 Individuals with late-life depression LLD experience high levels of disability, mortality, and poor responses to antidepressants. The MRI hallmark of vascular depression in this population is significant ischemic white matter lesion WML severity, a finding associated with poor antidepressant outcomes. Despite observations of diffuse white matter disease in LLD, we propose in our disconnection hypothesis that focal damage to fiber tracts negatively affects the function of connected regions, resultantly contributing to cognitive deficits and clinical symptoms such as depression severity and negativity bias. Focal WMLs may also reduce the likelihood of an antidepressant response when the specific antidepressant used acts on neurotransmitter systems projecting through the damaged fiber tract. This implies that the effect of tract damage on clinical response may differ between drugs with different mechanism of action. 