Abstract: Alzheimer’s disease (AD) is the most common form of dementia and is diagnosed clinically by cognitive deficits, and anatomically by accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFT) containing hyper-phosphorylated Tau. Over the past three decades of AD research, the “amyloid hypothesis” gained the most attention as the main player in neurodegeneration. This was mostly based on specific hereditary forms of AD and patients with Down syndrome that linked the level of amyloid-beta (Aβ) directly to the risk of developing these diseases. However, in non-hereditary forms of AD, little correlation exists between Aβ levels or its location with the clinical stages of the disease. While still a hotly debated topic, a large body of literature based on years of preclinical models, suggests that Aβ deposition alone is not sufficient to induce AD, rather it is a pre-requisite for formation of NFT by promoting Tau hyper-phosphorylation. Neuropathology and imaging studies also suggest that hyper-phosphorylation of Tau and its spreading through the brain, better conform to the clinical stages of the disease  (Long and Holtzman, 2019).