Mutations Behind Rare Form Of Early-Onset Dementia Identified

New research has revealed how mutations could cause a rare form of early-onset dementia. Orawan Pattarawimonchai/

A new study has identified two mutations behind an “ultra-rare” form of early-onset dementia, called Adult onset Leukoencephalopathy with axonal Spheroids and Pigmented glia (ALSP). ALSP is a progressive disease where the white matter in the brain degenerates. Initial symptoms are psychiatric and behavioral changes, with those affected suffering from rapid progression of dementia in their thirties or forties.

“Our findings have shed light on a novel mechanism of neurodegeneration that may ultimately teach us more about common forms of dementia," said Associate Professor at Trinity College Dublin Dr Matthew Campbell in a statement.

Researchers identified two families with ALSP, and analyzed post-mortem brain samples taken from them. They identified two mutations in the CSF-1R gene, which codes for the colony stimulating factor-1 receptor (CSF1R). These mutations decrease signaling activity, and this induces disruption of the blood-brain barrier.


Researchers also discovered that the mutation caused dysfunction in macrophages, a type of white blood cell that engulfs and removes debris. In mouse studies, ALSP macrophages showed a reduced response to amyloid-β, which makes up a large part of the amyloid plaques found in Alzheimer’s disease patients. The authors claim that this diminished response may lead to the gradual accumulation of amyloid-β in the brain. The first author of the study Dr Conor Delaney explained that "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. Additionally, our data suggest that modifying white blood cell function may be therapeutically relevant for progressive neurodegenerative conditions."

Previously, inhibition of CSF1R signaling has been suggested as a potential therapeutic method for Alzheimer’s disease patients. The authors of this study warn that based on these results, this approach may actually do more harm than good, making the disease worse.

There is a lack of approved therapies for Alzheimer’s and similar conditions. Understanding the processes and pathways that cause them could lead to better treatment options in the future. Professor Colin Doherty says that "It is absolutely critical that we focus our research endeavors 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."


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