In this study the authors hypothesize that targeting Abeta immunotherapy to skin tissue might provide an immunotherapeutic approach that is both efficacious and safe. To test this hypothesis the investigators developed a transcutaneous (t.c.) Abeta vaccination approach and evaluated its efficacy and monitored for deleterious side effects, including meningoencephalitis and microhemorrhage. The data demonstrate that t.c. immunization of wild type mice with aggregated Abeta 1–42 plus the adjuvant cholera toxin (CT) results in high-titer Abeta antibodies (mainly of the Ig G1 class) and Abeta1–42-specific splenocyte immune responses. To evaluate the efficacy of t.c. immunization in reducing cerebral amyloidosis, transgenic PSAPP (APPsw, PSEN1dE9) mice were immunized with aggregated Abeta 1–42 peptide plus CT. Immunization with Abeta1–42 plus CT resulted in significant decreases in cerebral Abeta 1–40 and 1-42 levels coincident with increased circulating levels of Abeta 1–40,1-42, suggesting brain-to-blood efflux of Abeta.Reduction in cerebral amyloidosis was not associated with deleterious side effects, including brain T cell infiltration or cerebral microhemorrhage. Together, these data suggest that t.c. immunization constitutes an effective and potentially safe treatment strategy for AD.