O1–01–01: Caffeine: Evidence for protection against, and treatment for, Alzheimer's disease by direct suppression of disease pathogenesis

Background: A recent retrospective study found that Alzheimer's patients consumed markedly less caffeine during the 20 years preceding diagnosis compared with age-matched controls. In addition, a 10-year prospective study found coffee consumption linked to slower cognitive decline in aging men. Although both studies suggest that chronic caffeine intake may protect against Alzheimer's Disease (AD), highly controlled longitudinal studies in humans over decades are impractical. Objectives: The present study utilized AD transgenic mice in well-controlled studies to determine if caffeine administration can protect against or treat Alzheimer's cognitive impairment and limit/decrease AD neuropathology. Methods: Chronic administration: Caffeine was added to the drinking water of either "young adult" or "aged" mutant APP transgenic (Tg) mice for protection-based (5 months) and treatment-based (1-2 months) studies, respectively. The average daily intake of caffeine per mouse was the human equivalent of 500 mg caffeine (the amount typically present in 5 cups of coffee). Acute administration: Caffeine was given by gavage (1.5 mg) to aged mAPP Tg mice for one or 7 days, to determine affects on plasma A levels. Results: Tg mice given chronic caffeine from young adulthood into older age showed protection against impairment in multiple cognitive tasks and had lower hippocampal A levels compared to untreated Tg mice. Moreover, "aged" cognitively-impaired Tg mice exhibited substantial memory improvement and lower hippocampal A levels following 1-2 months of treatment. Hippocampal presenilin 1 (PS1) and BACE 1 were both reduced in caffeine-treated Tg mice, indicating that caffeine had decreased A production. Caffeine's suppression of A production was confirmed in SweAPP N2a neuronal cultures, wherein concentration-dependent decreases in both A1-40 and A1-42 were observed. In acute studies, 1 or 7 days of oral caffeine treatment via gavage significantly reduced plasma A1-40 and A1-42 levels. Conclusions: These results indicate a surprising ability of moderate caffeine intake to protect against or treat AD-like cognitive impairment, and importantly through mechanisms that directly suppress the disease's pathogenesis. On the basis of these promising results, clinical trials involving caffeine administration have been initiated.