Alzheimer disease (AD) is the most common form of dementia in the elderly and the number of individuals developing the disease is rapidly rising. Interventions focused on reducing beta-amyloid (Aβ), a component of senile plaques within the AD brain offer a promising approach to prevent or slow disease progression. In this review, we describe the immune system and cognitive and neurobiological features of a natural model of human brain aging, the beagle. The immune system of dogs shares many features of the human immune system, including developmental and aging characteristics. Further, dogs naturally accumulate human sequence Aβ as they age, which coincides with declines in learning and memory. A longitudinal study (∼2 years) of the response of aged beagles to vaccination with fibrillar Aβ1-42 indicated that despite significant clearance of Aβ, there were limited benefits in cognitive function. However, there was evidence for maintenance of executive function over time. These results are strikingly similar to reports of human clinical immunotherapy trials. We propose that the canine model complements existing animal models and will be helpful in developing new vaccine approaches to slowing or preventing Aβ pathology that can be translated to human clinical trials.