 Developing vaccines for the treatment of Alzheimer’s disease poses unique challenges. Success for a vaccine approach aimed at endogenous targets relies on the ability to break immune tolerance and generate a humoral antibody response against the desired epitopes. AN1792 was created using a synthetic full-length Aβ1–42 peptide. Nineteen percent of patients in the trial generated anti-Aβ antibody responses and showed improved memory and decreased levels of tau protein in the CSF. Postmortem pathology examination of former AN1792 patients showed that the vaccine had markedly cleared plaques from the brain. Vaccine candidates such as CAD106 and UB-311 use selective epitopes and were developed to avoid the undesirable inflammatory effects that were seen with AN1792. Studies of recent and current amyloid targeting immunotherapies (18 therapeutics) and vaccine therapeutics (8) illustrate lessons learned regarding patient selection, clinical and biomarker outcomes, dosing regimens and assessment of antibody response. A meta-analysis of 13 RCT of amyloid-based immunotherapies in AD showed statistically significant improvement in ADAS-cog (p<0.01) on drug. Solanezumab and AN1792 showed the largest effect sizes and safest profiles, but the rates of ARIA-E were significantly higher with monoclonal antibodies. Positive ADAS-cog effect sizes were seen for AN1792, Solanezumab EXPEDITION 3, BAN2401 and Aducanumab ENGAGE. Earlier EXPEDITION studies also included moderate disease, with substantially lower effect sizes.