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

Abstract

Alzheimer disease (AD) is an incurable, progressive neurodegenerative disorder with a long presymptomatic period that is clinically characterized by cognitive and behavioural impairment, social and occupational dysfunction and, ultimately, death. In the USA, AD was the sixth most common cause of death in 2015 and showed the largest age-adjusted increase (16%) relative to 2014 (ref. 1). According to current estimates, 17% of people aged 75-84 years in the USA have AD, and the disease costs the country US$236 billion per year. The prevalence is projected to triple by 2050 to >15 million, with annual costs of >$700 billion 2. Diagnosis of AD is usually based on medical history and clinical findings, sometimes corroborated by brain imaging. Therapies are symptomatic and do not affect disease progression; currently, cholinesterase inhibitors and the N-methyl-d-aspartate receptor antagonist memantine are the only available options. Despite extensive research into the pathophysiology of AD, the large number of drugs entering clinical development and the enormous expenditure on large and complex trials, no new drug has been approved since memantine in 2003. Many reasons have been proposed to explain this failure, including inappropriate patient selection, variable rates of progression, suboptimal dosing, drug exposure and/or target engagement, inappropriate time of intervention, inappropriate outcome measures and low sensitivity of clinical scales. In addition, an incomplete understanding of AD pathophysiology might have led to selection of the wrong targets. Most of the drugs tested for AD in the past 20 years have targeted the accumulation of the amyloid-β (Aβ) peptide. In this article, we consider the current anti-Aβ drugs and the possible reasons for their failure to provide meaningful clinical benefits. Anti-Aβ therapies have been extensively tested in sporadic late-onset forms of AD, which will be the main focus of our discussion; no therapeutic studies have yet been conducted in individuals with the less common familial forms. The amyloid cascade hypothesis The Aβ peptide is generated by metabolism of amyloid precursor protein (APP), a type I transmembrane glycoprotein of 695-770 amino acids. APP is cleaved close to the membrane by an extracellular protease known as α-secretase. This cleavage liberates a soluble extracellular fragment, sAPPα. APP is also cleaved by an aspartyl protease known as β-secretase 1 (BACE1),

Extracellular Vesicles from Mesenchymal Stem Cells Exert Pleiotropic Effects on Amyloid‐β, Inflammation, and Regeneration: A Spark of Hope for Alzheimer's Disease from Tiny Structures?

“…If that is the case, it should not be surprising that targeting amyloid deposits in the brain has proven to be a faulty approach in AD therapeutics. Approaches are now being developed that target soluble Aβ oligomers in AD brains, but these still need to be rigorously tested …”

Preclinical Models of Alzheimer's Disease: Relevance and Translational Validity

“…As a result, considerable resources have been expended over the past forty years in searching for therapeutics to treat AD, all of which have failed—sometimes repeatedly—in late‐stage clinical trials (Khachaturian, ; Martin, ; Morris, Clark, & Vissel, ; Mullane & Williams, ; Panza et al., ). Among the reasons for these failures are: (i)The politicization of AD, which has tended to confuse the guidelines for the diagnosis and treatment of a disease that is increasingly viewed as multifactorial and non‐linear in both causality and progression (De Strooper & Karran, ; Medina, Khachaturian, Rossor, Avila, & Cedazo‐Minguez, ).…”

“…As a result, considerable resources have been expended over the past forty years in searching for therapeutics to treat AD, all of which have failed-sometimes repeatedly-in late-stage clinical trials (Khachaturian, 2018;Martin, 2018;Morris, Clark, & Vissel, 2018;Mullane & Williams, 2018a;Panza et al, 2019). Among the reasons for these failures are:…”

Flavonoid‐Derived Human Phenyl‐γ‐Valerolactone Metabolites Selectively Detoxify Amyloid‐β Oligomers and Prevent Memory Impairment in a Mouse Model of Alzheimer's Disease

“…AβOs, which have been shown not to be obligate intermediates of the fibrillization pathway, are nevertheless thought to be in a dynamic equilibrium with fibrillar aggregates and amyloid plaques, which are currently considered as potentially harmless Aβ storage forms . According to this view, AβO accumulation resulting from drug‐induced interference with plaque formation and/or promotion of their disaggregation has been proposed as a possible explanation for the failure of many candidate AD drugs that primarily target large Aβ aggregates rather than AβOs . Another recently added complexity may stem from the unexpectedly high diversity of Aβ peptide variants found in the brain of AD patients, that may hamper recognition of many of their aggregate species by sequence‐specific monoclonal antibodies …”