Simple! In our mechanistic views of how drug discovery works, we have a target (amyloid) and we have a spreading pattern (Braak’s spatio-temporal map) – so why don’t we have a therapy yet?
This approach seems to work for many other diseases – once you know the pathogenesis and its (spatio-) temporal pattern, you know where to look and how to target and disrupt the pathogenic process. Unfortunately, this approach does not seem to work for the brain and especially not in AD.
“Older” yet still frequently used therapeutic approaches aim at altering synaptic transmission in order to enhance cognitive performance in AD patients – with less than satisfying results.This is not surprising – these approaches are symptomatic, rather than causal.
The novel therapeutic approaches, antibodies against different forms of Amyloid beta, enjoyed the summer media hype, however are far from being a cure. Several companies tried this approach; Eli Lilly’s Solanezumab targeting the soluble forms of Aβ currently seems to provide the most promising results. Especially when the drug is given in earlier stages of the disease, the cognitive decline seems to be, somewhat, delayed.
The clinical relevance of these findings is however debated, as the numerical significance is smaller than what clinicians usually consider as clinically significant. Biogen’s Aducanumab, an antibody against insoluble Aβ, also led to a delay in cognitive decline, however with a puzzling dose-response relationship.
In contrast, Roche’s Gantenerumab (also targeting insoluble Aβ) failed to achieve the study goal (possibly due to dosing issues) and it is highly questionable, if we will witness another study with this agent.
Be that as it may, (at least) for the first time we are at a stage where disease modifying approaches are used for AD – after more than 60 years of treating patients with drugs offering poor symptomatic control and many undesired side effects – this can indeed be described as a breakthrough.
Focusing on a single target seems to be one major problem in a disease where almost every week new molecules and pathways are suspected to be involved somehow. Let’s keep in mind – there are also many experts who claim that pathologies involving Tau, a cytoskeletal protein, are involved in AD pathogenesis to the same extent than Aβ.
But even the amyloid pathology is anything but straight forward. Recently, for example, Amyloid eta (Aη) , another proteolytic amyloid fragment, was implicated to be pathogenically relevant.
These findings could provide explanation why drugs that inhibit the generation of Aβ, and indeed have been shown to reduce Aβ levels in the brain, are not as successful as expected. These drugs, so called beta secretase inhibitors, concomitantly lead to an increase in Aη production. The authors do not claim (yet?) that Aη targeting drugs or antibodies are the novel holy grail of AD research; their findings merely demonstrate the many facets of the complex disease.
But why do we need to be sceptic about such novel developments? Why is it so difficult to adapt therapeutic strategies to novel findings in the context of AD?