We assessed the contribution of ApoE4 to the outcome of focal brain ischemia in aged mice maintained on a HF diet and show for the first time that ApoE4 together with long-term intake of a HF diet containing 5.3 times more fat and having 1.5 times higher energy density compared with normal chow leads to significant sensorimotor deficits as analyzed by an adhesive removal test. Here, APOE is linked to brain ischemia.