Amyloid-β (Aβ) immunotherapy lowers cerebral Aβ and improves cognition in mouse models of Alzheimer's disease (AD). A clinical trial using active immunization with Aβ1–42 was suspended after ∼6% of patients developed meningoencephalitis, possibly because of a T-cell reaction against Aβ. Nevertheless, beneficial effects were reported in antibody responders. Consequently, alternatives are required for a safer vaccine. The Aβ1–15 sequence contains the antibody epitope(s) but lacks the T-cell reactive sites of full-length Aβ1–42. Therefore, we tested four alternative peptide immunogens encompassing either a tandem repeat of two lysine-linked Aβ1–15 sequences (2×Aβ1–15) or the Aβ1–15 sequence synthesized to a cross-species active T1 T-helper-cell epitope (T1-Aβ1–15) and each with the addition of a three-amino-acid RGD (Arg-Gly-Asp) motif (R-2×Aβ1–15; T1-R-Aβ1–15). High anti-Aβ antibody titers were observed in wild-type mice after intranasal immunization with R-2×Aβ1–15 or 2×Aβ1–15 plus mutant Escherichia coli heat-labile enterotoxin LT(R192G) adjuvant. Moderate antibody levels were induced after immunization with T1-R-Aβ1–15 or T1-Aβ1–15 plus LT(R192G). Restimulation of splenocytes with the corresponding immunogens resulted in moderate proliferative responses, whereas proliferation was absent after restimulation with full-length Aβ or Aβ1–15. Immunization of human amyloid precursor protein, familial AD (hAPPFAD) mice with R-2×Aβ1–15 or 2×Aβ1–15 resulted in high anti-Aβ titers of noninflammatory T-helper 2 isotypes (IgG1 and IgG2b), a lack of splenocyte proliferation against full-length Aβ, significantly reduced Aβ plaque load, and lower cerebral Aβ levels. In addition, 2×Aβ1–15-immunized hAPPFAD animals showed improved acquisition of memory compared with vehicle controls in a reference-memory Morris water-maze behavior test that approximately correlated with anti-Aβ titers. Thus, our novel immunogens show promise for future AD vaccines.