Alzheimer's disease (AD) is an aging-associated disorder that disproportionately impacts Hispanics/Latinos, who exhibit AD rates 1.5 times higher and average onset 7 years earlier than do older whites. Yet, few longitudinal studies have focused on AD in Hispanics, and the underlying causes of the differences between Hispanics and non-Hispanics are not well understood. Two of the most robust risk factors for AD, Apolipoprotein E-4 and high blood pressure (BP) have not systematically been studied in Hispanic populations residing in their country of origin. We took advantage of the rich existing longitudinal cardiovascular and cognition data on the Hispanic cohort of the Maracaibo Aging Study (MAS) to analyze the significance prognosis of BP levels, measured by ambulatory blood pressure monitoring (ABPM), and ApoE-e4 for the development of AD. A dementia-free cohort of 1665 community-dwelling persons aged 55 years and older in Maracaibo, Venezuela was followed to detect patients with AD using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnostic criteria. ABPM included 24-h recording of systolic BP, diastolic BP, pulse pressure (PP), and mean arterial pressure (MAP). Data were analyzed using Cox proportional hazards models with adjustment for several potential confounders. The mean age of participants at baseline assessment was 65.8 years, and 69.4% of them were women. Within an averaged follow-up time of 5.1±2.9y, 43 individuals developed AD. Risk of AD was higher among APOE-ε4 carriers than in those homozygous for ε3 (ε3/ε4 HR=2.9, CI95%=1.3-6.7, p=0.006; ε4/ε4 HR=15.6, CI95%=4.9-49.5, p<0.001). Incidence of AD was 4.6, 7.8 and 35.4 per 1000/person year, respectively for ε3/ε4, ε3/ε4 and ε4/ε4 carriers. Increasing levels of 24-h and nocturnal (but not diurnal) systolic BP, MAP, and PP increased the hazard ratio for AD (p<0.05) but only among individuals exhibiting APOE-ε4 allele, independent of antihypertensive drug use. Increasing BP levels in Hispanics, particularly at night, and that are carriers of the APOE-ε4 allele are at higher risk of AD. The pathobiological mechanisms of this interaction warrants further studies.