A Multi-Cohort Study of ApoE ɛ4 and Amyloid-β Effects on the Hippocampus in Alzheimer’s Disease.

Wasim Khan, Vincent Giampietro, Tobias Banaschewski, Gareth J. Barker, Arun L.W. Bokde, Christian Büchel, Patricia Conrod, Herta Flor, Vincent Frouin, Hugh Garavan, Penny Gowland, Anreas Heinz, Bernd Ittermann, Hervé Lemaître, Frauke Nees, Tomas Paus, Zdenka Pausova, Marcella Rietschel, Michael N. Smolka, Andreas Ströhle, Jeurgen Gallinat, Bruno Vellas, Hilkka Soininen, Iwona Kloszewska, Magda Tsolaki, Patrizia Mecocci, Christian Spenger, Victor L. Villemagne, Colin L. Masters, J-Sebastian Muehlboeck, Lars Bäckman, Laura Fratiglioni, Grégoria Kalpouzos, Lars-Olof Wahlund, Gunther Schumann, Simon Lovestone, Steven C.R. Williams, Eric Westman, Andrew Simmons,
JAD. 2017-02-03; 56(3): 1159-1174
DOI: 10.3233/JAD-161097

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Khan W(1)(2)(3), Giampietro V(1), Banaschewski T(4)(5), Barker GJ(1), Bokde
AL(6), Büchel C(7), Conrod P(1)(8), Flor H(4)(5), Frouin V(9), Garavan H(10)(11),
Gowland P(12), Heinz A(13), Ittermann B(14), Lemaître H(15), Nees F(4)(5), Paus
T(16)(17)(18), Pausova Z(19), Rietschel M(4)(5), Smolka MN(20), Ströhle A(13),
Gallinat J(13), Vellas B(21), Soininen H(22), Kloszewska I(23), Tsolaki M(24),
Mecocci P(25), Spenger C(26), Villemagne VL(27)(28), Masters CL(27)(28),
Muehlboeck JS(1)(2), Bäckman L(29), Fratiglioni L(29), Kalpouzos G(29), Wahlund
LO(30), Schumann G(1)(2), Lovestone S(1)(2)(3), Williams SC(1)(2)(3), Westman
E(1)(30), Simmons A(1)(2)(3)(30); Alzheimer–s Disease Neuroimaging Initiative;
AddNeuroMed Consortium, Australian, Imaging, Biomarkers, and Lifestyle Study
Research Group; IMAGEN consortium.

Author information:
(1)King’s College London, Institute of Psychiatry, London, UK.
(2)NIHR Biomedical Research Centre for Mental Health, King’s College London,
London, UK.
(3)NIHR Biomedical Research Unit for Dementia, King’s College London, London, UK.
(4)Central Institute of Mental Health, Mannheim, Germany.
(5)Medical Faculty Mannheim, University of Heidelberg, Germany.
(6)Institute of Neuroscience and Discipline of Psychiatry, School of Medicine,
Trinity College Dublin, Dublin, Ireland.
(7)Universitaetsklinikum Hamburg Eppendorf, Hamburg, Germany.
(8)Department of Psychiatry, Universite de Montreal, CHU Ste Justine Hospital,
(9)Neurospin, Commissariat à l’Energie Atomique et aux Energies Alternatives,
Paris, France.
(10)Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
(11)Departments of Psychiatry and Psychology, University of Vermont, USA.
(12)School of Physics and Astronomy, University of Nottingham, UK.
(13)Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité –
Universitätsmedizin Berlin, Berlin, Germany.
(14)Physikalisch-Technische Bundesanstalt (PTB), Braunschweig und Berlin, Berlin,
(15)Institute National de la Santé et de la Recherche Médicale, INSERM CEA Unit
1000 “Imaging & Psychiatry”, University Paris Sud, Orsay, and AP-HP Department of
Adolescent Psychopathology and Medicine, Maison de Solenn, University Paris
Descartes, Paris, France.
(16)otman Research Institute, University of Toronto, Toronto, Canada.
(17)School of Psychology, University of Nottingham, UK.
(18)Montreal Neurological Institute, McGill University, Canada.
(19)The Hospital for Sick Children, University of Toronto, Toronto, Canada.
(20)Neuroimaging Center, Department of Psychiatry and Psychotherapy, Technische
Universität Dresden, Germany.
(21)INSERM U 558, University of Toulouse, Toulouse, France.
(22)Department of Neurology, University of Eastern Finland and Kuopio University
Hospital, Kuopio, Finland.
(23)Medical University of Lodz, Lodz, Poland.
(24)Aristotle University of Thessaloniki, Thessaloniki, Greece.
(25)Institute of Gerontology and Geriatrics, University of Perugia, Perugia,
(26)Department of Clinical Science, Intervention and Technology, Karolinska
Institutet, Stockholm, Sweden.
(27)The Florey Institute of Neuroscience and Mental Health, Parkville, Vic.,
(28)University of Melbourne, Parkville, Vic., Australia.
(29)Aging Research Center, Karolinska Institutet and Stockholm University,
Stockholm, Sweden.
(30)Department of Neurobiology, Care Sciences and Society, Karolinska Institute,
Stockholm, Sweden.

The apolipoprotein E (APOE) gene has been consistently shown to modulate the risk
of Alzheimer’s disease (AD). Here, using an AD and normal aging dataset primarily
consisting of three AD multi-center studies (n = 1,781), we compared the effect
of APOE and amyloid-β (Aβ) on baseline hippocampal volumes in AD patients, mild
cognitive impairment (MCI) subjects, and healthy controls. A large sample of
healthy adolescents (n = 1,387) was also used to compared hippocampal volumes
between APOE groups. Subjects had undergone a magnetic resonance imaging (MRI)
scan and APOE genotyping. Hippocampal volumes were processed using FreeSurfer. In
the AD and normal aging dataset, hippocampal comparisons were performed in each
APOE group and in ɛ4 carriers with positron emission tomography Aβ who were
dichotomized (Aβ+/Aβ-) using previous cut-offs. We found a linear reduction in
hippocampal volumes with ɛ4 carriers possessing the smallest volumes, ɛ3 carriers
possessing intermediate volumes, and ɛ2 carriers possessing the largest volumes.
Moreover, AD and MCI ɛ4 carriers possessed the smallest hippocampal volumes and
control ɛ2 carriers possessed the largest hippocampal volumes. Subjects with both
APOE ɛ4 and Aβ+ had the lowest hippocampal volumes when compared to Aβ- ɛ4
carriers, suggesting a synergistic relationship between APOE ɛ4 and Aβ. However,
we found no hippocampal volume differences between APOE groups in healthy
14-year-old adolescents. Our findings suggest that the strongest neuroanatomic
effect of APOE ɛ4 on the hippocampus is observed in AD and groups most at risk of
developing the disease, whereas hippocampi of old and young healthy individuals
remain unaffected.


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