Discovery of mutations associated with early onset dementia

Principal Investigator with FutureNeuro and Associate Professor at Trinity College Dublin, Dr Mattthew Campbell and his team, have discovered mutations associated with early onset dementia that may lead to better understanding of how Alzheimer’s disease occurs.

Adult onset Leukoencephalopathy with axonal Spheroids and Pigmented glia (ALSP) is an ultra-rare condition characterised by mutations in a gene called Colony stimulating factor-1 receptor (CSF1R).

The condition manifests initially with psychiatric and behavioural changes in patients followed by a rapid progression of dementia in the third or fourth decade of life. While the condition is very rare, for affected families it can represent a devastating diagnosis.

As the condition involves the degeneration of white matter in the brain, scientists previously thought that immune cells within the brain termed microglia were the primary culprits in driving pathology observed in this condition.

However, this multidisciplinary team, working with patient samples as well as pre-clinical models, were able to show that dysfunctional circulating white blood cells were the key driver of neurodegeneration.

Dr Matthew Campbell, FutureNeuro and TCD, said:

“This was fundamentally a translational research project, where data obtained from patient samples critically informed the direction of our pre-clinical studies. Our findings have shed light on a novel mechanism of neurodegeneration that may ultimately teach us more about common forms of dementia.”

Importantly, the work has identified that a disruption in CSF1R function in patients, as well as in pre-clinical models, induces damage to the so-called blood-brain barrier (BBB).

This damage can subsequently change the integrity of capillaries in the brain, causing them to leak and spark the deterioration of the brain. Intriguingly, dysfunctional white blood cells seem to be the main driver of this BBB breakdown.

Unfortunately, there are currently no approved therapies for conditions such as Alzheimer’s disease, which is in part due to the lack of a robust understanding of the early initiators of disease. If we can better understand what the early hallmarks of Alzheimer’s are, we may be able to develop novel forms of therapy that target these newly discovered mechanistic pathways.

A multidisciplinary team of geneticists, immunologists, neurologists and neuropathologists from Trinity, the Royal College of Surgeons Ireland (RCSI), University College Cork (UCC), Sligo General Hospital and the University of Ghent undertook the study. To see the full findings click here. 

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