ABSTRACT
The apolipoprotein APOE4 allele confers greater risk of Alzheimer's disease (AD) for women than men, in conjunction with greater clinical deficits per unit of AD neuropathology (plaques, tangles). Cerebral microbleeds, which contribute to cognitive dysfunctions during AD, also show APOE4 excess, but sex-APOE allele interactions are not described. We report that elderly men diagnosed for mild cognitive impairment and AD showed a higher risk of cerebral cortex microbleeds with APOE4 allele dose effect in 2 clinical cohorts (ADNI and KIDS). Sex-APOE interactions were further analyzed in EFAD mice carrying human APOE alleles and familial AD genes (5XFAD (+/-) /human APOE(+/+)). At 7 months, E4FAD mice had cerebral cortex microbleeds with female excess, in contrast to humans. Cerebral amyloid angiopathy, plaques, and soluble Aß also showed female excess. Both the cerebral microbleeds and cerebral amyloid angiopathy increased in proportion to individual Aß load. In humans, the opposite sex bias of APOE4 allele for microbleeds versus the plaques and tangles is the first example of organ-specific, sex-linked APOE allele effects, and further shows AD as a uniquely human condition.
Subject(s)
Alleles , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Apolipoproteins E/genetics , Cerebral Hemorrhage/genetics , Cerebral Hemorrhage/pathology , Genetic Association Studies , Sex Characteristics , Adult , Aged , Aged, 80 and over , Alzheimer Disease/psychology , Amyloid beta-Peptides/metabolism , Animals , Cerebral Amyloid Angiopathy/genetics , Cerebral Amyloid Angiopathy/metabolism , Cerebral Amyloid Angiopathy/pathology , Cerebral Cortex/pathology , Cognition , Cognitive Dysfunction/genetics , Cognitive Dysfunction/pathology , Epistasis, Genetic/genetics , Female , Humans , Male , Mice , Middle Aged , RiskABSTRACT
BACKGROUND: Because mitochondria play an essential role in energy metabolism, generation of reactive oxygen species (ROS), and apoptosis, sequence variation in the mitochondrial genome has been postulated to be a contributing factor to the etiology of multifactorial age-related diseases, including cancer. The aim of the present study was to compare the frequencies of mitochondrial DNA (mtDNA) haplogroups as well as control region (CR) polymorphisms of patients with malignant melanoma (n = 351) versus those of healthy controls (n = 1598) in Middle Europe. METHODOLOGY AND PRINCIPAL FINDINGS: Using primer extension analysis and DNA sequencing, we identified all nine major European mitochondrial haplogroups and known CR polymorphisms. The frequencies of the major mitochondrial haplogroups did not differ significantly between patients and control subjects, whereas the frequencies of the one another linked CR polymorphisms A16183C, T16189C, C16192T, C16270T and T195C were significantly higher in patients with melanoma compared to the controls. Regarding clinical characteristics of the patient cohort, none of the nine major European haplogroups was associated with either Breslow thickness or distant metastasis. The CR polymorphisms A302CC-insertion and T310C-insertion were significantly associated with mean Breslow thickness, whereas the CR polymorphism T16519C was associated with metastasis. CONCLUSIONS AND SIGNIFICANCE: Our results suggest that mtDNA variations could be involved in melanoma etiology and pathogenesis, although the functional consequence of CR polymorphisms remains to be elucidated.
