Introduction This study examined whether interarm differences in systolic blood pressure (IDSBP) ≥10 mm Hg were associated with the risk of incident dementia and subclinical brain injury. Methods Between 1992 and 1998, 2063 participants of the Framingham Heart Study underwent assessment of IDSBP with results related to the 10-year risk of incident dementia including clinically characterized Alzheimer's disease. Secondary outcomes included markers of subclinical brain injury on magnetic resonance imaging. Results High IDSBP were associated with a greater risk of incident dementia (hazard ratio [HR] 1.92; 95% confidence interval [CI], 1.09-3.40) and Alzheimer's disease (HR, 2.32; 95% CI, 1.29-4.18), but only in those who carried an apolipoprotein E (APOE) ϵ4 allele. IDSBP also predicted lower total brain volumes and more prevalent silent brain infarcts in those who were APOE ϵ4 positive. Discussion High IDSBP were associated with an increased risk of dementia, including clinical Alzheimer's disease, and subclinical brain injury in those who were APOE ϵ4 positive.