Genetic Analysis of Association Between Calcium Signaling and Hippocampal Activation, Memory Performance in the Young and Old, and Risk for Sporadic Alzheimer Disease
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Genetic Analysis of Association Between Calcium Signaling and Hippocampal Activation, Memory Performance in the Young and Old, and Risk for Sporadic Alzheimer Disease. / Heck, Angela; Fastenrath, Matthias; Coynel, David; Auschra, Bianca; Bickel, Horst; Freytag, Virginie; Gschwind, Leo; Hartmann, Francina; Jessen, Frank; Kaduszkiewicz, Hanna; Maier, Wolfgang; Milnik, Annette; Pentzek, Michael; Riedel-Heller, Steffi G; Spalek, Klara; Vogler, Christian; Wagner, Michael; Weyerer, Siegfried; Wolfsgruber, Steffen; de Quervain, Dominique J-F; Papassotiropoulos, Andreas.
In: JAMA PSYCHIAT, Vol. 72, No. 10, 10.2015, p. 1029-36.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Genetic Analysis of Association Between Calcium Signaling and Hippocampal Activation, Memory Performance in the Young and Old, and Risk for Sporadic Alzheimer Disease
AU - Heck, Angela
AU - Fastenrath, Matthias
AU - Coynel, David
AU - Auschra, Bianca
AU - Bickel, Horst
AU - Freytag, Virginie
AU - Gschwind, Leo
AU - Hartmann, Francina
AU - Jessen, Frank
AU - Kaduszkiewicz, Hanna
AU - Maier, Wolfgang
AU - Milnik, Annette
AU - Pentzek, Michael
AU - Riedel-Heller, Steffi G
AU - Spalek, Klara
AU - Vogler, Christian
AU - Wagner, Michael
AU - Weyerer, Siegfried
AU - Wolfsgruber, Steffen
AU - de Quervain, Dominique J-F
AU - Papassotiropoulos, Andreas
PY - 2015/10
Y1 - 2015/10
N2 - IMPORTANCE: Human 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 Alzheimer disease (AD), an age-associated neurodegenerative disorder that primarily affects the hippocampus. Exploring the molecular underpinnings of human 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 AD.DESIGN, SETTING, AND PARTICIPANTS: 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 participants. 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 Dementia in Primary Care Patients cohort consisted of 763 elderly participants without dementia who were assessed for episodic memory performance. The International Genomics of Alzheimer's Project case-control sample consisted of 54 162 participants (17 008 patients with sporadic AD and 37 154 control participants). 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 Dementia in Primary Care Patients cohort was quantified by picture and verbal delayed free recall tasks. 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 sporadic AD served as the phenotype of interest.RESULTS: In the discovery sample, we detected significant enrichment for genes constituting the calcium signaling pathway, especially those related to the elevation of cytosolic calcium (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 participants (P = .004). Hippocampal activation (P = 4 × 10-4) and the risk for sporadic AD (P = .01) were also significantly enriched for genes related to the elevation of cytosolic calcium.CONCLUSIONS AND RELEVANCE: By detecting consistent significant enrichment in independent cohorts of young and elderly participants, this study identified that calcium signaling plays a central role in hippocampus-dependent human memory processes in cognitive health and disease, contributing to the understanding and potential treatment of hippocampus-dependent cognitive pathology.
AB - IMPORTANCE: Human 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 Alzheimer disease (AD), an age-associated neurodegenerative disorder that primarily affects the hippocampus. Exploring the molecular underpinnings of human 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 AD.DESIGN, SETTING, AND PARTICIPANTS: 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 participants. 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 Dementia in Primary Care Patients cohort consisted of 763 elderly participants without dementia who were assessed for episodic memory performance. The International Genomics of Alzheimer's Project case-control sample consisted of 54 162 participants (17 008 patients with sporadic AD and 37 154 control participants). 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 Dementia in Primary Care Patients cohort was quantified by picture and verbal delayed free recall tasks. 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 sporadic AD served as the phenotype of interest.RESULTS: In the discovery sample, we detected significant enrichment for genes constituting the calcium signaling pathway, especially those related to the elevation of cytosolic calcium (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 participants (P = .004). Hippocampal activation (P = 4 × 10-4) and the risk for sporadic AD (P = .01) were also significantly enriched for genes related to the elevation of cytosolic calcium.CONCLUSIONS AND RELEVANCE: By detecting consistent significant enrichment in independent cohorts of young and elderly participants, this study identified that calcium signaling plays a central role in hippocampus-dependent human memory processes in cognitive health and disease, contributing to the understanding and potential treatment of hippocampus-dependent cognitive pathology.
KW - Adult
KW - Age Factors
KW - Aged
KW - Aged, 80 and over
KW - Alzheimer Disease
KW - Calcium Signaling
KW - Case-Control Studies
KW - Cohort Studies
KW - Female
KW - Functional Neuroimaging
KW - Hippocampus
KW - Humans
KW - Magnetic Resonance Imaging
KW - Male
KW - Memory
KW - Memory, Episodic
KW - Middle Aged
KW - Prospective Studies
KW - Young Adult
U2 - 10.1001/jamapsychiatry.2015.1309
DO - 10.1001/jamapsychiatry.2015.1309
M3 - SCORING: Journal article
C2 - 26332608
VL - 72
SP - 1029
EP - 1036
JO - JAMA PSYCHIAT
JF - JAMA PSYCHIAT
SN - 2168-622X
IS - 10
ER -