Review Article | Published:

A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease

Abstract

Brain accumulation of the amyloid-β (Aβ) peptide is believed to be the initial event in the Alzheimer disease (AD) process. Aβ accumulation begins 15–20 years before clinical symptoms occur, mainly owing to defective brain clearance of the peptide. Over the past 20 years, we have seen intensive efforts to decrease the levels of Aβ monomers, oligomers, aggregates and plaques using compounds that decrease production, antagonize aggregation or increase brain clearance of Aβ. Unfortunately, these approaches have failed to show clinical benefit in large clinical trials involving patients with mild to moderate AD. Clinical trials in patients at earlier stages of the disease are ongoing, but the initial results have not been clinically impressive. Efforts are now being directed against Aβ oligomers, the most neurotoxic molecular species, and monoclonal antibodies directed against these oligomers are producing encouraging results. However, Aβ oligomers are in equilibrium with both monomeric and aggregated species; thus, previous drugs that efficiently removed monomeric Aβ or Aβ plaques should have produced clinical benefits. In patients with sporadic AD, Aβ accumulation could be a reactive compensatory response to neuronal damage of unknown cause, and alternative strategies, including interference with modifiable risk factors, might be needed to defeat this devastating disease.

Key points

  • Genetic, biochemical, histopathological, biomarker and cognitive studies have suggested that brain accumulation of the amyloid-β (Aβ) peptide is the initial event in the Alzheimer disease (AD) process.

  • Over the past 15 years, several drugs that decrease Aβ production, antagonize Aβ aggregation or increase brain Aβ clearance have been tested in patients with mild to moderate AD but without success.

  • Anti-Aβ drugs have also produced disappointing results in individuals at earlier stages of the disease who have biomarker evidence of Aβ brain deposition.

  • This series of clinical failures has raised the possibility that Aβ accumulation represents an epiphenomenon rather than a cause of AD, casting doubt on the prevailing amyloid cascade hypothesis of AD.

  • Aducanumab, a potent monoclonal antibody specifically directed against Aβ oligomers, produced encouraging preliminary results in patients with prodromal or mild AD, suggesting that oligomeric Aβ species may represent a valid biological target.

  • As accumulation of Aβ in the brain starts 15–20 years before the onset of clinical symptoms, drugs are now being tested in preclinical or asymptomatic stages of AD and in cognitively healthy individuals at risk of AD.

  • Other promising approaches directed against key elements of the disease, such as CNS inflammation, brain insulin resistance and tau aggregation, must be more intensively pursued to avoid a therapeutic vacuum should the present anti-Aβ therapies fail even in asymptomatic individuals.

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All authors researched the data for the article, provided substantial contributions to discussions of its content, wrote the article and undertook the review and/or editing of the manuscript before submission.

Competing interests

B.P.I. is an employee at Chiesi Farmaceutici and has developed anti-Alzheimer disease (AD) drugs. He is co-inventor of patents on anti-AD drugs. He does not hold stock options. The other authors declare no competing interests.

Correspondence to Francesco Panza.

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Fig. 1: Targets of anti-Aβ drugs.
Fig. 2: Stage of clinical development of anti-Aβ drugs to treat Alzheimer disease.