Lacklustre performance: drugs targeting β-amyloid in Alzheimer’s disease

The Alzheimer’s Association International Conference (AAIC) is the largest gathering of the Alzheimer’s disease (AD) research community in the world, and provides a unique forum for the discussion of ideas and dissemination of knowledge. One of the key concepts grappled by the AD research community at AAIC 2016 in Toronto, Canada, was the validity of the amyloid hypothesis.

It is generally accepted that the accumulation of b-amyloid (Ab), particularly Ab40-42, in the extracellular spaces around neurons as amyloid plaques is central to the pathogenesis of AD. This idea is expressed in the ‘amyloid cascade hypothesis’ [1,2]. It thus follows that by reducing the production of Ab or eliminating the amyloid plaques from the brain, the progression of disease could be slowed, halted, or even reversed [3]. Alzheimer’s disease is the most important cause of dementia, which affects a staggering 40 million people worldwide, a number which is predicted to double every 20 years until 2050 [4]. Therefore, achieving prevention, or even just slowing of disease progression, would have a significant impact on morbidity, mortality, and burden on healthcare systems worldwide.

Hence, significant funding has been directed by both public research institutions and private pharmaceutical corporations towards the development of drugs that target Ab. Ab is produced by two steps of enzymatic processing: first by b-secretase, and then by g-secretase [5]. The latter has been targeted by drugs collectively known as g-secretase inhibitors, most prominently avagacestat and semagacestat. Both of these drugs failed in Phase 2 and 3 trials, and notably were associated with cognitive decline, an increased risk of skin cancers, and an overall increased risk of serious adverse events [6-10]. It was suspected that the failure of g-secretase inhibitors, particularly with regards to the adverse events profile, was due to off-target inhibition of Notch, a receptor that is involved in a signalling pathway that is particularly prevalent in the skin and gastrointestinal system [9-11]. However, tarenflurbil, a g-secretase modulator that spared the active site of g-secretase and hence spared Notch, also failed to be clinically efficacious, as measured by changes in cognitive indicators such as the Mini-Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale – cognitive component (ADAS-cog), and the Clinical Dementia Rating – sum of boxes (CDR-sb) [12,13]. Hence, drug development has largely moved away from inhibition of g-secretase, and b-secretase (BACE) inhibitors are now in early development as a potential alternative.

Active and passive immunotherapeutic agents targeting Ab have also been tested, with mixed results. While bapineuzumab was successful in lowering amyloid concentrations in two Phase 3 trials, it did not cause any clinical improvement, compared to placebo, and was associated with the development of amyloid-related imaging abnormalities (ARIA) [14-17]. ARIA comprise two separate changes: vasogenic oedema and cerebral microhaemorrhages. These changes may occur due to destabilisation of amyloid in vascular walls [18,19]. While often asymptomatic, in combination with a lack of clinical efficacy this was sufficient to halt the development of bapineuzumab. Another immunotherapeutic, solanezumab, was underwhelming in its Phase 3 trial performance, but was better tolerated than bapineuzumab and showed some cognitive improvement in patients with mild AD [20-22]. Aducanumab [23], crenezumab [24], and gantenerumab [25] have all also shown promise and currently have Phase 3 trials in planning or underway. Hence, it appears that immunotherapy may be a more viable modality for the treatment of AD than inhibition of g-secretase.

It is possible that all trialled therapeutics have targeted AD too late in the disease course, when clinical features such as memory decline and functional impairments have become frankly apparent. Hence, some trials have now shifted towards targeting AD earlier in its disease course. Mild cognitive impairment (MCI), also known as prodromal AD, is the accepted early pre-AD stage in which it is now believed the greatest improvements can be made, by preventing further decline [26]. Another stage prior to this, subjective cognitive impairment (SCI), in which patients report some cognitive changes but their scores on the MMSE and other indicators are unchanged, is also being recognised and may soon be targeted by therapeutic or preventive strategies [27].

It is also possible, of course, that the current paradigm of the amyloid cascade hypothesis is wrong. Perhaps the drugs have failed to show clinical efficacy, despite reducing cerebrospinal fluid Ab levels, because Ab is not actually central to disease pathogenesis. Another player in the game is tau – a protein that accumulates intracellularly in the classical neurofibrillary tangles. It was originally thought that tau accumulation occurred later in the disease course than that of Ab and was in some way triggered by Ab, supporting the role of Ab accumulation as the primary mediator of disease progression. However, it is now being argued that tau may actually develop concurrently and independently of Ab, and hence this may prove to be a viable target for pharmaceuticals in the future. What is certain, however, is that the pathogenesis of AD is complex, and it is unlikely that engaging with a single target will be sufficient for prevention or a cure [28].

Next year, when AD researchers congregate for AAIC 2017 in London, it is likely that the amyloid cascade hypothesis will further be tested by results from clinical trials of drugs targeting Ab, particularly those of immunotherapeutic agents. Whether there is a significant paradigm shift in terms of our understanding of AD pathogenesis, or a reorientation of our efforts towards prevention over treatment, will largely depend on these results over the next decade. It is certainly important that significant progress is made in the near future, lest pharmaceutical companies that fund drug development put AD in the ‘too hard’ basket and move on to simpler challenges.


Conflicts of interest

None declared



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