Background: Recent research has demonstrated that DBS sites in Alzheimer’s (AD) and Parkinson’s (PD) influencing cognition are functionally connected to the subiculum. However, the results are mixed, and it is unclear how or if DBS site-subiculum connectivity can be optimized to improve patient cognition. Methods: We studied how subiculum connectivity influenced cognitive outcomes in both PD (subthalamic nucleus) and AD (fornix) DBS patients (total n = 110). We first confirmed DBS site-subiculum connectivity had opposite cognitive effects in each disease. We next investigated patient factors underlying these opposing effects. Lastly, we related our findings back to clinical practice to guide DBS programming in PD and AD. Results: DBS site-subiculum connectivity correlated with cognitive improvement in AD but decline in PD. This was dependent upon hippocampal atrophy; such that higher subiculum connectivity was beneficial when the hippocampus was atrophic but deleterious when it was intact. Finally, we related our findings back to anatomy with cadaveric dissections and present how DBS stimulation can be optimized to improve patient cognition. Conclusions: DBS site-subiculum connectivity influences cognition but depends on patient factors. Thus, to optimize cognition based on patient factors, DBS electrodes can be programmed to stimulate subregions with higher or lower subiculum connectivity.