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.
| Original language | English |
|---|---|
| Pages (from-to) | 1274-1285 |
| Number of pages | 12 |
| Journal | Alzheimer's and Dementia |
| Volume | 15 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 2019 |
Keywords
- Alzheimer's disease
- BACE1 biomarkers
- Disease modifying
- Plasma BACE1
- Sexual dimorphism
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Brain Aβ load association and sexual dimorphism of plasma BACE1 concentrations in cognitively normal individuals at risk for AD. / the INSIGHT-preAD study group; Alzheimer Precision Medicine Initiative (APMI).
In: Alzheimer's and Dementia, Vol. 15, No. 10, 10.2019, p. 1274-1285.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Brain Aβ load association and sexual dimorphism of plasma BACE1 concentrations in cognitively normal individuals at risk for AD
AU - the INSIGHT-preAD study group
AU - Alzheimer Precision Medicine Initiative (APMI)
AU - Vergallo, Andrea
AU - Houot, Marion
AU - Cavedo, Enrica
AU - Lemercier, Pablo
AU - Vanmechelen, Eugeen
AU - De Vos, Ann
AU - Habert, Marie Odile
AU - Potier, Marie Claude
AU - Dubois, Bruno
AU - Lista, Simone
AU - Hampel, Harald
AU - Bakardjian, H.
AU - Benali, H.
AU - Bertin, H.
AU - Bonheur, J.
AU - Boukadida, L.
AU - Boukerrou, N.
AU - Cavedo, E.
AU - Chiesa, P.
AU - Colliot, O.
AU - Dubois, B.
AU - Dubois, M.
AU - Epelbaum, S.
AU - Gagliardi, G.
AU - Genthon, R.
AU - Habert, M. O.
AU - Hampel, H.
AU - Houot, M.
AU - Kas, A.
AU - Lamari, F.
AU - Levy, M.
AU - Metzinger, C.
AU - Mochel, F.
AU - Nyasse, F.
AU - Poisson, C.
AU - Potier, M. C.
AU - Revillon, M.
AU - Santos, A.
AU - Andrade, K. S.
AU - Sole, M.
AU - Surtee, M.
AU - Thiebaud de Schotten, M.
AU - Vergallo, A.
AU - Younsi, N.
AU - Afshar, Mohammad
AU - Flores Aguilar, Lisi
AU - Akman-Anderson, Leyla
AU - Arenas, Joaquín
AU - Avila, Jesus
AU - Palermo, Giovanni
N1 - Funding Information: This research benefited from the support of the program “ PHOENIX ” led by the Sorbonne University Foundation and sponsored by la Fondation pour la Recherche sur Alzheimer . Funding Information: All florbetapir-PET scans are acquired in a single session on a Philips Gemini GXL CT-PET scanner 50 (±5) minutes after injection of approximately 370 MBq (333-407 MBq) of florbetapir. PET acquisition consists of 3 × 5 minutes frames, a 128 × 128 acquisition matrix and a voxel size of 2 × 2 × 2 mm³. Images are then reconstructed using iterative line-of-response row-action maximum likelihood algorithm (10 iterations), with a smooth postreconstruction filter. All corrections (attenuation, scatter, and random coincidence) are integrated in the reconstruction. Finally, frames are realigned, averaged, and quality-checked by the Centre d'Acquisition et de Traitement d'Images pour la maladie d'Alzheimer (CATI) team. CATI is a French neuroimaging platform funded by the French Plan Alzheimer (available at http://cati-neuroimaging.com ) [23,24] . Funding Information: Prof. Harald Hampel is an employee of Eisai Inc. During part of this work he was supported by the AXA Research Fund, the “ Fondation partenariale Sorbonne Université ” and the “ Fondation pour la Recherche sur Alzheimer ”, Paris, France. The research leading to these results has received funding from the program “ Investissements d'avenir ” ANR-10-IAIHU-06 ( Agence Nationale de la Recherche -10-IA Agence Institut Hospitalo-Universitaire -6). Funding Information: Prof. Harald Hampel is an employee of Eisai, Inc.; serves as the Senior Associate Editor for the Journal Alzheimer's & Dementia; he received lecture fees from Servier, Biogen and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Functional Neuromodulation, Axovant, Eli Lilly and company, Takeda and Zinfandel, GE-Healthcare, and Oryzon Genomics, consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare and Oryzon Genomics, and Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics, and Roche Diagnostics.This research benefited from the support of the program ?PHOENIX? led by the Sorbonne University Foundation and sponsored by la Fondation pour la Recherche sur Alzheimer. This work was in part supported by the Agency for Innovation by Science and Technology (IWT O&O 140105 and VLAIO, www.vlaio.be, grant number HBC.2016.0548). Prof. Harald Hampel is an employee of Eisai Inc. During part of this work he was supported by the AXA Research Fund, the ?Fondation partenariale Sorbonne Universit?? and the ?Fondation pour la Recherche sur Alzheimer?, Paris, France. The research leading to these results has received funding from the program ?Investissements d'avenir? ANR-10-IAIHU-06 (Agence Nationale de la Recherche-10-IA Agence Institut Hospitalo-Universitaire-6). The authors kindly acknowledge Kimberley Mauroo for her technical assistance in the determination of the plasma BACE1 levels. The INSIGHT-preAD study group: Bakardjian H, Benali H, Bertin H, Bonheur J, Boukadida L, Boukerrou N, Cavedo E, Chiesa P, Colliot O, Dubois B, Dubois M, Epelbaum S, Gagliardi G, Genthon R, Habert MO, Hampel H, Houot M, Kas A, Lamari F, Levy M, Lista S, Metzinger C, Mochel F, Nyasse F, Poisson C, Potier MC, Revillon M, Santos A, Andrade KS, Sole M, Surtee M, Thiebaud de Schotten M, Vergallo A, Younsi N. Contributors to the Alzheimer Precision Medicine Initiative?Working Group (APMI?WG): Mohammad Afshar (Paris), Lisi Flores Aguilar (Montr?al), Leyla Akman-Anderson (Sacramento), Joaqu?n Arenas (Madrid), Jesus Avila (Madrid), Claudio Babiloni (Rome), Filippo Baldacci (Pisa), Richard Batrla (Rotkreuz), Norbert Benda (Bonn), Keith L. Black (Los Angeles), Arun L.W. Bokde (Dublin), Ubaldo Bonuccelli (Pisa), Karl Broich (Bonn), Francesco Cacciola (Siena), Filippo Caraci (Catania), Juan Castrillo1 (Derio), Enrica Cavedo (Paris), Roberto Ceravolo (Pisa), Patrizia A. Chiesa (Paris), Jean-Christophe Corvol (Paris), Augusto Claudio Cuello (Montr?al), Jeffrey L. Cummings (Las Vegas), Herman Depypere (Gent), Bruno Dubois (Paris), Andrea Duggento (Rome), Enzo Emanuele (Robbio), Valentina Escott-Price (Cardiff), Howard Federoff (Irvine), Maria Teresa Ferretti (Z?rich), Massimo Fiandaca (Irvine), Richard A. Frank (Malvern), Francesco Garaci (Rome), Hugo Geerts (Berwyn), Filippo S. Giorgi (Pisa), Edward J. Goetzl (San Francisco), Manuela Graziani (Roma), Marion Haberkamp (Bonn), Marie-Odile Habert (Paris), Harald Hampel (Paris), Karl Herholz (Manchester), Felix Hernandez (Madrid), Dimitrios Kapogiannis (Baltimore), Eric Karran (Cambridge), Steven J. Kiddle (Cambridge), Seung H. Kim (Seoul), Yosef Koronyo (Los Angeles), Maya Koronyo-Hamaoui (Los Angeles), Todd Langevin (Minneapolis-Saint Paul), St?phane Leh?ricy (Paris), Pablo Lemercier (Paris), Alejandro Luc?a (Madrid), Simone Lista (Paris), Jean Lorenceau (Paris), Dalila Mango (Rome), Mark Mapstone (Irvine), Christian Neri (Paris), Robert Nistic? (Rome), Sid E. O'Bryant (Fort Worth), Giovanni Palermo (Pisa), George Perry (San Antonio), Craig Ritchie (Edinburgh), Simone Rossi (Siena), Amira Saidi (Rome), Emiliano Santarnecchi (Siena), Lon S. Schneider (Los Angeles), Olaf Sporns (Bloomington), Nicola Toschi (Rome), Steven R. Verdooner (Sacramento), Andrea Vergallo (Paris), Nicolas Villain (Paris), Lindsay A. Welikovitch (Montr?al), Janet Woodcock (Silver Spring), Erfan Younesi (Esch-sur-Alzette). Author's contributions: A.V. wrote the article and provided data interpretation and a critical review of the literature. M.H. performed the statistical analyses, contributed to the writing of the article, and made artwork. E.C. contributed to the writing of the article and provided a critical review of the literature. P.L. performed the statistical analyses, contributed to the writing of the article, and made artwork. E.V.M. provided the plasma biomarkers assessment and data interpretation. A.D.V. provided the plasma biomarkers assessment and data interpretation. M.-O.H. provided the amyloid-PET biomarker assessment. M.-C.P. provided the APOE genotype assessment. B.D. contributed the writing of the article and conceptualization. S.L. contributed to the writing and conceptualization of the article and data interpretation. H.H. wrote the article and provided data interpretation and a critical review of the whole manuscript. Funding Information: This work was in part supported by the Agency for Innovation by Science and Technology (IWT O&O 140105 and VLAIO, www.vlaio.be , grant number HBC.2016.0548 ). Publisher Copyright: © 2019 The Authors
PY - 2019/10
Y1 - 2019/10
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - BACE1 biomarkers
KW - Disease modifying
KW - Plasma BACE1
KW - Sexual dimorphism
UR - http://www.scopus.com/inward/record.url?scp=85072861170&partnerID=8YFLogxK
U2 - 10.1016/j.jalz.2019.07.001
DO - 10.1016/j.jalz.2019.07.001
M3 - Article
C2 - 31627825
AN - SCOPUS:85072861170
VL - 15
SP - 1274
EP - 1285
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
SN - 1552-5260
IS - 10
ER -