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Alzheimer’s disease (AD) and the evolution of the Amyloid Hypothesis: The primary risk factor for dementia is aging, as the overwhelming majority of individuals who have the disease (~95%) are 65 years old or older, and the rate of development of AD dou-bles roughly every five years from that age, peaking at a nearly 50% population prevalence by the age of 85. The disease is progressive and irreversible, with an average time course of 8 to 10 years. Re-gardless of catastrophic forecasts for the next decades, its actual prevalence has huge family and social costs. The exact mechanisms leading to AD remain unknown, limiting the identification of ef-fective disease-modifying therapies. The two principal neuropatho-logical hallmarks of AD are extracellular β-amyloid (Aβ) peptide deposition (senile plaques, SPs) and intracellular neurofibrillary tangles, containing hyperphosphorylated tau protein. In 1999, with a pioneering work, Dale and Hardy (2016) opened the way to theera of the so-called Amyloid Hypothesis. It supports the con-cept that an imbalance between production and clearance of Aβ42 and related Aβ neurotoxic peptides may be the initiating factor in AD, with consequent accumulation and deposition of oligomeric or fibrillar forms of Aβ. Since then, many therapies have focused on the removal of extracellular Aβ (eAβ). All these have given good cognitive benefits on animal models, but, as far as we know, none of them allowed the recovery to the cognitive starting point in all respects. The predominant role that the Aβ has in the development of AD is now widely accepted. While eAβ has historically gered the greatest attention, the intracellular Aβ (iAβ) is receiving in-creasing consideration for its pathophysiological contributions to AD (LaFerla et al., 2007). Similarly to Caccamo et al. (2010), we also consider our approach more efcacious on iAβ than on neuro-fibrillary tangle removal (Cassano et al., 2019). We therefore moved towards the latest version of the Amyloid Hypothesis, aiming to set up a fully and readily translational protocol.