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Original Investigation |

Genetic Analysis of Association Between Calcium Signaling and Hippocampal Activation, Memory Performance in the Young and Old, and Risk for Sporadic Alzheimer Disease

Angela Heck, PhD1,2; Matthias Fastenrath, PhD1,3; David Coynel, PhD1,3; Bianca Auschra, MS1; Horst Bickel, PhD4; Virginie Freytag, MS1; Leo Gschwind, MS1,3; Francina Hartmann, MS1; Frank Jessen, MD5,6; Hanna Kaduszkiewicz, MD7; Wolfgang Maier, MD6,8; Annette Milnik, MD1,2; Michael Pentzek, PhD9; Steffi G. Riedel-Heller, MD10; Klara Spalek, PhD3; Christian Vogler, PhD1,2; Michael Wagner, PhD6,8; Siegfried Weyerer, PhD11; Steffen Wolfsgruber, MS6,8; Dominique J.-F. de Quervain, MD2,3; Andreas Papassotiropoulos, MD1,2,12
[+] Author Affiliations
1Division of Molecular Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland
2Psychiatric University Clinic, University of Basel, Basel, Switzerland
3Division of Cognitive Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland
4Department of Psychiatry, Technical University of Munich, Munich, Germany
5Department of Psychiatry, University of Cologne, Medical Faculty, Cologne, Germany
6German Center for Neurodegenerative Diseases, Bonn, Germany
7Institute of General Practice, Kiel University, Kiel, Germany
8Department of Psychiatry, University of Bonn, Bonn, Germany
9Department of General Practice, University Medical Center Düsseldorf, Düsseldorf, Germany
10Institute of Social Medicine, Occupational Health, and Public Health, University of Leipzig, Leipzig, Germany
11Central Institute of Mental Health, Mannheim/Heidelberg University, Mannheim, Germany
12Life Sciences Training Facility, Department Biozentrum, University of Basel, Basel, Switzerland
JAMA Psychiatry. 2015;72(10):1029-1036. doi:10.1001/jamapsychiatry.2015.1309.
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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.

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Figure 1.
Schematic Description of Study Workflow and Included Samples

A, Testing for episodic memory (EM) performance in the discovery (n = 1458) and replication (n = 1176) samples of healthy young adults was done by quantifying the delayed free recall of pictures taken from the International Affective Picture System. The identical picture set was presented in both samples. B, This functional magnetic resonance imaging sample of healthy young adults (n = 1119) was a subsample of the replication sample and was used for quantification of hippocampal activation during the encoding of pictures taken from the International Affective Picture System (identical picture set as before). C, These additional samples of 409 healthy young adults and 763 healthy elderly adults were tested for EM performance by quantifying the delayed free recall of pictures taken from the International Affective Picture System (young sample, different picture set compared with the discovery and replication samples) or of words (elderly sample). D, This large case-control sample (n = 54 162) was used to test for enrichment of the EM core gene set. The phenotype of interest was the diagnosis of Alzheimer disease.

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Figure 2.
Allelic Load–Dependent Increases in Episodic Memory (EM)–Related Brain Activity (n = 1119)

The red circles show the activation in the right hippocampus. The local maximum is located at 33, −16.5, −16 (t = 3.35; uncorrected P= 4 × 10−4; small volume–corrected P< .05). Activations are overlaid on coronal (upper left), sagittal (upper right), and axial (lower left) sections of the study-specific group template displayed at uncorrected P = .001 using color-coded t values.

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Figure 3.
Gene Set Enrichment Analysis Results of the 66 Nonsignificant Genes and the Episodic Memory (EM) Core Gene Set

Enrichment P values of the respective gene sets in 3 samples (Zurich sample, Study on Aging, Cognition, and Dementia in Primary Care Patients sample, and International Genomics of Alzheimer’s Project sample). Box plot of gene size distribution stratified by gene set. Filled circles indicate outliers, and open circles indicate extreme values. The mean (SD) length of the 26 significant genes is 144.6 (139.7) kb. The mean (SD) length of the 66 nonsignificant genes is 143.8 (226.9) kb. The difference is not significant (P = .90).

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