A Multi-Cohort Study of ApoE ɛ4 and Amyloid-β Effects on the Hippocampus in Alzheimer's Disease.
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.
King's College London, Institute of Psychiatry, London, UK.|NIHR Biomedical Research Centre for Mental Health, King's College London, London, UK.|NIHR Biomedical Research Unit for Dementia, King's College London, London, UK.
Wasim
W
Khan
King's College London, Institute of Psychiatry, London, UK.
Vincent
V
Giampietro
Central Institute of Mental Health, Mannheim, Germany.|Medical Faculty Mannheim, University of Heidelberg, Germany.
Tobias
T
Banaschewski
King's College London, Institute of Psychiatry, London, UK.
Gareth J
GJ
Barker
Institute of Neuroscience and Discipline of Psychiatry, School of Medicine, Trinity College Dublin, Dublin, Ireland.
Arun L W
AL
Bokde
Universitaetsklinikum Hamburg Eppendorf, Hamburg, Germany.
Christian
C
Büchel
King's College London, Institute of Psychiatry, London, UK.|Department of Psychiatry, Universite de Montreal, CHU Ste Justine Hospital, Canada.
Patricia
P
Conrod
Central Institute of Mental Health, Mannheim, Germany.|Medical Faculty Mannheim, University of Heidelberg, Germany.
Herta
H
Flor
Neurospin, Commissariat à l'Energie Atomique et aux Energies Alternatives, Paris, France.
Vincent
V
Frouin
Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.|Departments of Psychiatry and Psychology, University of Vermont, USA.
Hugh
H
Garavan
School of Physics and Astronomy, University of Nottingham, UK.
Penny
P
Gowland
Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Anreas
A
Heinz
Physikalisch-Technische Bundesanstalt (PTB), Braunschweig und Berlin, Berlin, Germany.
Bernd
B
Ittermann
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.
Hervé
H
Lemaître
Central Institute of Mental Health, Mannheim, Germany.|Medical Faculty Mannheim, University of Heidelberg, Germany.
Frauke
F
Nees
otman Research Institute, University of Toronto, Toronto, Canada.|School of Psychology, University of Nottingham, UK.|Montreal Neurological Institute, McGill University, Canada.
Tomas
T
Paus
The Hospital for Sick Children, University of Toronto, Toronto, Canada.
Zdenka
Z
Pausova
Central Institute of Mental Health, Mannheim, Germany.|Medical Faculty Mannheim, University of Heidelberg, Germany.
Marcella
M
Rietschel
Neuroimaging Center, Department of Psychiatry and Psychotherapy, Technische Universität Dresden, Germany.
Michael N
MN
Smolka
Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Andreas
A
Ströhle
Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Jeurgen
J
Gallinat
INSERM U 558, University of Toulouse, Toulouse, France.
Bruno
B
Vellas
Department of Neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
Hilkka
H
Soininen
Medical University of Lodz, Lodz, Poland.
Iwona
I
Kloszewska
Aristotle University of Thessaloniki, Thessaloniki, Greece.
Magda
M
Tsolaki
Institute of Gerontology and Geriatrics, University of Perugia, Perugia, Italy.
Patrizia
P
Mecocci
Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
Christian
C
Spenger
The Florey Institute of Neuroscience and Mental Health, Parkville, Vic., Australia.|University of Melbourne, Parkville, Vic., Australia.
Victor L
VL
Villemagne
The Florey Institute of Neuroscience and Mental Health, Parkville, Vic., Australia.|University of Melbourne, Parkville, Vic., Australia.
Colin L
CL
Masters
King's College London, Institute of Psychiatry, London, UK.|NIHR Biomedical Research Centre for Mental Health, King's College London, London, UK.
J-Sebastian
JS
Muehlboeck
Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
Lars
L
Bäckman
Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
Laura
L
Fratiglioni
Aging Research Center, Karolinska Institutet and Stockholm University, Stockholm, Sweden.
Grégoria
G
Kalpouzos
Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden.
Lars-Olof
LO
Wahlund
King's College London, Institute of Psychiatry, London, UK.|NIHR Biomedical Research Centre for Mental Health, King's College London, London, UK.
Gunther
G
Schumann
King's College London, Institute of Psychiatry, London, UK.|NIHR Biomedical Research Centre for Mental Health, King's College London, London, UK.|NIHR Biomedical Research Unit for Dementia, King's College London, London, UK.
Simon
S
Lovestone
King's College London, Institute of Psychiatry, London, UK.|NIHR Biomedical Research Centre for Mental Health, King's College London, London, UK.|NIHR Biomedical Research Unit for Dementia, King's College London, London, UK.
Steven C R
SC
Williams
King's College London, Institute of Psychiatry, London, UK.|Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden.
Eric
E
Westman
King's College London, Institute of Psychiatry, London, UK.|NIHR Biomedical Research Centre for Mental Health, King's College London, London, UK.|NIHR Biomedical Research Unit for Dementia, King's College London, London, UK.|Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden.
Andrew
A
Simmons
D000293:Adolescent; D000368:Aged; D000375:Aging / Q000473:pathology; D000544:Alzheimer Disease / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D001057:Apolipoproteins E / Q000235:genetics*; D060825:Cognitive Dysfunction / Q000000981:diagnostic imaging* / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D006579:Heterozygote; D006624:Hippocampus / Q000000981:diagnostic imaging* / Q000378:metabolism*; D006801:Humans; D021621:Imaging, Three-Dimensional; D008279:Magnetic Resonance Imaging; D008297:Male; D009929:Organ Size; D049268:Positron-Emission Tomography
D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E
APOE ɛ4; Alzheimer’s disease; amyloid; hippocampus; magnetic resonance imaging; mild cognitive impairment