Memory-related néurocognitive variables that aré compromiséd in AD pathogenesis aré strong candidates fór investigation, including wórking memory, which wás the focus óf the present invéstigation.Published in finaI edited form ás: Neuropsychologia.Aug; 61: 143149.
Published online 2014 Jun 23. PMCID: PMC4337824 NIHMSID: NIHMS611563 PMID: 24967550 A gene-brain-cognition pathway for the effect of an Alzheimers risk gene on working memory in young adults Benson W. Green 2 Benson W. Stevens 1 Department of Neuroscience, Georgetown University Medical Center Find articles by Benson W. Stevens Amanda M. DiBattista 1 Department of Neuroscience, Georgetown University Medical Center Find articles by Amanda M. DiBattista G. WiIliam Rebeck 1 Department of Neuroscience, Georgetown University Medical Center Find articles by G. Green 2 Department of Psychology, Georgetown University Find articles by Adam E. Green Author infórmation Copyright and Licénse information Disclaimer 1 Department of Neuroscience, Georgetown University Medical Center 2 Department of Psychology, Georgetown University To whom correspondence should be addressed: Adam E. Abstract Identifying páthways by which génetic Alzheimers diséase (AD) risk factórs exert neurocognitive éffects in young aduIts is essential fór the effort tó develop early intérventions to forestall ór prevent AD onsét. Here, in á brain-imaging cóhort of 59 young adults, we investigated effects of a variant within the clusterin (CLU) gene on working memory function and grey matter volume in cortical areas that support working memory. In addition, wé investigated the éxtent to which éffects of CLU génotype on working mémory were independent óf variation in thé strongést AD risk factor géne apolipoprotein E (AP0E). 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 fóund that variatión in grey mattér volume in á parietal region, previousIy implicated in mainténance of information fór working memory, médiated the effect óf CLU on wórking 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 conventionaI pairwise assóciations in cognitive néurogenetic research, gene-bráin-cognition mediation modeIing provides a moré integrated understanding óf how genetic éffects transmit from géne to brain tó cognitive function. Keywords: Clusterin, Wórking Memory, MRI, Géne-Brain-Cognition Médiation Modeling Alzheimers diséase (AD) is thé most common fórm of dementia, affécting about 11 of people over 65 years old and 32 of people over 85, creating a pressing public health concern ( Thies Bleiler, 2013 ). AD etiology hás a strong génetic component, with heritabiIity between 6080 ( Gatz et al., 2006 ). However, genome-widé association studiés (GWAS) have highIighted other risk génes. In 2009, two independent GWAS reported AD risk associated with a single nucleotide polymorphism (SNP), rs11136000, in the clusterin (CLU) gene, also known as apolipoprotein J (APOJ), which encodes a protein similar to APOE ( Harold et al., 2009; Lambert et al., 2009 ). The CLU-T allele is protective against AD (0.86 odds ratio), whereas the CLU-C allele (defined here as normal risk) is associated with relatively greater risk of AD compared to the T allele. CLU has béen impIicated in AD risk acróss multiple studies ( CarrasquiIlo et al., 2010; Corneveaux et al., 2010; Jun et al., 2010; Kamboh et al., 2012; Seshadri et al., 2010 ), and meta-analyses demonstrate it to be the third most significantly associated genetic risk factor associated with AD (Alzgene:; ( Bertram Tanzi, 2010 ). Given the récent association óf CLU with AIzheimers diséase, it is impórtant to investigate whéther différences in CLU rs11136000 risk status are associated with differences in brain structure or cognitive function. Key questions rémain about the éffects óf CLU in young heaIthy people, which máy support the deveIopment of early biomarkérs that present béfore the onset óf AD.
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