Abstract
Genetic polymorphisms in the APOE ɛ and TOMM40 ‘523' poly-T repeat gene loci have been associated with significantly increased risk of Alzheimer's disease. This study investigated the independent effects of these polymorphisms on human cognitive ageing, and the extent to which nominally significant associations with cognitive ageing were mediated by previously reported genetic associations with brain white matter tract integrity in this sample. Most participants in the Lothian Birth Cohort 1936 completed a reasoning-type intelligence test at age 11 years, and detailed cognitive/physical assessments and structural diffusion tensor brain magnetic resonance imaging at a mean age of 72.70 years (s.d.=0.74). Participants were genotyped for APOE ɛ2/ɛ3/ɛ4 status and TOMM40 523 poly-T repeat length. Data were available from 758–814 subjects for cognitive analysis, and 522–543 for mediation analysis with brain imaging data. APOE genotype was significantly associated with performance on several different tests of cognitive ability, including general factors of intelligence, information processing speed and memory (raw P-values all<0.05), independently of childhood IQ and vascular disease history. Formal tests of mediation showed that several significant APOE-cognitive ageing associations—particularly those related to tests of information processing speed—were partially mediated by white matter tract integrity. TOMM40 523 genotype was not associated with cognitive ageing. A range of brain phenotypes are likely to form the anatomical basis for significant associations between APOE genotype and cognitive ageing, including white matter tract microstructural integrity.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by cognitive impairment
Of the 1091 Lothian Birth Cohort 1936 (LBC1936) participants originally enrolled in the study, 866 attended Waves 1 and 2
This left 859 participants, of which 811 and 823 participants had successful genotyping for Covariate models
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by cognitive impairment. Two genetic risk factors for late onset Alzheimer’s disease are in the apolipoprotein-e (APOE; http://www.ncbi.nlm.nih.gov/gene/348) and translocase of outer mitochondrial membrane 40 (TOMM40) gene poly-T repeat loci (http://www.ncbi.nlm.nih.gov/gene/10452).[1,2]. Previous studies have investigated associations between APOE genotype and cognitive ability in non-demented older adults. Wisdom et al.[3] conducted a meta-analysis of 77 studies, excluding samples with any disorders that may affect cognitive ability such as dementia or Parkinson’s disease There were no significant effects on verbal ability, primary memory, attention or visuospatial functioning
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