Team NANOPATH
Dementia frontiers fund
Multi-modal nanoscopic and molecular mapping and modelling of human neurodegenerative disease progression.
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Led by
Dr Annelies Quaegebeur (University of Cambridge)
Locations
UK
Research question
What are the relative contributions of different brain pathologies to the development of dementia?
Research institutions
2
Together with
Professor David Klenerman (University of Cambridge), Dr Georg Meisl (University of Cambridge), Professor Joanne Jones (University of Cambridge) and Professor Sonia Gandhi (University College London)
Project summary
This project seeks to redefine understanding of dementia progression by investigating the earliest molecular events that drive neurodegeneration, focusing on nanoscopic protein aggregates that emerge long before the large pathological inclusions detected by conventional neuropathology.
The central hypothesis is that these small protein assemblies, rather than mature deposits, initiate disease processes that subsequently lead to synaptic dysfunction, cellular stress responses and cognitive decline.
The programme further proposes that mixed pathologies involving amyloid-β, tau, α-synuclein and TDP-43 arise through convergent biological mechanisms rather than independent processes.
Using 100 well-characterised post-mortem brains spanning the full spectrum of Alzheimer’s disease neuropathological change, the researchers will generate a detailed atlas of protein aggregation, synaptic pathology and molecular responses across multiple brain regions and disease stages.
Advanced single-molecule imaging, super-resolution microscopy, single-nucleus transcriptomics and spatial proteomics will be used to characterise aggregate formation, synapse loss, neuroinflammation and cellular stress pathways. Particular emphasis will be placed on understanding how co-pathologies influence protein propagation, clearance mechanisms and synaptic vulnerability.
The project will integrate these data into quantitative mathematical models describing the formation, spread and removal of pathological proteins across the brain. By establishing biologically grounded frameworks for disease progression, the research aims to identify novel biomarkers, improve disease staging and reveal new therapeutic targets for precision interventions in dementia.
Plain English summary
This project is studying the very first biological changes that occur in dementia, before significant brain damage develops. The researchers are focusing on tiny clusters of harmful proteins that may trigger disease many years before symptoms appear.
By understanding how these proteins form, spread and interact, the team hopes to improve early diagnosis and identify new targets for treatment.
Potential future impact
This research could transform understanding of the earliest stages of dementia by revealing how small protein aggregates form, interact and spread through the brain before significant damage occurs.
By uncovering how disease-related proteins contribute to disease progression, the project may identify distinct biological subtypes of dementia and explain why some people experience more rapid decline than others.
The detailed models generated through this work could support the development of earlier and more accurate diagnostic tools, helping to identify patients at the most appropriate stage for intervention.
In the longer term, the findings may enable more precise patient stratification and inform the development of targeted therapies tailored to the underlying biology of an individual's disease.