Alzheimer's disease and Lewy body diseases are the most common causes of 
neurodegeneration and dementia. Amyloid-beta (Aβ) and alpha-synuclein (αSyn) are 
two key proteins involved in the pathogenesis of these neurodegenerative 
diseases. Immunotherapy aims to reduce the harmful effects of protein 
accumulation by neutralising toxic species and facilitating their removal. The 
results of the first immunisation trial against Aβ led to a small percentage of 
meningoencephalitis cases which revolutionised vaccine design, causing a shift 
in the field of immunotherapy from active to passive immunisation. While the 
vast majority of immunotherapies have been developed for Aβ and tested in 
Alzheimer's disease, the field has progressed to targeting other proteins 
including αSyn. Despite showing some remarkable results in animal models, 
immunotherapies have largely failed final stages of clinical trials to date, 
with the exception of Aducanumab recently licenced in the US by the FDA. 
Neuropathological findings translate quite effectively from animal models to 
human trials, however, cognitive and functional outcome measures do not. The 
apparent lack of translation of experimental studies to clinical trials suggests 
that we are not obtaining a full representation of the effects of 
immunotherapies from animal studies. Here we provide a background understanding 
to the key concepts and challenges involved in therapeutic design. This review 
further provides a comprehensive comparison between experimental and clinical 
studies in Aβ and αSyn immunotherapy and aims to determine the possible reasons 
for the disconnection in their outcomes.