Beta-secretase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

ABSTRACT

Introduction: BACE 1 is a protease that cleaves the transmembrane amyloid precursor protein and generates amyloid-β peptides that accumulate in AD brains. No known mutations are identified in the gene encoding BACE1 in AD. However, enzyme levels are elevated in AD and a single residue mutation in amyloid precursor protein protects against protein cleavage by BACE1, suggesting BACE involvement in disease pathogenesis. Drugs that can inhibit BACE1 would theoretically prevent Aβ accumulation and halt AD onset and progression.

Areas covered: This review discusses clinical developments of BACE1 inhibitors and focuses on what is learned about these inhibitors as a potential treatment.

Expert opinion: BACE1 inhibition as a therapeutic strategy to improve cognition in AD has been challening. Brain-penetrant BACE1 inhibitors have been developed and clinical trials are underway, both safety and efficacy are questionable. Several clinical trials suggest that BACE1 inhibition and other immunotherapies to reduce brain Aβ are insufficient to improve cognition in AD. This may be due to the emphasis on the amyloid hypothesis despite big failures. We may have to seriously consider shifting attention to therapeutic strategies other than BACE1 inhibition or reduction of Aβ alone and pay more attention to simultaneous clearance of tau and Aβ.

KEYWORDS:

• Alzheimer
• amyloid
• dementia
• clinical trials
• BACE1
• tau
• Aβ

Article highlights

1. BACE1 inhibition as a therapeutic strategy to improve cognition in AD has been challenging.

2. Clinical trials suggest that BACE1 inhibition and other immunotherapies to reduce brain Aβ are insufficient to improve cognition in AD.

3. Emphasis on the amyloid hypothesis alone may not lead to an effective treatment.

4. Shifting attention to therapeutic strategies that include BACE1 inhibition or reduction of Aβ together with tau clearance may be more beneficial

5. Imaging strategies may also help us better understand the importance of simultaneous tau and amyloid reduction

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded