Alzheimer's disease risk variants modulate endophenotypes in mild cognitive impairment

Eva Louwersheimer; Steffen Wolfsgruber; Ana Espinosa; André Lacour; Stefanie Heilmann-Heimbach; Montserrat Alegret; Isabel Hernández; Maitée Rosende-Roca; Lluís Tárraga; Mercè Boada; Johannes Kornhuber; Oliver Peters; Lutz Frölich; Michael Hüll; Eckart Rüther; Jens Wiltfang; Martin Scherer; Steffi Riedel-Heller; Frank Jessen; Markus M Nöthen; Wolfgang Maier; Ted Koene; Philip Scheltens; Henne Holstege; Michael Wagner; Agustín Ruiz; Wiesje M van der Flier; Tim Becker; Alfredo Ramirez

doi:10.1016/j.jalz.2016.01.006

Alzheimer's disease risk variants modulate endophenotypes in mild cognitive impairment

Alzheimers Dement. 2016 Aug;12(8):872-81. doi: 10.1016/j.jalz.2016.01.006. Epub 2016 Feb 26.

Authors

Eva Louwersheimer¹, Steffen Wolfsgruber², Ana Espinosa³, André Lacour⁴, Stefanie Heilmann-Heimbach⁵, Montserrat Alegret³, Isabel Hernández³, Maitée Rosende-Roca³, Lluís Tárraga³, Mercè Boada³, Johannes Kornhuber⁶, Oliver Peters⁷, Lutz Frölich⁸, Michael Hüll⁹, Eckart Rüther¹⁰, Jens Wiltfang¹⁰, Martin Scherer¹¹, Steffi Riedel-Heller¹², Frank Jessen¹³, Markus M Nöthen⁵, Wolfgang Maier², Ted Koene¹⁴, Philip Scheltens¹⁵, Henne Holstege¹⁶, Michael Wagner², Agustín Ruiz³, Wiesje M van der Flier¹⁷, Tim Becker¹⁸, Alfredo Ramirez¹⁹

Affiliations

¹ Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands. Electronic address: e.louwersheimer@vumc.nl.
² Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
³ Alzheimer Research Center and Memory Clinic of Fundació ACE, Institut Català de Neurociències Aplicades, Barcelona, Spain.
⁴ German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
⁵ Institute of Human Genetics, University of Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
⁶ Department of Psychiatry and Psychotherapy, University Clinic Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany.
⁷ Department of Psychiatry, Charité University Medicine, Berlin, Germany.
⁸ Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
⁹ Centre for Geriatric Medicine and Section of Gerontopsychiatry and Neuropsychology, Medical School, University of Freiburg, Freiburg, Germany.
¹⁰ Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen, Germany.
¹¹ Department of Primary Medical Care, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹² Institute of Social Medicine, Occupational Health and Public Health, University of Leipzig, Leipzig, Germany.
¹³ Department of Psychiatry and Psychotherapy, University of Cologne, Cologne, Germany.
¹⁴ Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands; Alzheimer Center and Department of Medical Psychology, VU University Medical Center, Amsterdam, The Netherlands.
¹⁵ Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands.
¹⁶ Alzheimer Center and Department of Clinical Genetics, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands.
¹⁷ Alzheimer Center and Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Centre, Amsterdam, The Netherlands; Department of Epidemiology & Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
¹⁸ Institute for Community Medicine, Ernst Moritz Arndt University Greifswald, Greifswald, Germany.
¹⁹ Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; Institute of Human Genetics, University of Bonn, Bonn, Germany. Electronic address: alfredo.ramirez@ukb.uni-bonn.de.

PMID: 26921674
DOI: 10.1016/j.jalz.2016.01.006

Abstract

Introduction: We evaluated the effect of Alzheimer's disease (AD) susceptibility loci on endophenotypes closely related with AD pathology in patients with mild cognitive impairment (MCI).

Methods: We selected 1730 MCI patients from four independent data sets. Weighted polygenic risk scores (PGS) were constructed of 18 non-apolipoprotein E (APOE) AD risk variants. In addition, we determined APOE genotype. AD endophenotypes were cognitive decline over time and cerebrospinal fluid (CSF) biomarkers (aβ, tau, ptau).

Results: PGS was modestly associated with cognitive decline over time, as measured by mini-mental state examination (MMSE) (β ± SE:-0.24 ± 0.10; P = .012), and with CSF levels of tau and ptau (tau: 1.38 ± 0.36, P = 1.21 × 10(-4); ptau: 1.40 ± 0.36, P = 1.02 × 10(-4)).

Discussion: In MCI, we observed a joint effect of AD susceptibility loci on nonamyloid endophenotypes, suggesting a link of these genetic loci with neuronal degeneration in general rather than with Alzheimer-related amyloid deposition.

Keywords: Alzheimer's disease; Endophenotypes; Genetic risk variants; Mild cognitive impairment; Polygenic risk score.

Publication types

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

MeSH terms

Aged
Aged, 80 and over
Alzheimer Disease / cerebrospinal fluid
Alzheimer Disease / diagnosis
Amyloid beta-Peptides / cerebrospinal fluid
Apolipoproteins E / genetics
Cognitive Dysfunction / cerebrospinal fluid*
Cognitive Dysfunction / complications*
Cognitive Dysfunction / genetics
Cohort Studies
Datasets as Topic / statistics & numerical data
Endophenotypes / cerebrospinal fluid*
Female
Humans
Male
Mental Status Schedule
Middle Aged
Multifactorial Inheritance / genetics*
Neuropsychological Tests
Odds Ratio
Polymorphism, Single Nucleotide / genetics
Statistics, Nonparametric

Substances

Amyloid beta-Peptides
Apolipoproteins E