Previous epidemiologic studies suggest that antihypertensive drugs may be protective against cognitive decline. To determine if subjects enrolled in the University of Kentucky longitudinal aging study who used antihypertensive drugs showed diminished progression to dementia, we used a 3-parameter logistic regression model to compare the rate of progression to dementia for subjects who used any of the five common categories of antihypertensive drugs to those with similar demographic characteristics but who did not use antihypertensives. Regression modeling showed that subjects who used calcium channel blockers (CCBs) but not the other classes of antihypertensives showed a significant decrease in the rate of progression to dementia. Significantly, use of CCBs ameliorated the negative effects of the presence of APOE-4 alleles on cognitive decline. To determine if CCBs could minimize amyloid beta peptide (Aβ(1-42)) production, H4 neuroglioma cultures transfected to overexpress APP were treated with various CCBs and Aβ(1-42) levels and levels of proteins involved in Aβ production were quantified. Results show that treatment with nifedipine led to a significant decrease in levels of Aβ(1-42), with no significant decrease in cell viability. Collectively, these data suggest that use of CCBs significantly diminishes the rate of progression to dementia and may minimize formation of Aβ(1-42).