Andrea Vergallo1, Marion Houot2, Enrica Cavedo2, Pablo Lemercier2, Eugeen Vanmechelen3, Ann De Vos3, Marie-Odile Habert4, Marie-Claude Potier5, Bruno Dubois6, Simone Lista6, Harald Hampel7. 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: andrea.vergallo@icm-institute.org. 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.
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.
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.
Authors: Harald Hampel; Robert Vassar; Bart De Strooper; John Hardy; Michael Willem; Neeraj Singh; John Zhou; Riqiang Yan; Eugeen Vanmechelen; Ann De Vos; Robert Nisticò; Massimo Corbo; Bruno Pietro Imbimbo; Johannes Streffer; Iryna Voytyuk; Maarten Timmers; Amir Abbas Tahami Monfared; Michael Irizarry; Bruce Albala; Akihiko Koyama; Naoto Watanabe; Teiji Kimura; Lisa Yarenis; Simone Lista; Lynn Kramer; Andrea Vergallo Journal: Biol Psychiatry Date: 2020-02-13 Impact factor: 13.382