Genetic interaction of PICALM and APOE is associated with brain atrophy and cognitive impairment in Alzheimer's disease

Katrin Morgen; Alfredo Ramirez; Lutz Frölich; Heike Tost; Michael M Plichta; Heike Kölsch; Fabian Rakebrandt; Otto Rienhoff; Frank Jessen; Oliver Peters; Holger Jahn; Christian Luckhaus; Michael Hüll; Hermann-Josef Gertz; Johannes Schröder; Harald Hampel; Stefan J Teipel; Johannes Pantel; Isabella Heuser; Jens Wiltfang; Eckart Rüther; Johannes Kornhuber; Wolfgang Maier; Andreas Meyer-Lindenberg

doi:10.1016/j.jalz.2013.11.001

Genetic interaction of PICALM and APOE is associated with brain atrophy and cognitive impairment in Alzheimer's disease

Alzheimers Dement. 2014 Oct;10(5 Suppl):S269-76. doi: 10.1016/j.jalz.2013.11.001. Epub 2014 Mar 6.

Authors

Katrin Morgen¹, Alfredo Ramirez², Lutz Frölich³, Heike Tost³, Michael M Plichta³, Heike Kölsch⁴, Fabian Rakebrandt⁵, Otto Rienhoff⁵, Frank Jessen⁶, Oliver Peters⁷, Holger Jahn⁸, Christian Luckhaus⁹, Michael Hüll¹⁰, Hermann-Josef Gertz¹¹, Johannes Schröder¹², Harald Hampel¹³, Stefan J Teipel¹⁴, Johannes Pantel¹⁵, Isabella Heuser⁷, Jens Wiltfang¹⁶, Eckart Rüther¹⁷, Johannes Kornhuber¹⁸, Wolfgang Maier¹⁹, Andreas Meyer-Lindenberg³

Affiliations

¹ Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Heidelberg, Germany. Electronic address: katrin.morgen@zi-mannheim.de.
² Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; Institute of Human Genetics, University of Bonn, Bonn, Germany.
³ Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Heidelberg, Germany.
⁴ Institute of Human Genetics, University of Bonn, Bonn, Germany.
⁵ Department of Medical Informatics, University of Göttingen, Göttingen, Germany.
⁶ Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
⁷ Department of Psychiatry and Psychotherapy, Charité Berlin, Berlin, Germany.
⁸ Department of Psychiatry and Psychotherapy, University of Hamburg, Hamburg, Germany.
⁹ Department of Psychiatry and Psychotherapy, University of Düsseldorf, Düsseldorf, Germany.
¹⁰ Department of Psychiatry and Psychotherapy, University of Freiburg, Freiburg, Germany.
¹¹ Department of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany.
¹² Department of Psychiatry and Psychotherapy, University of Heidelberg, Heidelberg, Germany.
¹³ Département de Neurologie Institut de la Mémoire et de la Maladie d'Alzheimer, Université Pierre et Marie Curie, Hôpital de la Salpétriére Paris, France.
¹⁴ Department of Psychiatry and Psychotherapy, University of Rostock, Rostock, Germany; German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany.
¹⁵ Institute of General Practice, University of Frankfurt, Frankfurt, Germany.
¹⁶ Department of Psychiatry and Psychotherapy, University of Essen, Essen, Germany.
¹⁷ Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany.
¹⁸ Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
¹⁹ Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases, Bonn, Germany.

PMID: 24613704
DOI: 10.1016/j.jalz.2013.11.001

Abstract

Background: Evidence has emerged indicating that the ε4 allele of APOE and PICALM interact in conferring risk of Alzheimer's disease (AD). The biologic basis of this interaction is unclear, but it is likely to have phenotypic relevance and contribute to the structural and clinical heterogeneity of AD.

Methods: The aim of this study was to investigate interaction effects of the APOE ε4 allele and the alleles at the single-nucleotide polymorphism rs3851179 located in the PICALM locus. We analyzed brain volumes and cognitive phenotypes of 165 patients with early AD dementia.

Results: There was a synergistic adverse effect of homozygosity for the PICALM risk allele G in rs3851179 and APOE ε4 on volume in prefrontal and performance on the Trail Making Test A, which is sensitive to processing speed and working memory function.

Conclusions: The data suggest a neural mechanism for APOE-PICALM interactions in patients with manifest AD and indicate that the PICALM genotype modulates both brain atrophy and cognitive performance in APOE ε4 carriers.

Keywords: APOE; Alzheimer's disease; Brain atrophy; Genetic interaction; PICALM.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Alzheimer Disease / genetics*
Alzheimer Disease / pathology*
Alzheimer Disease / physiopathology
Alzheimer Disease / psychology
Apolipoproteins E / genetics*
Atrophy
Brain / pathology*
Cognition Disorders / genetics*
Cognition Disorders / pathology
Cognition Disorders / physiopathology
Female
Genetic Predisposition to Disease
Genotyping Techniques
Humans
Magnetic Resonance Imaging
Male
Monomeric Clathrin Assembly Proteins / genetics*
Neuropsychological Tests
Organ Size
Phenotype
Polymorphism, Single Nucleotide

Substances

Apolipoproteins E
Monomeric Clathrin Assembly Proteins
PICALM protein, human