These results, along with the wealth of other clinical evidence [34,41], support and extend previous findings that combination treatment is associated with clinically significant benefits in reducing 24-week decline in cognition, function, global status, and the occurrence of marked clinical worsening. In the absence references of disease-modifying therapies, retaining greater cognitive and functional abilities can produce disease-course-modifying effects that may help patients with AD remain independent for longer. Importantly, combination therapy with memantine added to donepezil demonstrates good safety and tolerability, and the observed benefits are over and above those of donepezil alone.

Taken together, these results support a risk-benefit calculus that is in favour of combination therapy with memantine added to donepezil in moderate, as well as moderate to severe AD, and imply translation of clinically meaningful benefits to patients, caregivers, and society. Abbreviations AD: Alzheimer’s disease; ADAS-Cog: Alzheimer’s Disease Assessment Scale-cognitive subscale; ADCS-ADL: Alzheimer’s Disease Cooperative Study-Activities of Daily Living; ADL: activity of daily living; AE: adverse event; APT: all-patients-treated; ChEI: cholinesterase inhibitor; CIBIC-Plus: Clinician’s Interview-Based Impression of Change Plus Caregiver Input; IRB: Institutional Review Board; ITT: intention-to-treat; LOCF: last observation carried forward; MMSE: Mini-Mental State Examination; MOD: moderate Alzheimer’s disease; MOD-SEV: moderate to severe Alzheimer’s disease; NMDA: N-methyl-D-aspartate; OC: observed cases; RCT: randomised, double-blind, placebo-controlled trial; SIB: Severe Impairment Battery; SMD: standardised mean difference.

Competing interests A Atri has no equity, shares or salary from any pharma company and is not a member of any pharma speakers’ bureau. In the past 5 years, he has received honoraria for educational lectures or webcasts at scientific, medical and educational conferences, meetings, programmes or advisory boards from Forest, Harvard Medical School Continuing Education, Massachusetts General Hospital Academy of Medical Educators, Lundbeck, Merck, Merz, Novartis, and Reed-Elsevier Medical Education. Institutional research grant funding has been received from Forest for research unrelated to this study and manuscript.

J Molinuevo has no equity, shares or salary Brefeldin_A from any thorough pharma company. He has received honoraria for speaking and for attending advisory boards from Lundbeck, Merck, Merz, and Novartis. O Lemming is a full-time employee of H. Lundbeck A/S. Y Wirth is a former full-time employee of Merz Pharmaceuticals GmbH. I Pulte is a full-time employee of Merz Pharmaceuticals GmbH. D Wilkinson has no equity, shares or salary from any pharma company.