title: Genetic modifiers of cognitive maintenance among older adults.
abstract: OBJECTIVE
  Identify genetic factors associated with cognitive maintenance in late life and assess their association with gray matter (GM) volume in brain networks affected in aging.
  
  
  METHODS
  We conducted a genome-wide association study of ∼2.4 M markers to identify modifiers of cognitive trajectories in Caucasian participants (N = 7,328) from two population-based cohorts of non-demented elderly. Standardized measures of global cognitive function (z-scores) over 10 and 6 years were calculated among participants and mixed model regression was used to determine subject-specific cognitive slopes. "Cognitive maintenance" was defined as a change in slope of ≥ 0 and was compared with all cognitive decliners (slope < 0). In an independent cohort of cognitively normal older Caucasians adults (N = 122), top association findings were then used to create genetic scores to assess whether carrying more cognitive maintenance alleles was associated with greater GM volume in specific brain networks using voxel-based morphometry.
  
  
  RESULTS
  The most significant association was on chromosome 11 (rs7109806, P = 7.8 × 10(-8)) near RIC3. RIC3 modulates activity of α7 nicotinic acetylcholine receptors, which have been implicated in synaptic plasticity and beta-amyloid binding. In the neuroimaging cohort, carrying more cognitive maintenance alleles was associated with greater volume in the right executive control network (RECN; PFWE  = 0.01).
  
  
  CONCLUSIONS
  These findings suggest that there may be genetic loci that promote healthy cognitive aging and that they may do so by conferring robustness to GM in the RECN. Future work is required to validate top candidate genes such as RIC3 for involvement in cognitive maintenance.
authors.affiliation: Department of Neurology, Memory and Aging Center, University of California, San Francisco, California.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Yokoyama
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Evans
authors.forename: Giovanni
authors.initials: G
authors.lastname: Coppola
authors.forename: Joel H
authors.initials: JH
authors.lastname: Kramer
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tranah
authors.forename: Kristine
authors.initials: K
authors.lastname: Yaffe
mesh_terms: D000368:Aged; D000375:Aging / Q000235:genetics* / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D002880:Chromosomes, Human, Pair 11; D003071:Cognition; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study; D066128:Gray Matter / Q000473:pathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009434:Neural Pathways / Q000473:pathology; D009483:Neuropsychological Tests; D044465:White People / Q000235:genetics
keywords: aging; cognition; genetics; genome wide association study; genomics; neuroimaging