Plasma Aβ₄₂ as a Biomarker of Prodromal Alzheimer’s Disease Progression in Patients with Amnestic Mild Cognitive Impairment: Evidence from the PharmaCog/E-ADNI Study

Article type: Research Article

Authors: Albani, Diego^{a; *} | Marizzoni, Moira^b | Ferrari, Clarissa^c | Fusco, Federica^a | Boeri, Lucia^a | Raimondi, Ilaria^a | Jovicich, Jorge^d | Babiloni, Claudio^{e; f} | Soricelli, Andrea^g | Lizio, Roberta^e | Galluzzi, Samantha^b | Cavaliere, Libera^b | Didic, Mira^{h; i} | Schönknecht, Peter^j | Molinuevo, José Luis^k | Nobili, Flavio^l | Parnetti, Lucilla^m | Payoux, Pierreⁿ | Bocchio, Luisella^o | Salvatore, Marco^g | Rossini, Paolo Maria^{p; q} | Tsolaki, Magda^r | Visser, Pieter Jelle^s | Richardson, Jill C.^t | Wiltfang, Jens^{u; v; w} | Bordet, Régis^x | Blin, Olivier^y | Forloni, Gianluigi^a | Frisoni, Giovanni B.^{b; z} | PharmaCog Consortium

Affiliations: [a] Department of Neuroscience, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy | [b] Laboratory of Neuroimaging and Alzheimer’s Epidemiology, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy | [c] Unit of Statistics, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy | [d] MR Lab Head, Center for Mind/Brain Sciences, University of Trento, Italy | [e] Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, Rome, Italy | [f] Department of Neuroscience, IRCCS San Raffaele Pisana of Rome and Cassino, Rome and Cassino, Italy | [g] IRCCS SDN Istituto di Ricerca Diagnostica e Nucleare, Napoli, Italy | [h] Aix-Marseille Université, INSERM, INS UMR_S 1106, Marseille, France | [i] APHM, Timone, Service de Neurologie et Neuropsychologie, APHM Hôpital Timone Adultes, Marseille, France | [j] Department of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany, Germany | [k] Alzheimer’s Disease Unit and Other Cognitive Disorders Unit, Hospital Clínic de Barcelona, and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalunya, Spain | [l] Clinical Neurology, Dept. of Neuroscience (DINOGMI), University of Genoa and IRCCS AOU San Martino-IST, Genoa, Italy | [m] Clinica Neurologica, Università di Perugia, Ospedale Santa Maria della Misericordia, Perugia, Italy | [n] INSERM, Imagerie cérébrale et handicaps neurologiques UMR 825, Toulouse, France | [o] Genetic Unit, IRCCS Centro Giovanni di Dio, Fatebenefratelli, Brescia, Italy; Faculty of Psychology, University eCampus, Novedrate (Como), Italy | [p] Department of Gerontology, Neurosciences and Orthopedics, Catholic University, Rome, Italy | [q] Policlinic A. Gemelli Foundation | [r] 3rd Neurologic Clinic, Medical School, G. Papanikolaou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece | [s] Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, The Netherlands | [t] Neurosciences Therapeutic Area, GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage, United Kingdom | [u] LVR-Hospital Essen, Department of Psychiatry and Psychotherapy, Faculty of Medicine, University of Duisburg-Essen, Essen, Germany | [v] Department of Psychiatry and Psychotherapy, University Medical Center (UMG), Georg-August-University, Goettingen, Germany | [w] iBiMED, Medical Sciences Department, University of Aveiro, Aveiro, Portugal | [x] University of Lille, Inserm, CHU Lille, U1171 - Degenerative and vascular cognitive disorders, Lille, France | [y] Aix Marseille University, UMR-CNRS 7289, Service de Pharmacologie Clinique, AP-HM, Marseille, France | [z] Memory Clinic and LANVIE - Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva, Geneva, Switzerland

Correspondence: [*] Correspondence to: Dr. Diego Albani, Neuroscience Department, IRCCS – Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy. Tel.: +39 02 39014594; Fax: +39 02 3546277; Email: [email protected].

Abstract: It is an open issue whether blood biomarkers serve to diagnose Alzheimer’s disease (AD) or monitor its progression over time from prodromal stages. Here, we addressed this question starting from data of the European FP7 IMI-PharmaCog/E-ADNI longitudinal study in amnesic mild cognitive impairment (aMCI) patients including biological, clinical, neuropsychological (e.g., ADAS-Cog13), neuroimaging, and electroencephalographic measures. PharmaCog/E-ADNI patients were classified as “positive” (i.e., “prodromal AD” n = 76) or “negative” (n = 52) based on a diagnostic cut-off of Aβ42/P-tau in cerebrospinal fluid as well as APOE ε 4 genotype. Blood was sampled at baseline and at two follow-ups (12 and 18 months), when plasma amyloid peptide 42 and 40 (Aβ42, Aβ40) and apolipoprotein J (clusterin, CLU) were assessed. Linear Mixed Models found no significant differences in plasma molecules between the “positive” (i.e., prodromal AD) and “negative” groups at baseline. In contrast, plasma Aβ42 showed a greater reduction over time in the prodromal AD than the “negative” aMCI group (p = 0.048), while CLU and Aβ40 increased, but similarly in the two groups. Furthermore, plasma Aβ42 correlated with the ADAS-Cog13 score both in aMCI patients as a whole and the prodromal AD group alone. Finally, CLU correlated with the ADAS-Cog13 only in the whole aMCI group, and no association with ADAS-Cog13 was found for Aβ40. In conclusion, plasma Aβ42 showed disease progression-related features in aMCI patients with prodromal AD.

Keywords: Amnesic mild cognitive impairment, amyloid-beta peptide, biomarkers, clinical trial, clusterin, PharmaCog project, prodromal Alzheimer’s disease

DOI: 10.3233/JAD-180321

Journal: Journal of Alzheimer's Disease, vol. 69, no. 1, pp. 37-48, 2019