title: A gene-brain-cognition pathway for the effect of an Alzheimer׳s risk gene on working memory in young adults.
abstract: Identifying pathways by which genetic Alzheimer׳s disease (AD) risk factors exert neurocognitive effects in young adults are essential for the effort to develop early interventions to forestall or prevent AD onset. Here, in a brain-imaging cohort of 59 young adults, we investigated effects of a variant within the clusterin (CLU) gene on working memory function and gray matter volume in cortical areas that support working memory. In addition, we investigated the extent to which effects of CLU genotype on working memory were independent of variation in the strongest AD risk factor gene apolipoprotein E (APOE). CLU is among the strongest genetic AD risk factors and, though it appears to share AD pathogenesis-related features with, APOE, it has been far less well studied. CLU genotype was associated with working memory performance in our study cohort. Notably, we found that variation in gray matter volume in a parietal region, previously implicated in maintenance of information for working memory, mediated the effect of CLU on working memory performance. APOE genotype did not affect working memory within our sample, and did not interact with CLU genotype. To our knowledge, this work represents the first evidence of a behavioral effect of CLU genotype in young people. In addition, this work identifies the first gene-brain-cognition mediation effect pathway for the transmission of the effect of an AD risk factor. Relative to conventional pairwise associations in cognitive neurogenetic research, gene-brain-cognition mediation modeling provides a more integrated understanding of how genetic effects transmit from gene to brain to cognitive function.
authors: Department of Neuroscience, Georgetown University Medical Center, United States.
authors: Benson W
authors: BW
authors: Stevens
authors: Department of Neuroscience, Georgetown University Medical Center, United States.
authors: Amanda M
authors: AM
authors: DiBattista
authors: Department of Neuroscience, Georgetown University Medical Center, United States.
authors: G
authors: G
authors: William Rebeck
authors: Department of Psychology, Georgetown University, 37(th) and O Streets, NW, 302-C White-Gravenor, Washington DC 20057, United States. Electronic address: aeg58@georgetown.edu.
authors: Adam E
authors: AE
authors: Green
mesh_terms: D000293:Adolescent; D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D051152:Clusterin / Q000235:genetics*; D003071:Cognition / Q000502:physiology*; D015331:Cohort Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D060005:Genotyping Techniques; D066128:Gray Matter / Q000033:anatomy & histology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008570:Memory, Short-Term / Q000502:physiology*; D009483:Neuropsychological Tests; D009929:Organ Size; D010296:Parietal Lobe / Q000033:anatomy & histology*; D012307:Risk Factors; D055815:Young Adult
chemical_list: D001057:Apolipoproteins E; C495242:CLU protein, human; D051152:Clusterin
keywords: Clusterin; Gene−brain−cognition mediation modeling; MRI; Working memory