Irish scientists discover mutations associated with early onset dementia

Scientists at Trinity College Dublin (TCD) have discovered mutations associated with early onset dementia that may lead to better understanding of how Alzheimer's disease occurs.

Although the form of early onset dementia known as leukoencephalopathy is extremely rare, the team has identified the role genetic mutations play in generating dysfunctional white blood cells circulating around the body.

Investigating the role these may play in dementia could unlock potential treatments.

There is no cure for these neurodegenerative conditions, and Alzheimer's is the seventh leading cause of death in the world, according to the World Health Organisation.

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The full name of the condition investigated in TCD is adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), and it is characterised by mutations in a gene called colony stimulating factor-1 receptor (CSF1R).

It manifests itself 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 disease is extremely rare, it can be a devastating diagnosis for families.

As the condition involves degeneration of white matter in the brain, scientists previously thought immune cells within the brain called microglia were the primary culprits.

However, the Trinity team was able to show defective circulating white blood cells were the key drivers of neurodegeneration, which went on to impact on brain function.

"Our findings have shed light on a novel mechanism of neurodegeneration that may ultimately teach us more about common forms of dementia," said Dr Matthew Campbell of the TCD school of genetics and microbiology.

“Importantly, the work identified a disruption in CSF1R function in patients . . . [that] 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.”

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, he added.

“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.

"The most exciting aspect of our study is that we have now honed in on a novel pathway that to date has not been explored in great detail," said postdoctoral research fellow Dr Conor Delaney, first author of a study outlining the breakthrough published in the journal EMBO Molecular Medicine this week.

“Additionally, our data suggest that modifying white blood cell function may be therapeutically relevant for progressive neurodegenerative conditions,” he pointed out.

A team of geneticists, immunologists, neurologists and neuropathologists from Trinity, the Royal College of Surgeons in Ireland, University College Cork, Sligo General Hospital and the University of Ghent undertook the study.

TCD professor of epilepsy Colin Doherty said: "It is absolutely critical that we focus our research endeavours on identifying the underlying cause of neurodegenerative conditions. Studies like these will pave the way for better clinical management of our patients and hopefully new medicines to treat the condition."

The research was supported by the Irish Research Council, Science Foundation Ireland-Future Neuro Centre, St James's Hospital foundation and the Ellen Mayston Bates bequest.