The big picture: Describe your vision for a game-changing future technology. Why is it new? What difference would it make for Europe's economy, society and citizens?

There exists no disease-modifying therapy for Alzheimer’s disease.  All approaches to treatment of advanced Alzheimer’s have failed, in part due to irreversible damage to parts of the brain that are associated with memory.  Focus in Alzheimer’s research is therefore shifting from treatment of advanced disease to early detection of markers of disease combined with early therapeutic intervention of high-risk individuals.  In order to do so, novel, extremely sensitive methods are required to detect disease markers ten to twenty years before the onset of cognitive decline.  One promising candidate for such a disease marker is amyloid-beta, a peptide that forms aggregates and accumulates in the form of senile plaques in the brain of Alzheimer’s patients.  The presence of these amyloid plaques is indeed one of the hallmarks of the disease, as described by Dr. Alois Alzheimer more than 100 years ago.

The latest research in the field of Alzheimer’s disease and amyloid-beta shows that small soluble oligomers of amyloid-beta are the most neurotoxic forms of amyloids.  These oligomers appear, however, in various sizes and shapes and it is clear that both characteristics influence their toxicity.  Therefore, there exists an urgent need for sensitive detection of amyloids in biofluids with the capability to determine exactly the shape and size of each amyloid aggregate.  Fulfilling this requirement is an extremely challenging problem because amyloid-beta exists in all sizes and shapes starting from monomers and ending with long fibers.  Due to this extreme heterogeneity in size and shape, no existing analytical technique is able to characterize small quantities of aggregated amyloids in biological solutions with adequate detail, sensitivity, and speed.  What makes matters worse, is that amyloid aggregation is time-dependent such that samples containing amyloids changes over time, likely loosing diagnostic information unless freshly obtained patient samples can be analyzed before these changes occur.

The work needed: What are the main breakthroughs that a proactive initiative on this would need to achieve? What range of disciplines and stakeholders should be involved?

What is therefore needed is a novel bioanalytical platform technology for rapid amyloid characterization on a single molecule and single aggregate level.  Only a technique capable of characterizing individual amyloid particles in high throughput will overcome the problem of heterogeneity in size and shape.  And only a solution-based, point-of-care diagnostic platform will be sufficiently fast to provide a meaningful assessment of the concentration of specific neurotoxic oligomers before ongoing aggregation destroys the disease-specific information content of the sample.

The opportunity: What makes you believe that, with suitable time and investment, this can be achieved? Are there developments in science or society that make it plausible? What will drive this to real innovation and impact?

The advent of optical and electrical single molecule detection techniques, combined with advanced computational tools for signal analysis and interpretation is now making it possible to develop such an advanced bioanalytical platform for molecular characterization of single amyloid aggregates in solution.  In order to overcome, however, the significant challenges and to meet the requirements of rapid point-of-care detection of amyloids with sub-nanomolar sensitivity in cerebrospinal fluid and in peripheral blood samples, a concerted effort from a broad range of disciplines is needed.  These include neurology, single molecule optics, single molecule electrical detection techniques, biophysics, biochemistry, analytical chemistry, materials science, computational analysis, software development, and device design.

Once developed, such a diagnostic platform has the potential to encourage early therapeutic intervention with drugs that have already been tested for Alzheimer’s treatment but were applied too late to change the course of the disease, despite promising effects in reducing the amyloid burden in Alzheimer’s patients.  Moreover, the same diagnostic platform may be able to detect other amyloids than amyloid-beta, which have been associated with Parkinson’s disease, Huntington’s disease, and diabetes mellitus.

Enabling a disease-modifying intervention as well as monitoring the efficacy of therapeutics based on a meaningful biomarker for these devastating neurodegenerative diseases would tremendously benefit society.  The medical community in the field of neurodegenerative diseases is waiting for such an early diagnostic approach.