Introduction: The amyloid hypothesis of Alzheimer’s disease (AD) affirms that brain accumulation of amyloid-β (Aβ) oligomers and soluble aggregates represent the major pathological event of the disease. Several anti-Aβ small organic molecules, monoclonal antibodies and antigens were developed to interfere with Aβ production and clearance, including β–site amyloid precursor protein cleaving enzyme (BACE) inhibitors, blocking the first enzymatic step of Aβ formation. All these approaches, including BACE inhibitors, have failed in large randomized clinical trials (RCTs) in mild-to-moderate AD, but further studies are now being carried out in patients at early AD stages and in asymptomatic subjects at risk of developing AD. Areas covered: The paper provides a comprehensive review of BACE inhibitors for AD treatment, focusing on the most advanced compounds in Phase III RCTs. Expert commentary: BACE inhibitors inhibited robustly, and dose-dependently, Aβ formation in cerebrospinal fluid of AD patients, but without cognitive, clinical, or functional benefit in large RCTs. BACE inhibition may be not sufficient to decrease brain Aβ plaques and aggregates. Indeed, several BACE inhibitors were found to be poorly tolerated and some of them failed also in patients with prodromal AD. This may indicate that blocking the formation of nascent Aβ is not useful in AD.

BACE inhibitors in clinical development for the treatment of Alzheimer’s disease

Panza, Francesco;Lozupone, Madia;Solfrizzi, Vincenzo;Giannelli, Gianluigi;Daniele, Antonio;Logroscino, Giancarlo;
2018

Abstract

Introduction: The amyloid hypothesis of Alzheimer’s disease (AD) affirms that brain accumulation of amyloid-β (Aβ) oligomers and soluble aggregates represent the major pathological event of the disease. Several anti-Aβ small organic molecules, monoclonal antibodies and antigens were developed to interfere with Aβ production and clearance, including β–site amyloid precursor protein cleaving enzyme (BACE) inhibitors, blocking the first enzymatic step of Aβ formation. All these approaches, including BACE inhibitors, have failed in large randomized clinical trials (RCTs) in mild-to-moderate AD, but further studies are now being carried out in patients at early AD stages and in asymptomatic subjects at risk of developing AD. Areas covered: The paper provides a comprehensive review of BACE inhibitors for AD treatment, focusing on the most advanced compounds in Phase III RCTs. Expert commentary: BACE inhibitors inhibited robustly, and dose-dependently, Aβ formation in cerebrospinal fluid of AD patients, but without cognitive, clinical, or functional benefit in large RCTs. BACE inhibition may be not sufficient to decrease brain Aβ plaques and aggregates. Indeed, several BACE inhibitors were found to be poorly tolerated and some of them failed also in patients with prodromal AD. This may indicate that blocking the formation of nascent Aβ is not useful in AD.
File in questo prodotto:
File Dimensione Formato  
Panza Expert Opinion on Pharmacotherapy .pdf

non disponibili

Tipologia: Documento in Post-print
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 1.35 MB
Formato Adobe PDF
1.35 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11586/229260
Citazioni
  • ???jsp.display-item.citation.pmc??? 18
  • Scopus 46
  • ???jsp.display-item.citation.isi??? 46
social impact