Graduation Year


Document Type




Degree Granting Department


Major Professor

Gary Arendash, Ph.D.

Committee Member

Huntington Potter, Ph.D.

Committee Member

Sidney Pierce, Ph.D.


Amyloid, S-adenosylmethionine, PS1, Adenosine, Transgenic mice


A recent epidemiological study suggested that higher caffeine intake reduces the risk of Alzheimer's disease (AD). Caffeine, a widely consumed stimulatory drug, is a non-selective adenosine receptor antagonist that has been shown to increase plasma adenosine levels in rodents. To determine any long-term protective effects of caffeine in a controlled longitudinal study, caffeine was added to the drinking water of APPsw transgenic (Tg) mice between 4 and 9 1/2 months of age, with behavioral testing done during the last 6 weeks of treatment. The average daily intake of caffeine per mouse (1.5 mg) was the human equivalent of 5 cups of coffee/day. Across multiple cognitive tasks of spatial learning/reference memory, working memory, and recognition/identification, Tg mice given caffeine (Tg+Caff) performed significantly better than Tg control mice and similar to non-transgenic controls. Discriminant Function Analysis involving multiple cognitive measures clearly showed the superior overall cognitive performance of Tg+Caff mice compared to Tg controls. Analysis of Aβ in the hippocampus by ELISA revealed Tg+Caff mice had significantly less soluble Aβ1-40 and insoluble Aβ1-42. In a follow-up study involving neurochemical analysis only, caffeine was added to the drinking water of 17 month old APPsw mice for 18 days. In this study, Tg+Caff mice also showed a significant reduction of insoluble Aβ1-42 in the hippocampus. In contrast to the reduced extracellular brain levels of adenosine in Tg controls, caffeine treatment normalized brain adenosine levels in Tg mice to that of non-transgenic controls. Analysis of amyloidogenic secretase activity revealed the reduction in Αβ is likely because of a reduction in gamma secretase activity as a result of increased SAM silencing of PS1 expression. This study suggest that a modest, long-term caffeine intake of approximately 500 mg per day (5 cups of coffee) may reduce considerably the risk of AD by decreasing amyloidogenesis.