Affiliations: Research Laboratory, Complex Structure of Geriatrics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy
Correspondence:
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Correspondence to: Giulia Paroni and Davide Seripa, BiolD, PhD, Research Laboratory, Complex Structure of
Geriatrics, Department of Medical Sciences, Fondazione I.R.C.C.S. Ospedale “Casa Sollievo della Sofferenza”,
Viale Cappuccini 1, 71013 San Giovanni Rotondo (FG), Italy. Tel.: +390882416263; Fax: +390882416264;
[email protected] (Giulia Paroni) and Tel.: +390882416260; Fax: +390882416264;
[email protected] (Davide Seripa).
Abstract: The amyloid hypothesis (AH) is still the most accepted model to explain the pathogenesis of inherited Alzheimer’s disease (IAD). However, despite the neuropathological overlapping with the non-inherited form (NIAD), AH waver in explaining NIAD. Thus, 30 years after its first statement several questions are still open, mainly regarding the role of amyloid plaques (AP) and apolipoprotein E (APOE). Accordingly, a pathogenetic model including the role of AP and APOE unifying IAD and NIAD pathogenesis is still missing. In the present understanding of the AH, we suggested that amyloid-β (Aβ) peptides production and AP formation is a physiological aging process resulting from a systemic age-related decrease in the efficiency of the proteins catabolism/clearance machinery. In this pathogenetic model Aβ peptides act as neurotoxic molecules, but only above a critical concentration [Aβ]c. A threshold mechanism triggers IAD/NIAD onset only when [Aβ]≥[Aβ]c. In this process, APOE modifies [Aβ]c threshold in an isoform-specific way. Consequently, all factors influencing Aβ anabolism, such as amyloid beta precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) gene mutations, and/or Aβ catabolism/clearance could contribute to exceed the threshold [Aβ]c, being characteristic of each individual. In this model, AP formation does not depend on [Aβ]c. The present interpretation of the AH, unifying the pathogenetic theories for IAD and NIAD, will explain why AP and APOE4 may be observed in healthy aging and why they are not the cause of AD. It is clear that further studies are needed to confirm our pathogenetic model. Nevertheless, our suggestion may be useful to better understand the pathogenesis of AD.
