PT593. CSF Beta-Amyloid and APOE E4 Related Decline in Episodic Memory over 12 months measured using the CANTAB in individuals with amnestic MCI: Results from the European-ADNI study

Background: We performed an updated meta-analysis of randomized placebo-controlled trials testing memantine monotherapy for patients with Alzheimer’s disease (AD). Methods: The meta-analysis included randomized controlled trials of memantine monotherapy for AD, omitting those in which patients were also administered a cholinesterase inhibitor. Cognitive function, activities of daily living, behavioral disturbances, global function, stage of dementia, drug discontinuation rate, and individual side effects were compared between memantine monotherapy and placebo groups. The primary outcomes were cognitive function and behavioral disturbances; the others were secondary outcomes. Results: Nine studies including 2433 patients that met the study’s inclusion criteria were identified. Memantine monotherapy significantly improved cognitive function [standardized mean difference (SMD)=−0.27, 95% confidence interval (CI)=−0.39 to −0.14, p=0.0001], behavioral disturbances (SMD=−0.12, 95% CI=−0.22 to −0.01, p=0.03), activities of daily living (SMD=−0.09, 95% CI=−0.19 to −0.00, p=0.05), global function assessment (SMD=−0.18, 95% CI=−0.27 to −0.09, p=0.0001), and stage of dementia (SMD=−0.23, 95% CI=−0.33 to −0.12, p=0.0001) scores. Memantine was superior to placebo in terms of discontinuation because of inefficacy [risk ratio (RR)=0.36, 95% CI=0.17 to 0.74, p=0.006, number needed to harm (NNH)=non significant]. Moreover, memantine was associated with less agitation compared with placebo (RR=0.68, 95% CI=0.49 to 0.94, p=0.02, NNH=non significant). There were no significant differences in the rate of discontinuation because of all causes, all adverse events, and individual side effects other than agitation between the memantine monotherapy and placebo groups. Conclusions: Memantine monotherapy improved cognition, behavior, activities of daily living, global function, and stage of dementia and was well-tolerated by AD patients. However, the effect size in terms of efficacy outcomes was small and thus there is limited evidence of clinical benefit. PT593 CSF Beta-Amyloid and APOE E4 Related Decline in Episodic Memory over 12 months measured using the CANTAB in individuals with amnestic MCI: Results from the European-ADNI study *Pradeep J. Nathan1,2, *Rosemary Abbott3, Yen Ying Lim4, Samantha Galluzzi5, Moira Marizzoni5, Cristina Bagnoli5, Claudio Babiloni6,7, David Bartres-Faz8, Regis Bordet9, Mira Didic10, Lucia Farotti11, Gianluigi Forloni12, Jorge Jovicich13, Camillo Marra14, José Luis Molinuevo15, Flavio Nobili16, Jeremie Pariente17, Lucilla Parnetti11, Pierre Payoux17, Jean-Philippe Ranjeva18, Paolo Maria Rossini14, Peter Schonknecht19, Tilman Hensch19, Andrea Soricelli20, Magda Tsolaki21, Pieter Jelle Visser22, Jens Wiltfang23, Olivier Blin24, and Giovanni B.Frisoni5,25 on behalf of the PharmaCog Consortium 1Neuroscience Center of Excellence, Inventiv Health 2Department of Psychiatry, University of Cambridge, UK 3Cambridge Cognition, Cambridge, UK 4The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Australia 5Lab Alzheimer’s Neuroimaging & Epidemiology, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy 6Department of Physiology and Pharmacology, University of Rome “La Sapienza”, Rome, Italy 7IRCCS San Raffaele Pisana of Rome, Italy 8Department of Psychiatry and Clinical Psychobiology, Faculty of Medicine, University of Barcelona and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalunya, Spain 9University of Lille, Lille, France 10Service de Neurologie et Neuropsychologie, Marseille, France 11Clinica Neurologica, Università di Perugia, Ospedale Santa Maria della Misericordia, Perugia, Italy 12Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Milano, Italy 13Center for Mind/Brain Sciences, University of Trento, Italy 14Department of Gerontology, Neurosciences & Orthopedics, Catholic University, Rome, Italy 15Alzheimer’s Disease Unit and Other Cognitive Disorders Unit, Hospital Clinic de Barcelona, and Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalunya, Spain 16Clinical Neurology, Department of Neuroscience (DINOGMI), University of Genoa, Genoa, Italy 17Department of Neurology, CMRR and INSERM U825, Toulouse, France 18CIC-UPCET, CHU La Timone, AP-HM, UMR CNRS-Universite de la Mediterranee, Marseille, France 19Department of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany 20SDN Istituto di Ricerca Diagnostica e Nucleare, Napoli, Italy 21. 3rd Neurologic Clinic, Medical School, G. Papanikolou Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece 22Department of Neurology, Alzheimer Centre, VU Medical Centre, Amsterdam, The Netherlands 23University of Duisburg-Essen, Essen, Germany 24Mediterranean Institute of Cognitive Neuroscience (INCM), UMRCNRS (6193), Marseille, France 25Memory Clinic and Laboratory of Neuroimaging of Aging, University Hospitals and University of Geneva, Geneva, Switzerland Abstract Background: Accumulation of beta amyloid (Aβ) in the brain and carriage of the apolipoprotein E (APOE) ɛ4 allele have both been reported to independently and interactively linked with greater neurodegeneration, cognitive decline and incipient Alzheimer’s disease (AD). However, as most studies have observed these effects over 18-months or more, the effect of Aβ and ɛ4 on cognitive decline over 12-months remains unknown. Detecting rapid cognitive decline is critical for monitoring efficacy over shorter periods. In this study we examined the effects of Aβ and ɛ4 on rates of cognitive change assessed using the CANTAB over 12-months in aMCI patients. Methods: 145 participants with aMCI were recruited from the European-ADNI study. They were aged between 55–90, had a ≥1SD deficit in episodic memory and fulfilled a clinical diagnosis of aMCI. Participants underwent cognitive assessment using the CANTAB at baseline, 6 and 12 months and lumbar punctures for CSF measurement of Abeta42. Individuals were divided into Aβ+ (CSF-POS) (<550pg/ml)(n=55) and Aβ(CSF-NEG)(>550pg/ml) (n=90).Background: Accumulation of beta amyloid (Aβ) in the brain and carriage of the apolipoprotein E (APOE) ɛ4 allele have both been reported to independently and interactively linked with greater neurodegeneration, cognitive decline and incipient Alzheimer’s disease (AD). However, as most studies have observed these effects over 18-months or more, the effect of Aβ and ɛ4 on cognitive decline over 12-months remains unknown. Detecting rapid cognitive decline is critical for monitoring efficacy over shorter periods. In this study we examined the effects of Aβ and ɛ4 on rates of cognitive change assessed using the CANTAB over 12-months in aMCI patients. Methods: 145 participants with aMCI were recruited from the European-ADNI study. They were aged between 55–90, had a ≥1SD deficit in episodic memory and fulfilled a clinical diagnosis of aMCI. Participants underwent cognitive assessment using the CANTAB at baseline, 6 and 12 months and lumbar punctures for CSF measurement of Abeta42. Individuals were divided into Aβ+ (CSF-POS) (<550pg/ml)(n=55) and Aβ(CSF-NEG)(>550pg/ml) (n=90).