We have previously demonstrated that intracerebroventricular (ICV) injection of anti-Aβ (IgG1, kappa against the 1–28 region of Aβ) reduced cerebral amyloid plaques by 50% after 1 month without producing hemorrhage or activating IL-1β responses in Tg2576 brain [N.B. Chauhan, G.J. Siegel, Reversal of amyloid beta toxicity in Alzheimer's disease model Tg2576 by intraventricular antiamyloid beta antibody, J. Neurosci. Res. 69 (1) (2002) 10–23]. The current report compares the efficacy of IgG1, IgG2a and IgG2b isotypes of anti-Aβ against several different epitopes of Aβ in clearing cerebral Aβ after a single bolus ICV injection in TgCRND8. Consistent with earlier in vitro findings from other laboratories, these in vivo data demonstrate that all IgG1 isotype antibodies tested cleared cerebral Aβ more efficiently than did IgG2a and IgG2b antibodies without producing histotoxicity in brain, liver or kidney, while an antibody against the C-terminus of Aβ did not reduce plaques or diminish their accumulation with aging of the animals. Intriguingly, there was no significant difference between the Aβ-reducing efficiency of IgG1 anti-Aβ antibodies directed against residues 3–6, against residues 1–10 or against residues 1–28 of N-terminus Aβ.