ژن حساسیت بیماری آلزایمر APOE و TOMM40 و یکپارچگی ماده سفید مغزی در تولد لوزان کوهورت در سال 1936

Apolipoprotein E (APOE) ε genotype has previously been significantly associated with cognitive, brain imaging, and Alzheimer's disease-related phenotypes (e.g., age of onset). In the TOMM40 gene, the rs10524523 (“523”) variable length poly-T repeat polymorphism has more recently been associated with similar ph/enotypes, although the allelic directions of these associations have varied between initial reports. Using diffusion magnetic resonance imaging tractography, the present study aimed to investigate whether there are independent effects of apolipoprotein E (APOE) and TOMM40 genotypes on human brain white matter integrity in a community-dwelling sample of older adults, the Lothian Birth Cohort 1936 (mean age = 72.70 years, standard deviation = 0.74, N approximately = 640–650; for most analyses). Some nominally significant effects were observed (i.e., covariate-adjusted differences between genotype groups at p < 0.05). For APOE, deleterious effects of ε4 “risk” allele presence (vs. absence) were found in the right ventral cingulum and left inferior longitudinal fasciculus. To test for biologically independent effects of the TOMM40 523 repeat, participants were stratified into APOE genotype subgroups, so that any significant effects could not be attributed to APOE variation. In participants with the APOE ε3/ε4 genotype, effects of TOMM40 523 status were found in the left uncinate fasciculus, left rostral cingulum, left ventral cingulum, and a general factor of white matter integrity. In all 4 of these tractography measures, carriers of the TOMM40 523 “short” allele showed lower white matter integrity when compared with carriers of the “long” and “very-long” alleles. Most of these effects survived correction for childhood intelligence test scores and vascular disease history, though only the effect of TOMM40 523 on the left ventral cingulum integrity survived correction for false discovery rate. The effects of APOE in this older population are more specific and restricted compared with those reported in previous studies, and the effects of TOMM40 on white matter integrity appear to be novel, although replication is required in large independent samples.

The apolipoprotein E (APOE) gene is located on chromosome 19q13.2 and is 3.7 kilobases (KB) long. APOE ε genotype is composed of 2 single-nucleotide polymorphisms (SNPs): rs429358, which causes a Cys130Arg substitution; and rs7412, which causes an Arg176Cys substitution; different combinations of the rs429358 and/or rs7412 SNPs form the ε2 (Cys/Cys, respectively), ε3 (Cys/Arg), and ε4 (Arg/Arg) genotypes ( NCBI website, 2012a and Ringman and Cummings, 2009). Of these, the ε3 allele is the most common (frequency ∼78.3% in Caucasians), followed by ε4 (∼14.5%) and ε2 (∼6.4%), although these frequencies vary between populations ( Eisenberg et al., 2010). APOE plays a role in the transport and metabolism of lipids in the human body and brain ( Bu, 2009 and Corder et al., 1994). The ε4 allele of APOE is the “risk” variant for several phenotypes compared with ε3 (“neutral”), and ε2 (generally considered “protective”, although less consistently). These phenotypes include risk of Alzheimer's disease (AD) ( Corder et al., 1994), less successful cognitive aging ( Deary et al., 2004 and Wisdom et al., 2011), differences in brain structure (e.g., atrophy; Biffi et al., 2010), and functional connectivity ( Trachtenberg et al., 2012); vascular pathologies such as hyperlipidemia, coronary heart disease and stroke ( Lahoz et al., 2001), and brain microbleeds ( Schilling et al., 2013). It is not clear to what extent associations between APOE variants and worse cognitive aging in cross-sectional and longitudinal studies reflect preclinical “prodromal” AD ( Bretsky et al., 2003 and Deary et al., 2004). There might be complexities in how the APOE ε4 allele is associated with clinical onset of AD or cognitive decline ( Johnson et al., 2011). Other genetic variants aside from APOE, possibly in linkage disequilibrium with it, may play a role. The translocase of the outer membrane of 40 (TOMM40) gene is located adjacent to APOE and covers 12.5 KB on chromosome 19q13 ( NCBI website, 2012b). Several SNPs in the APOE and TOMM40 genes are in strong linkage disequilibrium; for example, rs429358 and 36 SNPs within ±1.17 KB of the APOE region including 15 TOMM40 SNPs; average D′ = 0.91, r2 = 0.22, n = 1262 ( Yu et al., 2007). The TOMM40 locus encodes for a channel-forming subunit of the translocase of the outer mitochondrial membrane complex ( Humphries et al., 2005). This complex imports precursor proteins into mitochondria ( Koehler et al., 1999). Mitochondrial dysfunction may play a significant role in cognitive decline and AD-related pathology (“The mitochondrial cascade hypothesis”; Swerdlow and Kahn, 2004). APOE and TOMM40 may interact to affect aspects of mitochondrial function although mechanistically it is unclear exactly how ( Roses et al., 2010). The rs10524523 locus (hereafter “523”) in the TOMM40 gene is characterized by a variable number of T residues (“poly-T repeats”) that can be classified into 3 different lengths: “short” (<20; “S”), “long” (20–29; “L”), and “very-long” (≥30; “VL”; Lutz et al., 2010). Roses et al. (2010) showed with phylogenetic mapping analyses that TOMM40 523 poly-T repeat length was strongly linked to APOE ε genotype in humans: ε4 is most commonly linked to the 523 L allele, with ε3 linked to either S or VL alleles in different evolutionary clades. The rarer ε2 allele appeared similar to ε3 although further research is required in large samples ( Roses et al., 2010). Studies have tested for association between TOMM40 523 repeat length and different brain-related phenotypes independently from APOE. For example, age of AD onset ( Roses et al., 2010) and worse cognitive aging ( Schiepers et al., 2012), were examined. However, reports vary in showing protective ( Johnson et al., 2011), null ( Chu et al., 2011), or deleterious ( Cruchaga et al., 2011) effects of the S allele. See Roses et al. (2013) for a discussion of early studies. Diffusion-tensor magnetic resonance imaging (MRI) and quantitative tractography allow examination of brain white matter microstructure in vivo in specific white matter tracts thought to relate to cognitive functions (Behrens et al., 2007 and Pierpaoli et al., 1996). Diffusion-tensor imaging (DTI) measures the magnitude and directional coherence of water molecule diffusion and, because water molecule diffusion is preferentially constrained along the principal fiber direction by axonal membranes and myelin sheaths, this property can be used to assess white matter structural integrity (Behrens et al., 2007 and Pierpaoli et al., 1996). Fractional anisotropy (FA) is an example of a common DTI-derived metric, and reflects the level of directional coherence of water molecule diffusion (Pierpaoli et al., 1996). Specifically, FA measures are high in healthy, structurally intact, coherently organized white matter, but fall in diseased tissue. Associations between the APOE gene and white matter integrity have been investigated previously (see Gold et al., 2012 for a review of significant findings; also Felsky and Voineskos, 2013). To our knowledge, the largest previous study had 203 participants ( Westlye et al., 2012; mean age = 47.6 years, standard deviation = 14.9). That report found widespread differences in microstructural integrity depending on APOE status. Controlling for age and gender, ε3/ε4 carriers had lower white matter integrity (vs. ε3/ε3) in the brainstem, basal temporal lobe, internal capsule, anterior parts of the corpus callosum, forceps minor, superior longitudinal fasciculus, occipital, and corticospinal motor pathways (Cohen's d range = 0.77–0.79; “medium-large effects”). We found no studies that examined the independent effects of the TOMM40 523 poly-T repeat. The present study aims to investigate the effects of APOE and TOMM40 genotypes on brain white matter integrity as assessed using quantitative tractography in a large, age-homogenous sample of relatively healthy older people. Fourteen major projection, commissural, and association fiber tracts were examined that have previously been significantly associated with cognitive abilities in this sample ( Penke et al., 2012).