Presence of vascular risk factors and the emergence of cognitive decline are both common in older people. A deterioration of cognitive functions may be the first sign of dementia. It is therefore important to identify vascular risk factors for cognitive decline and to treat vascular symptoms in order to minimize effects on cognition. The aim of this study was to investigate the effects of hypertension, diabetes and ApoE genotype on cognitive decline over a 12-year episode, in a normal aging population. Method: 1,823 healthy participants in the Maastricht Aging Study completed baseline assessment between 1993 and 1995. Twelve-year follow-up results at three different time points with six-year intervals were available for seventy-five percent of the baseline group (n = 903). Neuropsychological assessment was performed in three cognitive domains: verbal memory (delayed recall), psychomotor speed (letter-digit copying) and executive functioning (set shifting). Participants with evidence of exposure to high blood pressure for at least six years showed a larger cognitive decline in all three cognitive domains, compared to participants without hypertension or who had high blood pressure on only one occasion. Diabetes was negatively associated with cognitive performance at baseline; however, effects of diabetes on cognitive decline were not mediated by exposure time. Presence of at least one Apolipoprotein E-e4 (APOE-e4) allele increased the effect of hypertension on the three cognitive measures for individuals with hypertension and at least six exposure years. Effects of APOE-e4 genotype and exposure were only present in individuals with untreated hypertension. Conclusion: Hypertension-related cognitive decline is mediated by exposure duration, anti-hypertensive treatment, and APOE-e4 genotype. Effects of type-2 diabetes on cognitive decline are not mediated by exposure-time. Implications of these findings are discussed.