Abstract: Alzheimer’s disease (AD) is a major age-related form of dementia with a number of cases exponentially growing, causing enormous social and economic impact on individuals and society. Neuropathological hallmarks of AD, evident in postmortem AD brains, include a massive loss of the grey matter in the neocortex, extracellular deposition of amyloid-β (Aβ) in the form of senile plaques and cerebrovascular amyloid angiopathy, and intra-neuronal accumulation of neurofibrillary tangles, formed by hyper-phosphorylated tau protein. The (most popular) Aβ cascade hypothesis posits the causal role of the aberrant processing of amyloid precursor protein, leading to the release and accumulation of Aβ. This hypothesis stems (possibly erroneously) from the presumed similarity of sporadic AD to inherited, rare familial AD form, triggered by mutations in amyloid precursor protein itself and presenilins 1 and 2 that form a catalytic core of the amyloid precursor protein processing protease γ-secretase. For a long time Aβ cascade hypothesis guided drug development studies and clinical trials in AD field. However, the failure of clinical trials of potential anti-AD drugs reflects a much higher complexity of AD pathogenesis. The main conceptual achievement of the last three decades in AD research has been the understanding that the cellular and biochemical abnormalities precede, by several decades, the emergence of clinical symptoms, indicating that the onset of AD occurs at the youth/middle age of potential AD patients (Selkoe and Hardy, 2016). This highlights the preclinical and prodromal stages as the major window of opportunity for disease-modifying therapy (Figure 1).