title: Alzheimer's disease susceptibility genes APOE and TOMM40, and hippocampal volumes in the Lothian birth cohort 1936.
abstract: The APOE ε and TOMM40 rs10524523 ('523') variable length poly-T repeat gene loci have been significantly and independently associated with Alzheimer's disease (AD) related phenotypes such as age of clinical onset. Hippocampal atrophy has been significantly associated with memory impairment, a characteristic of AD. The current study aimed to test for independent effects of APOE ε and TOMM40 '523' genotypes on hippocampal volumes as assessed by brain structural MRI in a relatively large sample of community-dwelling older adults. As part of a longitudinal study of cognitive ageing, participants in the Lothian Birth Cohort 1936 underwent genotyping for APOE ε2/ε3/ε4 status and TOMM40 '523' poly-T repeat length, and detailed structural brain MRI at a mean age of 72.7 years (standard deviation = 0.7, N range = 624 to 636). No significant effects of APOE ε or TOMM40 523 genotype were found on hippocampal volumes when analysed raw, or when adjusted for either intracranial or total brain tissue volumes. In summary, in a large community-dwelling sample of older adults, we found no effects of APOE ε or TOMM40 523 genotypes on hippocampal volumes. This is discrepant with some previous reports of significant association between APOE and left/right hippocampal volumes, and instead echoes other reports that found no association. Previous significant findings may partly reflect type 1 error. Future studies should carefully consider: 1) their specific techniques in adjusting for brain size; 2) assessing more detailed sub-divisions of the hippocampal formation; and 3) testing whether significant APOE-hippocampal associations are independent of generalised brain atrophy.
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom ; Brain Research Imaging Centre, Division of Neuroimaging Sciences, University of Edinburgh, Edinburgh, United Kingdom ; Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom ; Medical Genetics Section, Centre for Genomics and Experimental Medicine and MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Donald M
authors.initials: DM
authors.lastname: Lyall
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Royle
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Harris
authors.forename: Mark E
authors.initials: ME
authors.lastname: Bastin
authors.forename: Susana Muñoz
authors.initials: SM
authors.lastname: Maniega
authors.forename: Catherine
authors.initials: C
authors.lastname: Murray
authors.forename: Michael W
authors.initials: MW
authors.lastname: Lutz
authors.forename: Ann M
authors.initials: AM
authors.lastname: Saunders
authors.forename: Allen D
authors.initials: AD
authors.lastname: Roses
authors.forename: Maria C
authors.initials: MC
authors.lastname: del Valdés Hernández
authors.forename: John M
authors.initials: JM
authors.lastname: Starr
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Wardlaw
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; D009929:Organ Size
chemical_list: D001057:Apolipoproteins E; D026901:Membrane Transport Proteins; D000090622:Mitochondrial Precursor Protein Import Complex Proteins; C400783:TOMM40 protein, human