Amyloid beta (Aß) immunotherapy has been shown to be effective in clearing cerebral Aß and improving cognition in mouse models of Alzheimer’s disease (AD). However, an Aß vaccine clinical trial was suspended after ∽6% of the subjects developed meningoencephalitis, possibly due to a T-cell reaction against Aß. The N-terminal Aß1-15 sequence contains the B cell epitope(s) but lacks the T cell reactive sites of full-length Aß1-42. Consequently, we tested two novel immunogens encompassing a tandem repeat of two lysine-linked Aß1-15 sequences, with (R-2xAß1-15) or without (2xAß1-15) the addition of a three amino acid RGD motif, first in wildtype mice as we reported at SFN 2004 and now here, in J20 APP tg mice. Weekly, intranasal (i.n.) immunization with 50μg R-2xAß1-15 or 2xAß1-15 plus 5 μg adjuvant LT(R192G) resulted in high anti-Aß antibody titers (719±213 SEM and 1322±468 μg/ml, respectively, at week 22) consisting mainly of IgG2b, IgG1 and IgG2a isotypes. Re-stimulation of splenocytes with R-2xAß1-15 result...