Introduction We investigated the TOMM40-APOE genomic region that has been associated with the risk and age of onset of late-onset Alzheimer's disease (LOAD) to determine if a highly polymorphic, intronic polyT within this region (rs10524523, hereafter 523) affects expression of the APOE and TOMM40 genes. Alleles of this locus are classified: short-S, long-L, very long-VL based on the number of T-residues. Methods We evaluated differences in APOE-mRNA and TOMM40-mRNA levels as a function of 523 genotype in two brain regions from APOEε3/3 Caucasian autopsy-confirmed LOAD cases and normal controls. We further investigated the effect of the 523 locus in its native genomic context using a luciferase expression system. Results The expression of both genes was significantly increased with disease. Mean expression of APOE and TOMM40-mRNA levels were higher in VL-homozygotes compared to S-homozygotes in temporal and occipital cortexes from Normal and LOAD subjects. Results of a luciferase reporter system were consistent with the human brain mRNA analysis: the 523-VL polyT resulted in significantly higher expression than the S-polyT. While the effect of polyT length on reporter expression was the same in HepG2 hepatoma and SH-SY5Y neuroblastoma cells, the magnitude of the effect was greater in the neuroblastoma than in the hepatoma cells, which implies tissue-specific modulation of the 523-polyT. Conclusions These results suggest that the 523 locus may contribute to LOAD susceptibility by modulating the expression of TOMM40 and/or APOE transcription.

It is hypothesized that retrotransposons have played a fundamental role in primate evolution and that enhanced neurologic retrotransposon activity in humans may underlie the origin of higher cognitive function. As a potential consequence of this enhanced activity, it is likely that neurons are susceptible to deleterious retrotransposon pathways that can disrupt mitochondrial function. An example is observed in the TOMM40 gene, encoding a β-barrel protein critical for mitochondrial preprotein transport. Primate-specific Alu retrotransposons have repeatedly inserted into TOMM40 introns, and at least one variant associated with late-onset Alzheimer's disease originated from an Alu insertion event. We provide evidence of enriched Alu content in mitochondrial genes and postulate that Alus can disrupt mitochondrial populations in neurons, thereby setting the stage for progressive neurologic dysfunction. This Alu neurodegeneration hypothesis is compatible with decades of research and offers a plausible mechanism for the disruption of neuronal mitochondrial homeostasis, ultimately cascading into neurodegenerative disease.

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