Abstract:

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 doubles 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. Regardless 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 effective disease-modifying therapies. The two principal neuropathological 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 the “era” of the so-called “Amyloid Hypothesis”. It supports the concept 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 garnered the greatest attention, the intracellular Aβ (iAβ) is receiving increasing consideration for its pathophysiological contributions to AD. Similarly to Caccamo et al. we also consider our approach more efficacious on iAβ than on neurofibrillary tangle removal . We therefore moved towards the latest version of the “Amyloid Hypothesis”, aiming to set up a fully and readily translational protocol.