The cognitive reserve hypothesis postulates that lifelong cognitive stimulation establishes a buffer that is instrumental for maintaining cognitive health. To examine this conceptual proposition in detail, we applied a novel, more general conceptual view including recent models of vulnerability and examined whether the longitudinal association between hepatobiliary diseases and later decline in executive functioning across six years varied by cognitive reserve. For this purpose, we investigated longitudinal data from 897 older individuals (M = 74.33 years) who were tested on the Trail Making Test (TMT) in two waves six years apart. Individuals reported information on key commonly-used indicators of lifelong cognitive reserve build-up (i.e., education, work, and leisure activity participation) and hepatobiliary diseases. Results revealed a significant interaction of hepatobiliary diseases with leisure activity participation on latent change in executive functioning. Specifically, only for individuals with little (but not for those with greater) leisure activity participation, hepatobiliary diseases significantly predicted a steeper decline in executive functioning over six years (i.e., increases in TMT finishing time). In conclusion, the unfavorable aftereffects of hepatobiliary diseases on later decline in executive functioning seem to be mitigated in individuals who have built up greater cognitive reserve via leisure activity participation during their life.