The amyloid hypothesis
The hope of transitioning to biomarker-supported diagnosis and molecular-specific therapies
Prof Gil Rabinovici (University of California, San Francisco, USA) began by discussing the amyloid cascade hypothesis, proposed to be at the heart of Alzheimer’s disease (AD) pathology1. Amyloid-beta released from amyloid precursor protein is cleaved to form polypeptide fragments, which aggregate to produce amyloid plaques. Downstream effects include activation of microglia and astrocyte leading to neuroinflammation, accumulation and spread of tau tangles, and interference of amyloid-beta oligomers with synaptic networks serving memory and cognition.
A desire for therapies that will modify the course of the disease
There is a desire by both patients and their clinicians for therapies that will modify the course of the disease alongside those providing symptom control. The development of antibodies that directly bind to amyloid-beta oligomers and insoluble fibrils has therefore been greeted with much interest.
The initial phase 3 clinical trials of one anti-amyloid antibody showed discordant results on clinical outcomes, with EMERGE demonstrating a slowing of cognitive decline whilst ENGAGE did not2. Biomarker results were consistent, with significant amyloid lowering on PET scan and changes in tau levels2. A particular safety concern was amyloid-related imaging abnormalities (ARIA), that can lead to oedema or haemorrhages2.
To prescribe or not?
One of the sessions posed the question as to whether these antibody treatments should be prescribed currently. Dr Alireza Atri (Harvard Medical School, Boston, USA) proposed yes, selected patients with early-stage AD should be given the opportunity for potential benefit, even if a modest effect, as current treatment options are limited. He pointed to published appropriate use recommendations that can aid clinicians in making these decisions3.
Published appropriate use recommendations can aid clinicians in making these decisions
Dr David Knopman (Mayo Clinic, Rochester, USA) took the opposing view, focusing on the inconsistency of current study data, the expertise and resources required to manage safety concerns, and the wisdom of waiting for further randomized controlled trial results.
Addressing the challenges
In light of the challenges posed by these emerging therapeutics for AD, Prof Vijay Ramanan (Mayo Clinic, Rochester, USA) discussed some of the workflow implications. Adaptions will be needed by providers and practice settings, with multidisciplinary local stakeholder engagement and shared decision-making with patients and care partners. Dr Tammie Benzinger (Washington University School of Medicine, St. Louis, USA) presented a standardized MRI acquisition protocol that can be used to facilitate monitoring and assessment of ARIA in the real-world setting and harmonize collection of longitudinal data.
A combination of disease-modifying treatments will be required
All the contributors agreed that amyloid beta is just the tip of the iceberg, and therapies will also be needed that focus on targets such as tau and the inflammatory process. They suggested that a combination of disease-modifying treatments will be required to make a significant impact on the clinical course of AD due to the complex pathology of the disease.