Although Alzheimer's disease (AD) poses a major health problem in both developing and developed countries, no definite treatment is available for its cure; hence efforts are being focused on introducing disease-modifying agents for slowing down its course. Recent studies on the effects of sildenafil on different organs have shown that PDE-5 inhibitors may offer new horizons in therapeutic treatment of pulmonary hypertension, multiple sclerosis, neuropathic pain, and age-related memory impairment. In this paper we introduce PDE-5 inhibitors as novel disease-modifying agents against AD and review the different impacts of PDE-5 inhibition on various pathogenic mechanisms leading to AD, including neuronal apoptosis, neurovascular dysfunction, neurotransmitter modulation, and impairment of neurogenesis.