title: Gene-environment interactions: lifetime cognitive activity, APOE genotype, and β-amyloid burden.
abstract: Carriers of the apolipoprotein E (APOE) ε4 allele, the major genetic risk for Alzheimer's disease (AD), harbor an increased load of β-amyloid (Aβ) plaque burden that is felt to be a major instigator of AD development. Data has suggested that lifestyle factors may reduce AD risk by directly mitigating Aβ pathology, which could be particularly beneficial in APOE ε4 carriers. We therefore examined the interaction between lifetime cognitive activity and the APOE ε4 allele in relation to brain Aβ burden. We obtained measures of lifetime cognitive activity in 118 cognitively normal human individuals (mean age: 76.13 ± 5.56 years, 70 women) using a validated questionnaire that included measures over early, middle, and current age epochs. Hierarchical regression models (adjusted for age, gender, and years of education) were conducted to examine effects of APOE ε4 carrier status, lifetime cognitive activity, and the interaction of the two factors with cortical Aβ deposition, quantified using [11C] Pittsburgh-compound-B (PIB)-PET. As expected, the ε4 carriers exhibited higher PIB retention compared with noncarriers. Lifetime cognitive activity moderated the APOE genotype effect such that cortical PIB retention was diminished in ε4 carriers that reported higher cognitive activity over the life course. The findings suggest that greater lifetime cognitive activity may forestall AD pathology, specifically in genetically susceptible individuals. The effect could imply that cognitive training promotes increased neural efficiency that might retard the lifelong neurally mediated deposition of Aβ.
authors.affiliation: Helen Wills Neuroscience Institute and miranka.wirth@gmail.com.
authors.forename: Miranka
authors.initials: M
authors.lastname: Wirth
authors.affiliation: Helen Wills Neuroscience Institute and.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Villeneuve
authors.affiliation: Helen Wills Neuroscience Institute and.
authors.forename: Renaud
authors.identifier: http://orcid.org/0000-0003-2581-8100
authors.initials: R
authors.lastname: La Joie
authors.affiliation: Helen Wills Neuroscience Institute and.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Marks
authors.affiliation: Helen Wills Neuroscience Institute and School of Public Health, University of California, Berkeley, California 94720, and Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720.
authors.forename: William J
authors.initials: WJ
authors.lastname: Jagust
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000235:genetics*; D053327:Apolipoprotein E4 / Q000235:genetics*; D001923:Brain Chemistry / Q000235:genetics; D003071:Cognition / Q000502:physiology*; D005260:Female; D059647:Gene-Environment Interaction; D006580:Genetic Carrier Screening; D005838:Genotype; D006801:Humans; D008136:Longevity / Q000235:genetics*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4
keywords: APOE; Alzheimer's disease; PIB-PET; aging; lifestyle activity; β-amyloid