Redefinition of dementia care in Italy in the era of amyloid-lowering agents for the treatment of Alzheimer’s disease: an expert opinion and practical guideline

Journal of Neurology https://doi.org/10.1007/s00415-023-11642-0 ORIGINAL COMMUNICATION Redefinition of dementia care in Italy in the era of amyloid‑lowering agents for the treatment of Alzheimer’s disease: an expert opinion and practical guideline Massimo Filippi1,2,3 · Giordano Cecchetti1,2,3 Lucilla Parnetti10 · Federica Agosta1,2,3 · Annachiara Cagnin4,5 · Camillo Marra6,7 · Flavio Nobili8,9 · Received: 12 January 2023 / Revised: 20 February 2023 / Accepted: 20 February 2023 © The Author(s) 2023 Abstract No disease-modifying therapies are currently available for Alzheimer’s disease (AD) in Europe. Current evidence from clinical trials testing anti-beta amyloid (Aβ) monoclonal antibodies (mAbs) in patients with early AD, though, suggests a likely marketing authorization in the next years. Since the implementation of disease-modifying therapies for AD in the clinical practice will evidently require a huge change of dementia care in all countries, a group of prominent AD clinical experts in Italy met to discuss patients’ selection and management strategies. The current diagnostic–therapeutic standard of care in Italy was taken as the starting point. The prescription of new therapies cannot ignore the definition of a biological diagnosis through the assessment of both amyloid- and tau-related biomarkers. The high risk/benefit ratio of anti-Aβ immunotherapies, moreover, needs a highly specialized diagnostic work-up and a thorough exclusion criteria assessment, which should be provided by a neurology specialist. The Expert Panel also suggests a reorganization of the Centers for dementia and cognitive decline in Italy into 3 levels of increasing complexity: community center, first- and second-level center. Tasks and requirements for each level were defined. Finally, specific characteristics of a center deputed to prescribe anti-Aβ mAbs were discussed. Keywords Expert opinion · Alzheimer · Italy · Disease-modifying therapies · Monoclonal antibodies Introduction After more than a century since the first description of clinical and neuropathological correlates of Alzheimer’s disease (AD), and after more than a decade of research, encouraging results of clinical trials testing anti-β amyloid (Aβ) monoclonal 6 Memory Clinic, IRCCS Policlinico Gemelli, Rome, Italy 7 Neurology Unit, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132 Milan, Italy Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy 8 Neuroimaging Research Unit, Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, 20132 Milan, Italy Neurology Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy 9 Department of Neuroscience (DINOGMI), University of Genova, Genoa, Italy 10 Centre for Memory Disturbances, Section of Neurology, Lab of Clinical Neurochemistry, Department of Medicine and Surgery, University of Perugia, Perugia, Italy * Massimo Filippi 1 2 antibodies (mAbs) in patients with AD have been achieved. Currently, three anti-Aβ mAbs have ongoing or recently completed phase-3 trials in early AD, and they have been approved or are under examination for accelerated approval in the United States (US). An approval of one or more of them also in Europe in the forthcoming years is expected. [1–3] 3 Vita-Salute San Raffaele University, Via Olgettina, 60, 20132 Milan, Italy 4 Neurology Unit, Department of Neuroscience, University of Padova, Padua, Italy 5 Padova Neuroscience Center (PNC), University of Padova, Padua, Italy 13 Vol.:(0123456789) Journal of Neurology In June 2021, based on the evidence of efficacious removal of cerebral amyloid plaques in EMERGE and ENGAGE studies, and despite the lack of definitively proven clinical benefit, the U.S. Food and Drug Administration (FDA) granted accelerated approval to A duhelm® (aducanumab, a human IgG1 anti-Aβ mAb, ascending intravenous doses to 10 mg/kg every 4 weeks–Biogen Inc.) for the treatment of mild cognitive impairment (MCI) due to AD and mild AD dementia [4]. Data from post-marketing studies will be crucial to determine whether continued approval will be warranted. On April 22, 2022, in light of a very unlikely marketing authorization, the company withdrew the application from the European Medicines Agency (EMA), and a phase-3b/4 confirmatory study (ENVISION trial) has been meanwhile implemented to possibly establish, by the end of 2026, a definite link between the biological effect (i.e., amyloid removal) and clinical improvement [5]. Encouraging results from phase-3 confirmatory Clarity AD clinical trial testing lecanemab (a humanized IgG1 anti-Aβ protofibril mAb, ascending intravenous doses to 10 mg/Kg biweekly–Eisai/Biogen Inc.) and from phase-2 TRAILBLAZER 1 study testing donanemab (a humanized IgG1 anti-Aβ mAb, ascending intravenous doses from 700 to 1400 mg every 4 weeks–Eli Lilly and Company), confirming a significant clinical effect, have been recently presented [6–8]. Indeed, on July 5, 2022, and August 4, 2022, the FDA formally accepted the company’s Biologics Licence Application (BLA) for lecanemab and donanemab, respectively, granting them priority reviews. On January 6, 2023, the agency approved lecanemab (Leqembi™) for the treatment of MCI due to AD and mild AD dementia [9], and on January 10, 2023, the company submitted marketing authorization application to the EMA [10]. A final decision of the FDA on donanemab is instead expected by early February 2023 [3]. On November 14, 2022, after having been granted breakthrough therapy designation by the FDA for the treatment of AD in October 2021, phase-3 clinical trials testing gantenerumab (a fully humanized IgG1 anti-Aβ mAb, ascending subcutaneous doses to 510 mg every 2 weeks–Hoffman-La Roche) were unfortunately discontinued based on the lack of evidence for clinical and biological efficacy in GRADUATE 1 and 2 studies [4, 11]. In light of this evidence, prominent clinical experts in Italy with complementary experience in AD clinical care, research, clinical trials, and diagnosis (including CSF, neuroradiology and nuclear medicine biomarkers) met to discuss major aspects regarding patient selection and to propose possible management strategies, should an anti-Aβ mAb obtain marketing authorization in our country. The introduction of an effective disease-modifying treatment for AD, indeed, will require enormous change in the delivery of dementia care [12]. The indications here included are based on the Italian scenario, but they could also be implemented in other 13 European countries with the necessary adjustments related to country-specific peculiarities. The transition toward a biomarker‑based biological diagnosis of AD Aiming at the early diagnosis of AD to increase the effectiveness of therapeutic interventions, MCI was proposed as an intermediate stage of a continuum that ranges from normal cognitive functioning to AD dementia [13]. MCI is a syndrome characterized by a decline in co (...truncated)