Researchers Identify Genes That Appear to Play Central Role in Memory and Alzheimer’s

Genes are not only important for regular memory performance, but also for the development of Alzheimer’s disease. Researchers at the University of Basel have identified a specific group of genes that plays a central role in both processes. This group of molecules controls the concentration of calcium ions inside the cell. Their results appear in the current issue of the journal JAMA Psychiatry.

Intact memory capacity is crucial for everyday life. This fact becomes apparent once a memory disorder has developed. Alzheimer’s disease is the most common cause of age-associated memory disorders. Due to increasing life expectancy, the disease is on the rise in Switzerland and worldwide. Unfortunately, there is no effective treatment to cure or even slow down Alzheimer’s yet. Thus, understanding the origins of this neurodegenerative disorder is key to the development of much needed treatments.

Scientists have known for some years now, that genes do not only play a crucial role in normal memory performance, but also in the development of Alzheimer’s. However, it was so far unclear if specific genes are involved in both these processes.

Researchers at the transfaculty research platform at the Psychiatric University Clinics Basel and the Faculty of Psychology at the University of Basel were now able to show in a large scale study that a specific group of genes controls several processes that are central for regular brain functions as well as for the development of Alzheimer. First author Dr. Angela Heck collected and analyzed data of over 57,000 participants for this study.

Image shows an MRI brain scan with the hippocampus highlighted.
Researchers from the University of Basel were able to show that memory function (image shows the hippocampus highlighted) depends on calcium-regulating genes. Credit: MCN University of Basel.

Calcium is crucial

The study identified genes responsible for the concentration of calcium ions in the cell as central players of physiological and disease processes in the brain. Calcium genes stand in mutual relationship with memory performance of young and older healthy adults as well as with the function of the hippocampus, a brain region that is central to intact memory. Furthermore, calcium genes correlate with the risk for Alzheimer disease. The results contribute to the understanding of the complex processes that lead to memory disorders, such as Alzheimer’s.

About this Alzheimer’s disease research

This study is part of the Basel Genetics Memory Project led by professors Dominique de Quervain and Andreas Papassotiropoulos. The two co-heads of the transfaculty research platform are dedicated to translating basic research results to therapy projects as fast as possible.

Source: Olivia Poisson – University of Basel
Image Source: The image is credited to MCN University of Basel
Original Research: Full open access research for “Genetic Analysis of Association Between Calcium Signaling and Hippocampal Activation, Memory Performance in the Young and Old, and Risk for Sporadic Alzheimer Disease” by Angela Heck, Matthias Fastenrath, David Coynel, Bianca Auschra, Horst Bickel, Virginie Freytag, Leo Gschwind, Francina Hartmann, Frank Jessen, Hanna Kaduszkiewicz, Wolfgang Maier, Annette Milnik, Michael Pentzek, Steffi G. Riedel-Heller, Klara Spalek, Christian Vogler, Michael Wagner, Siegfried Weyerer, Steffen Wolfsgruber, Dominique F. de Quervain, and Andreas Papassotiropoulos in JAMA Psychiatry. Published online September 2 2015 doi:10.1001/jamapsychiatry.2015.1309


Abstract

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

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.

“Genetic Analysis of Association Between Calcium Signaling and Hippocampal Activation, Memory Performance in the Young and Old, and Risk for Sporadic Alzheimer Disease” by Angela Heck, Matthias Fastenrath, David Coynel, Bianca Auschra, Horst Bickel, Virginie Freytag, Leo Gschwind, Francina Hartmann, Frank Jessen, Hanna Kaduszkiewicz, Wolfgang Maier, Annette Milnik, Michael Pentzek, Steffi G. Riedel-Heller, Klara Spalek, Christian Vogler, Michael Wagner, Siegfried Weyerer, Steffen Wolfsgruber, Dominique F. de Quervain, and Andreas Papassotiropoulos in JAMA Psychiatry. Published online September 2 2015 doi:10.1001/jamapsychiatry.2015.1309

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