Team ALGEBRA
Dementia Frontiers fund
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Led by
Dr Sourena Soheili-Nezhad (Radboud University Medical Center), Professor Christos Proukakis (University College London) and Professor Floris Foijer (European Institute for the Biology of Ageing)
Locations
The Netherlands and UK
Research institutions
3
Together with
Professor Christian Gilissen (Radboud University Medical Center), and Associate Professor Zane Jaunmuktane (University College London)
Project summary
This project will investigate whether DNA damage and somatic mutations that accumulate in brain cells during ageing contribute to the development and progression of Alzheimer’s disease (AD).
While inherited genetic risk factors have improved understanding of AD susceptibility, the potential role of age-related genomic instability within neurons and glial cells remains poorly understood.
The programme aims to generate a high-resolution map of genomic vulnerability in AD by identifying mutational hotspots and DNA damage signatures across different brain regions and cell types.
Using post-mortem tissue from individuals with AD and age-matched controls, the researchers will isolate neuronal and glial populations and apply long-read whole-genome sequencing, ultra-high-fidelity sequencing approaches and genome-wide DNA damage mapping technologies.
These methods will enable detection of several classes of genetic mutations, including single nucleotide variants, insertions and deletions, structural variants, tandem repeat length variations, copy number changes and DNA double-strand breaks.
Computational modelling will be used to characterise DNA damage patterns and identify genomic regions that are disproportionately affected in AD.
The project will also validate key findings at single-cell resolution, linking genomic damage to specific vulnerable cell populations. By uncovering previously unrecognised genetic mechanisms underlying neurodegeneration, this work could reveal novel therapeutic targets, improve understanding of disease progression and establish whether genomic instability represents a significant contributor to AD pathogenesis.
Plain English summary
As we age, our brain cells gradually accumulate changes in their DNA. This project will investigate whether some of these changes contribute to Alzheimer’s disease and whether certain parts of the genome are especially vulnerable.
By understanding these patterns of DNA damage, the team hopes to uncover new ways to identify, predict and ultimately treat the disease.
Potential future impact
This research could establish whether accumulated DNA damage and mutational hotspots are important drivers of Alzheimer’s disease.
By identifying the regions of the genome most vulnerable to damage, the project may uncover previously unknown biological pathways involved in neurodegeneration and reveal novel targets for therapeutic intervention.
The resulting maps of genomic vulnerability could improve understanding of why some brain cell types are more susceptible to disease than others.
In the longer term, if these genomic signatures can also be detected in DNA fragments circulating in blood or cerebrospinal fluid, they could form the basis of new biomarkers for earlier diagnosis, monitoring disease progression and supporting more personalised approaches to treatment.