association between HC volume and free recall in APOE ε4 carriers was present in combination with TOMM40 rs11556505 any T (r = 0.28, p < 0.01, R2 = 0.08) and rs2075650 any G (r = 0.28, p < 0.01, R2 = 0.08) “risk” alleles. This pattern might reflect higher reliance on HC volume for adequate EM performance among APOE ε4 carriers with additional TOMM40 “risk” alleles suggesting that the TOMM40 gene cannot merely be considered a marker of APOE genotype. Nevertheless, neither APOE nor TOMM40 influenced HC volume or EM in this population-based sample of cognitively intact individuals over the age of 60.
Highlights
Much is known about the clinical manifestations of Alzheimer’s disease (AD), the etiology and pathophysiology of this disease still remains to be determined
There was no main effect of the Apolipoprotein E (APOE) polymorphism on free recall performance (Figure 1A), meaning that presence or absence of the ε4 allele had no influence on episodic memory (EM) in the current sample [F(1, 409) = 0.49, p = 0.486]
The same pattern was observed that is no main or interaction effects of APOE and Translocase of outer mitochondrial membrane 40 (TOMM40) single nucleotide polymorphisms (SNPs), when age, sex and education were adjusted for using analysis of covariance (ANCOVA)
Summary
Much is known about the clinical manifestations of Alzheimer’s disease (AD), the etiology and pathophysiology of this disease still remains to be determined. In addition TOMM40 has been associated with risk of AD (Grupe et al, 2007; Abraham et al, 2008; Harold et al, 2009). These findings have not been consistently replicated (Cruchaga et al, 2011; Guerreiro and Hardy, 2012; Jun et al, 2012) and it is unclear if the effect can be attributed to TOMM40 or APOE as the two genes are in strong LD. There is limited information on the influence of other TOMM40 SNPs, besides the rs10524523 poly-T length, on age- and AD-sensitive markers, such as hippocampal (HC) volume and episodic memory (EM). Further research is required in normal old adults before we can tease out the influence of genetic variation in APOE and TOMM40 on HC volume and EM memory, irrespective of dementia
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