J Cent Nerv Syst Dis1
US Food and Drug Administration2
A growing disease burden
Alzheimer’s disease (AD) is the leading cause of dementia and one of the greatest medical challenges that we currently face. To put this into numbers, approximately 40 million people suffer from dementia worldwide, and this number is expected to double in 20 years. The cognitive decline caused by AD is extremely distressing for patients and caregivers, with this burden amplifying over the years as the disease progresses. As if this was not enough, AD costs healthcare systems and individuals a fortune, with nearly 1 out of every 5 medical dollars spent in the US going towards the treatment of this disease.
Until now, the only approved therapies in AD dealt with the symptoms of the disease, without modifying the underlying brain pathology driving the neuronal destruction. Such drugs include cholinesterase inhibitors and the N-methyl-D-aspartate antagonist memantine. These medications provide modest effects on cognitive symptoms by increasing the levels of certain neurotransmitters in the brain, but their benefits only last for a maximum of 1–2 years.
The first approved disease-modifying therapy in AD
June 2021 has marked a landmark in AD with the FDA approval of the monoclonal antibody aducanumab, the first disease-modifying therapy (DMT) to be given the green light. Unlike symptomatic agents, aducanumab targets the underlying disease pathology by removing the aggregated forms of amyloid beta (Aβ) believed to be responsible for driving a cascade of events that ultimately induce massive neuronal loss and cognitive decline.
Aβ elimination strategies
While aducanumab provides passive immunisation against Aβ aggregates, other exciting drugs in development target different steps of the Aβ pathway, with others exclusively interfering with tau phosphorylation. Six active Aβ immunotherapies are currently being investigated in clinical trials. Unlike passive immunisation strategies such as aducanumab, active immunisation trains the immune system to recognise and eliminate toxic Aβ aggregates, in the same way that vaccines allow our bodies to quickly produce antibodies to neutralise foreign microorganisms.
Another strategy being explored in a Phase 3 study (AMBAR) is the use of plasma exchange with albumin replacement on the basis that Aβ in the cerebrospinal fluid is in dynamic equilibrium with plasma Aβ through the blood–brain barrier. Thereby, removal of Aβ from the blood via plasma exchange will shift this balance, forcing the movement of cerebrospinal fluid Aβ into the circulation. Frequent albumin replacement binds the majority of plasma Aβ, and its routine removal by plasma exchange is believed to correct the imbalance between brain and plasma Aβ levels seen in AD.
Blocking Aβ production
Given that Aβ is generated by the sequential cleavage of amyloid precursor protein (APP) by β-secretase and γ-secretase, these enzymes were considered major therapeutic targets. However, γ-secretase is no longer considered a viable therapeutic strategy given that this enzyme cleaves several transmembrane proteins and its inhibition was associated with serious safety concerns (infections and skin cancer). Meanwhile, a number of β-secretase inhibitors demonstrated reductions in cerebrospinal fluid Aβ in clinical trials, but these changes did not translate into cognitive improvements, ultimately aborting their development.
In contrast, cleavage of APP by α-secretase does not result in the formation of Aβ, making the modulation of this enzyme an attractive target. Given that α-secretase activation appears to be promoted through the PI3K/Akt pathway, two drugs targeting this route are currently in ongoing Phase 2 studies.
Targeting tau hyperphosphorylation
Beyond Aβ, therapies targeting tau hyperphosphorylation represent another potential therapeutic strategy. Abnormally hyperphosphorylated tau forms insoluble fibrils that uncouple microtubules, inhibiting axonal transport and causing cell death. While the amyloid hypothesis considered tau hyperphosphorylation to be a downstream effect of Aβ deposition, it is now thought that tau and Aβ act in parallel in AD.
Currently there are over 10 agents with a tau-related mechanism of action being explored in clinical trials. As with Aβ interventions, both passive and active immunotherapeutic approaches targeting hyperphosphorylated tau are being studied.
Beyond tau elimination, another approach is to prevent tau from becoming hyperphosphorylated in the first place. Since hyperphosphorylation of tau is mediated by kinases, studies looking at inhibition of enzymes such as glycogen synthase kinase 3 are ongoing.
The pivotal role that tau plays in ensuring adequate microtubule function means that when this protein becomes hyperphosphorylated and starts forming tangles, the transport system within neurons collapses. As a consequence, microtubule stabilisers are currently being explored to counteract the destruction of these vital cellular structures.
The increased molecular understanding of AD and the exciting recent approval of aducanumab should accelerate the development of additional DMTs with the potential to transform the lives of patients and families affected by this devastating disease.
- Yiannopoulou KG, Papageorgiou SG. J Cent Nerv Syst Dis. 2020;12:1179573520907397.
- 2. FDA Peripheral and Central Nervous System Drugs Advisory Committee. Aducanumab for the treatment of Alzheimer’s disease. 6 November 2020. Available at: https://www.fda.gov/media/143507/download#:~:text=Aducanumab%20does%20exactly%20that., to%20brain%20parenchymal%20beta%2Damyloid.. Accessed June 2021.