Active vaccination with amyloid peptides shows promise for the treatment and prevention of Alzheimer’s disease (AD). Several studies in transgenic mouse models of AD have revealed the potency of vaccination to prevent or even clear amyloid plaques from mouse brain. However, the idea that soluble oligomeric species of β-amyloid (Aβ), rather than plaques, trigger the disease has gained momentum, and current active vaccination strategies affect the levels of total or soluble brain Aβ little or not at all. We describe an active vaccination method based on Aβ1-16 presented on the surface of virosomes, which triggered a dramatic decrease in both soluble Aβ40 (75% reduction; p=0.01) and soluble Aβ42 (62% reduction; p=0.03) in a double transgenic mouse model of AD. Whereas Aβ40 and Aβ42 levels in the insoluble fraction tended to be reduced (by 30% and 27%, respectively), the number of thioflavine-S-positive amyloid plaques was not affected. The high specific antibody responses, obtained without eliciting T-cell reactivity, demonstrate that immunostimulating reconstituted influenza virosomes are a promising antigen carrier system against the neuropathology of AD.