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PMID: 26332608 Published · ppublish English Journal Article Multicenter Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

JAMA psychiatry ·Vol. 72 ·No. 10 ·2015-10-00 ·Pages 1029-36

Heck A, Fastenrath M, Coynel D, Auschra B, Bickel H, Freytag V, Gschwind L, Hartmann F, Jessen F, Kaduszkiewicz H, Maier W, Milnik A, Pentzek M, Riedel-Heller SG, Spalek K, Vogler C, Wagner M, Weyerer S, Wolfsgruber S, de Quervain DJ, Papassotiropoulos A

Abstract

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. To determine whether biologically defined groups of genes are enriched in episodic memory performance across age, memory encoding-related brain activity, and AD. 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. 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. 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. 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.

MeSH Terms
Adult Age Factors Aged Aged, 80 and over Alzheimer Disease/genetics,physiopathology Calcium Signaling/genetics Case-Control Studies Cohort Studies Female Functional Neuroimaging Hippocampus/physiopathology Humans Magnetic Resonance Imaging Male Memory/physiology Memory, Episodic Middle Aged Prospective Studies Young Adult
Authors & Affiliations
21 authors, click to expand affiliations / ORCID
Heck Angela
Division of Molecular Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland2Psychiatric University Clinic, University of Basel, Basel, Switzerland.
Fastenrath Matthias
Division of Molecular Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland3Division of Cognitive Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland.
Coynel David
Division of Molecular Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland3Division of Cognitive Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland.
Auschra Bianca
Division of Molecular Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland.
Bickel Horst
Department of Psychiatry, Technical University of Munich, Munich, Germany.
Freytag Virginie
Division of Molecular Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland.
Gschwind Leo
Division of Molecular Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland3Division of Cognitive Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland.
Hartmann Francina
Division of Molecular Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland.
Jessen Frank
Department of Psychiatry, University of Cologne, Medical Faculty, Cologne, Germany6German Center for Neurodegenerative Diseases, Bonn, Germany.
Kaduszkiewicz Hanna
Institute of General Practice, Kiel University, Kiel, Germany.
Maier Wolfgang
German Center for Neurodegenerative Diseases, Bonn, Germany8Department of Psychiatry, University of Bonn, Bonn, Germany.
Milnik Annette
Division of Molecular Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland2Psychiatric University Clinic, University of Basel, Basel, Switzerland.
Pentzek Michael
Department of General Practice, University Medical Center Düsseldorf, Düsseldorf, Germany.
Riedel-Heller Steffi G
Institute of Social Medicine, Occupational Health, and Public Health, University of Leipzig, Leipzig, Germany.
Spalek Klara
Division of Cognitive Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland.
Vogler Christian
Division of Molecular Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland2Psychiatric University Clinic, University of Basel, Basel, Switzerland.
Wagner Michael
German Center for Neurodegenerative Diseases, Bonn, Germany8Department of Psychiatry, University of Bonn, Bonn, Germany.
Weyerer Siegfried
Central Institute of Mental Health, Mannheim/Heidelberg University, Mannheim, Germany.
Wolfsgruber Steffen
German Center for Neurodegenerative Diseases, Bonn, Germany8Department of Psychiatry, University of Bonn, Bonn, Germany.
de Quervain Dominique J-F
Psychiatric University Clinic, University of Basel, Basel, Switzerland3Division of Cognitive Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland.
Papassotiropoulos Andreas
Division of Molecular Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland2Psychiatric University Clinic, University of Basel, Basel, Switzerland12Life Sciences Training Facility, Department Biozentrum, University of Basel, Base.
Conflict of Interest

There are no conflicts of interest to declare.

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Article Info
Journal
JAMA psychiatry
Abbr.
JAMA Psychiatry
ISSN
2168-6238
DOI
10.1001/jamapsychiatry.2015.1309
Published
2015-10-00
Pages
1029-36
Language
English
Region
United States
NLM ID
101589550
PMCID
PMC5291164
Subset
IM
Grants
Wellcome Trust · 082604/2/07/Z · United Kingdom
NIA NIH HHS · N01AG12100 · United States
Medical Research Council · 503480 · United Kingdom
NIA NIH HHS · U24 AG021886 · United States
NIA NIH HHS · U01 AG032984 · United States
NIA NIH HHS · U01 AG016976 · United States
NHLBI NIH HHS · R01 HL105756 · United States
NIA NIH HHS · R01 AG008122 · United States
NIA NIH HHS · R01 AG033193 · United States
NIA NIH HHS · AG081220 · United States
NIA NIH HHS · N01-AG-12100 · United States
External Links
PubMed source DOI: 10.1001/jamapsychiatry.2015.1309 PMC Full Text View journal details
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