Alzheimer’s disease (AD) is the most common form of dementia characterized neuropathologically by senile plaques and neurofibrillary tangles (NFTs). Early breakthroughs in AD research led to the discovery of amyloid-β as the major component of senile plaques and tau protein as the major component of NFTs. Shortly following the identification of the amyloid-β (Aβ) peptide was the discovery that a genetic mutation in the amyloid precursor protein (APP), a type1 transmembrane protein, can be a cause of autosomal dominant familial AD (fAD). These discoveries, coupled with other breakthroughs in cell biology and human genetics, have led to a theory known as the “amyloid hypothesis”, which postulates that amyloid-β is the predominant driving factor in AD development. Nonetheless, more recent advances in imaging analysis, biomarkers and mouse models are now redefining this original hypothesis, as it is likely amyloid-β, tau and other pathophysiological mechanism such as inflammation, come together at a crossroads that ultimately leads to the development of AD.