We propose that, in the context of depression, neurobiological events, such as neurodegeneration, cerebrovascular disease, and neuroinflammation result in a brain that is more vulnerable to the consequences of the pathophysiological features of AD, lowering the threshold for the onset of the behavioral presentation of AD (i.e., cognitive decline and dementia). We discuss factors that can increase resilience to AD and LLD, including social support, physical and cognitive engagement, and cognitive reserve. We conclude with a discussion of future research directions.