O1‐04–04: Caffeine reverses cognitive impairment, decreases β‐amyloid levels, and reduces inflammation in aged Alzheimer's mice: Implications for Alzheimer's treatment

We have recently shown that APPsw mice given a moderate level of caffeine intake (the human equivalent of 5 cups of coffee per day) are protected from development of otherwise certain cognitive impairment and have decreased hippocampal Aβ levels due to suppression of both β-secretase (BACE) and PS1 expression (Neuroscience 142:941, 2006). Thus, we concluded that long-term caffeine intake may delay or reduce the risk of Alzheimer's Disease (AD). To determine if caffeine intake can have beneficial cognitive, neurohistologic, and neurochemical effects in “aged” APPsw mice already demonstrating confirmed cognitive impairment, we administered caffeine in the drinking water of 18–19 month old APPsw mice (0.3 mg/ml). These mice had been pre-tested and shown to be impaired in the radial arm water maze (RAWM) task of working memory. At 4–5 weeks into caffeine treatment, animals were re-tested in the RAWM and euthanatized immediately following behavioral testing at 20–21 months of age. The working memory impairment exhibited by control transgenic (Tg) mice given normal drinking water was reversed by caffeine treatment (Tg+Caff) to the extent that performance of aged Tg+Caff mice was essentially identical to that of non-trangenic controls. In addition, Tg+Caff mice had substantially reduced hippocampal (-41%) and entorhinal cortex (-48%) Aβ deposition, as well as markedly decreased levels of soluble Aβ in brain. Moreover, caffeine-treated Tg mice with the highest plasma levels of caffeine had the lowest plasma Aβ levels and most-suppressed plasma cytokines levels. In acute studies, a single gavage or i.p. caffeine treatment induces remarkably rapid reductions in plasma Aβ within 2–4 hours. Even with their pre-existing and substantial Aβ burdens, aged APPsw mice given long-term caffeine in their drinking water exhibited working memory restoration and a reversal of brain Aβ pathology, suggesting a treatment potential of caffeine in cases of established AD. These robust treatment effects of both acute and long-term caffeine treatment (the human equivalent of 5 cups of coffee per day) have laid the foundation for our recently-initiated clinical trials with caffeine. Results of these clinical trials will be discussed (Supported by AG025711 and funds from the Byrd Institute).