Genetic Analysis of Association Between XXXX Signaling and Hippocampal Activation, Memory Performance in the Young and Old, and Risk for Sporadic @entity195 .

@entity1 @entity303 @entity179 @entity460 @entity195 @entity2414
Importance: @entity1 episodic memory performance is linked to the function of specific brain regions, including the hippocampus; declines as a result of increasing age; and is markedly disturbed in @entity195 ( @entity195 ), an age-associated @entity179 that primarily affects the hippocampus. Exploring the molecular underpinnings of @entity1 episodic memory is key to the understanding of hippocampus-dependent cognitive physiology and pathophysiology. Objective: To determine whether biologically defined groups of genes are enriched in episodic memory performance across age, memory encoding-related brain activity, and @entity195 . Design, Setting, and @entity1 : In this multicenter collaborative study, which began in August 2008 and is ongoing, gene set enrichment analysis was done by using primary and meta-analysis data from 57   968 @entity1 . The Swiss cohorts consisted of 3043 healthy young adults assessed for episodic memory performance. In a subgroup (n   =   1119) of one of these cohorts, functional magnetic resonance imaging was used to identify gene set-dependent differences in brain activity related to episodic memory. The German Study on Aging, Cognition, and @entity303 in Primary Care @entity1 cohort consisted of 763 elderly @entity1 without @entity303 who were assessed for episodic memory performance. The International Genomics of Alzheimer's Project case-control sample consisted of 54   162 @entity1 (17   008 @entity1 with @entity195 and 37   154 control @entity1 ). Analyses were conducted between January 2014 and June 2015. Gene set enrichment analysis in all samples was done using genome-wide single-nucleotide polymorphism data. Main Outcomes and Measures: Episodic memory performance in the Swiss cohort and German Study on Aging, Cognition, and @entity303 in Primary Care @entity1 cohort was quantified by picture and @entity2414 . In the functional magnetic resonance imaging experiment, activation of the hippocampus during encoding of pictures served as the phenotype of interest. In the International Genomics of Alzheimer's Project sample, diagnosis of @entity195 served as the phenotype of interest. Results: In the discovery sample, we detected significant enrichment for genes constituting the @entity460 signaling pathway, especially those related to the elevation of cytosolic @entity460 (P   =   2   *   10-4). This enrichment was replicated in 2 additional samples of healthy young individuals (P   =   .02 and .04, respectively) and a sample of healthy elderly @entity1 (P   =   .004). Hippocampal activation (P   =   4   *   10-4) and the risk for @entity195 (P   =   .01) were also significantly enriched for genes related to the elevation of cytosolic @entity460 . Conclusions and Relevance: By detecting consistent significant enrichment in independent cohorts of young and elderly @entity1 , this study identified that @entity460 signaling plays a central role in hippocampus-dependent @entity1 memory processes in cognitive health and disease, contributing to the understanding and potential treatment of hippocampus-dependent cognitive pathology.
