Alzheimer’s disease (AD) is the most common form of dementia in the elderly population and is characterized by two prominent neuropathological lesions: extracellular amyloid-β (Aβ) containing plaques and intraneuronal fibrillary tangles comprised of aberrantly hyperphosphorylated tau protein. Current treatments targeting the amyloid pathology have had limited success so far. They aim at either reducing the production of Aβ peptides from the amyloid precursor protein or rely on immunotherapy (active or passive) to neutralize Aβ with antibodies. We previously found that by introducing a specific mutation in the cholesterol binding site of the amyloid precursor protein, we could generate short and non-toxic Aβ peptides. Here we will test i) if this specific mutation produces short and non-toxic Aβ peptides in human neuronal cells and in mouse models and, ii) when added on the top of a familial AD mutation, if it could prevent the production of toxic Aβ peptides due to AD mutation. In addition, we will develop new antibodies against these short Aβ peptides to measure their levels in biological fluids from elderly subjects with or without amyloid pathology in their brain. This project should provide data to consider long-term early preventive treatments producing short and non-toxic Aβ peptides such as γ-secretase modulators.