From beta amyloid to altered proteostasis in Alzheimer's disease.

Alzheimer's disease (AD) is an age related neurodegenerative disorder causing severe disability and important socio-economic burden, but with no cure available to date. To disentangle this puzzling disease genetic studies represented an important way for the comprehension of pathogenic mechanisms. Abnormal processing and accumulation of amyloid-β peptide (Aβ) has been considered the main cause and trigger factor of the disease. The amyloid cascade theory has fallen into crisis because the failure of several anti-amyloid drugs trials and because of the simple equation AD = abnormal Aβ deposition is not always the case. We now know that multiple neurodegenerative diseases share common pathogenic mechanisms leading to accumulation of misfolded protein species. Genome Wide Association studies (GWAS) led to the identification of large numbers of DNA common variants (SNPs) distributed on different chromosomes and modulating the Alzheimer's risk. GWAS genes fall into several common pathways such as immune system and neuroinflammation, lipid metabolism, synaptic dysfunction and endocytosis, all of them addressing to novel routes for different pathogenic mechanisms. Other hints could be derived from epidemiological and experimental studies showing some lifestyles may have a major role in the pathogenesis of many age-associated diseases by modifying cell metabolism, proteostasis and microglia mediated neuroinflammation.