Brain Aβ load association and sexual dimorphism of plasma BACE1 concentrations in cognitively normal individuals at risk for AD

Andrea Vergallo; Marion Houot; Enrica Cavedo; Pablo Lemercier; Eugeen Vanmechelen; Ann De Vos; Marie-Odile Habert; Marie-Claude Potier; Bruno Dubois; Simone Lista; Harald Hampel; INSIGHT-preAD study group; Alzheimer Precision Medicine Initiative (APMI)

doi:10.1016/j.jalz.2019.07.001

Brain Aβ load association and sexual dimorphism of plasma BACE1 concentrations in cognitively normal individuals at risk for AD

Alzheimers Dement. 2019 Oct;15(10):1274-1285. doi: 10.1016/j.jalz.2019.07.001.

Collaborators

H Bakardjian, H Benali, H Bertin, J Bonheur, L Boukadida, N Boukerrou, E Cavedo, P Chiesa, O Colliot, B Dubois, M Dubois, S Epelbaum, G Gagliardi, R Genthon, M O Habert, H Hampel, M Houot, A Kas, F Lamari, M Levy, S Lista, C Metzinger, F Mochel, F Nyasse, C Poisson, M C Potier, M Revillon, A Santos, K S Andrade, M Sole, M Surtee, M Thiebaud de Schotten, A Vergallo, N Younsi, Mohammad Afshar, Lisi Flores Aguilar, Leyla Akman-Anderson, Joaquín Arenas, Jesus Avila, Claudio Babiloni, Filippo Baldacci, Richard Batrla, Norbert Benda, Keith L Black, Arun L W Bokde, Ubaldo Bonuccelli, Karl Broich, Francesco Cacciola, Filippo Caraci, Juan Castrillo, Enrica Cavedo, Roberto Ceravolo, Patrizia A Chiesa, Jean-Christophe Corvol, Augusto Claudio Cuello, Jeffrey L Cummings, Herman Depypere, Bruno Dubois, Andrea Duggento, Enzo Emanuele, Valentina Escott-Price, Howard Federoff, Maria Teresa Ferretti, Massimo Fiandaca, Richard A Frank, Francesco Garaci, Hugo Geerts, Filippo S Giorgi, Edward J Goetzl, Manuela Graziani, Marion Haberkamp, Habert Marie-Odile, Harald Hampel, Karl Herholz, Felix Hernandez, Dimitrios Kapogiannis, Eric Karran, Steven J Kiddle, Seung H Kim, Yosef Koronyo, Maya Koronyo-Hamaoui, Todd Langevin, Stéphane Lehéricy, Alejandro Lucía, Simone Lista, Jean Lorenceau, Dalila Mango, Mark Mapstone, Christian Neri, Robert Nisticò, Sid E O'Bryant, Giovanni Palermo, George Perry, Craig Ritchie, Simone Rossi, Amira Saidi, Emiliano Santarnecchi, Lon S Schneider, Olaf Sporns, Nicola Toschi, Steven R Verdooner, Andrea Vergallo, Nicolas Villain, Lindsay A Welikovitch, Janet Woodcock, Erfan Younesi

Affiliations

¹ Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France; Brain and Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l'hôpital, Paris, France; Department of Neurology, Institute of Memory and Alzheimer's Disease (IM2A), Pitié-Salpêtrière Hospital, AP-HP, Boulevard de l'hôpital, Paris, France. Electronic address: [email protected].
² Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France; Brain and Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l'hôpital, Paris, France; Department of Neurology, Institute of Memory and Alzheimer's Disease (IM2A), Pitié-Salpêtrière Hospital, AP-HP, Boulevard de l'hôpital, Paris, France; Centre of Excellence of Neurodegenerative Disease (CoEN), ICM, CIC Neurosciences, APHP Department of Neurology, Hopital Pitié-Salpêtrière, University Paris 6, Paris, France.
³ ADx NeuroSciences NV, Ghent, Belgium.
⁴ Sorbonne Université, CNRS, INSERM, Laboratoire d'Imagerie Biomédicale, Paris, France; Centre pour l'Acquisition et le Traitement des Images (www.cati-neuroimaging.com), Paris, France; Département de Médecine Nucléaire, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France.
⁵ ICM Institut du Cerveau et de la Moelle épinière, CNRS UMR7225, INSERM U1127, UPMC, Hôpital de la Pitié-Salpêtrière, Paris, France.
⁶ Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France; Brain and Spine Institute (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l'hôpital, Paris, France; Department of Neurology, Institute of Memory and Alzheimer's Disease (IM2A), Pitié-Salpêtrière Hospital, AP-HP, Boulevard de l'hôpital, Paris, France.
⁷ Sorbonne University, GRC n° 21, Alzheimer Precision Medicine (APM), AP-HP, Pitié-Salpêtrière Hospital, Boulevard de l'hôpital, Paris, France; Eisai Inc., Neurology Business Group, Woodcliff Lake, NJ, USA.

PMID: 31627825
DOI: 10.1016/j.jalz.2019.07.001

Abstract

Introduction: Successful development of effective β-site amyloid precursor protein cleaving enzyme 1 (BACE1)-targeted therapies for early stages of Alzheimer's disease requires biomarker-guided intervention strategies.

Methods: We investigated whether key biological factors such as sex, apolipoprotein E (APOE ε4) allele, and age affect longitudinal plasma BACE1 concentrations in a large monocenter cohort of individuals at risk for Alzheimer's disease. We explored the relationship between plasma BACE1 concentrations and levels of brain amyloid-β (Aβ) deposition, using positron emission tomography global standard uptake value ratios.

Results: Baseline and longitudinal mean concentrations of plasma BACE1 were significantly higher in women than men. We also found a positive significant impact of plasma BACE1 on baseline Aβ-positron emission tomography global standard uptake value ratios.

Discussion: Our results suggest a sexual dimorphism in BACE1-related upstream mechanisms of brain Aβ production and deposition. We argue that plasma BACE1 should be considered in further biomarker validation and qualification studies as well as in BACE1 clinical trials.

Keywords: Alzheimer's disease; BACE1 biomarkers; Disease modifying; Plasma BACE1; Sexual dimorphism.

Publication types

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

MeSH terms

Aged
Alzheimer Disease / enzymology*
Alzheimer Disease / genetics
Amyloid Precursor Protein Secretases / blood
Amyloid Precursor Protein Secretases / genetics
Amyloid Precursor Protein Secretases / metabolism*
Amyloid beta-Peptides / biosynthesis*
Apolipoproteins E / genetics
Aspartic Acid Endopeptidases / blood*
Aspartic Acid Endopeptidases / genetics
Biomarkers / metabolism
Brain / metabolism
Cognition / physiology
Female
Healthy Volunteers
Humans
Male
Positron-Emission Tomography
Sex Factors

Substances

Amyloid beta-Peptides
Apolipoproteins E
Biomarkers
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human