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Abstract Background Recent data suggest that musical practice prevents age-related cognitive decline. But experimental evidence remains sparse and no concise information on the neurophysiological bases exists, although cognitive decline represents a major impediment to healthy aging. A challenge in the field of aging is developing training regimens that stimulate neuroplasticity and delay or reverse symptoms of cognitive and cerebral decline. To be successful, these regimens should be easily integrated in daily life and intrinsically motivating. This study combines for the first-time protocolled music practice in elderly with cutting-edge neuroimaging and behavioral approaches, comparing two types of musical education. Methods We conduct a two-site Hannover-Geneva randomized intervention study in altogether 155 retired healthy elderly (64–78) years, (63 in Geneva, 92 in Hannover), offering either piano instruction (experimental group) or musical listening awareness (control group). Over 12 months all participants receive weekly training for 1 hour, and exercise at home for ~ 30 min daily. Both groups study different music styles. Participants are tested at 4 time points (0, 6, and 12 months & post-training (18 months)) on cognitive and perceptual-motor aptitudes as well as via wide-ranging functional and structural neuroimaging and blood sampling. Discussion We aim to demonstrate positive transfer effects for faculties traditionally described to decline with age, particularly in the piano group: executive functions, working memory, processing speed, abstract thinking and fine motor skills. Benefits in both groups may show for verbal memory, hearing in noise and subjective well-being. In association with these behavioral benefits we anticipate functional and structural brain plasticity in temporal (medial and lateral), prefrontal and parietal areas and the basal ganglia. We intend exhibiting for the first time that musical activities can provoke important societal impacts by diminishing cognitive and perceptual-motor decline supported by functional and structural brain plasticity. Trial registration The Ethikkomission of the Leibniz Universität Hannover approved the protocol on 14.08.17 (no. 3604–2017), the neuroimaging part and blood sampling was approved by the Hannover Medical School on 07.03.18. The full protocol was approved by the Commission cantonale d’éthique de la recherche de Genève (no. 2016–02224) on 27.02.18 and registered at clinicaltrials.gov on 17.09.18 ( NCT03674931 , no. 81185).