Researchers Uncover a Major Driver of Dementia

Huntington’s disease may be linked to a toxic build-up of urea in the brain.

Although dementia affects numerous individuals across the globe, there is much that remains unknown about the cause of the condition and, importantly, what can treat it.

A team of researchers recently discovered a significant cause of dementia, which may result in advancements for treatments and diagnoses, according to a study published by the Proceedings of the National Academy of Sciences.

The study authors found that toxic build-up of urea can result in brain damage that can progress to dementia.

Previously, the team of researchers found a link between Huntington’s disease, other neurocognitive conditions, and type 2 diabetes. In the new study, the authors showed how Huntington’s disease—a type of age-related dementia—is strongly associated with urea levels in the brain and other metabolic processes.

The study also suggested that urea levels were elevated prior to the onset of dementia, which may provide physicians with a way to diagnose and treat the condition prior to the brain sustaining significant damage.

“This study on Huntington’s disease is the final piece of the jigsaw which leads us to conclude that high brain urea plays a pivotal role in dementia,” said researcher Garth Cooper, DPhil, DSc, FRCPA, FRSNZ, FMedSci. “Alzheimer’s and Huntington’s are at opposite ends of the dementia spectrum — so if this holds true for these types, then I believe it is highly likely it will hold true for all the major age-related dementias.”

Both urea and ammonia are metabolic byproducts of protein breakdown. Urea is commonly excreted from the body in urine; however, if urea and ammonia build up due to kidney dysfunction, patients can experience serious complications, according to the authors.

The authors used gas chromatography mass spectrometry to measure urea levels in donated human brains from deceased patients and transgenic sheep. Toxic levels of urea were defined as at least 4 times higher than normal.

“We already know Huntington’s Disease is an illness caused by a faulty gene in our DNA - but until now we didn’t understand how that causes brain damage — so we feel this is an important milestone,” Dr Cooper said.

Notably, there are current drugs used to treat high levels of urea. If similar drugs can lower brain levels of urea, it may open the door to a cure for dementia.

“Doctors already use medicines to tackle high levels of ammonia in other parts of the body Lactulose, a commonly used laxative, for example, traps ammonia in the gut. So it is conceivable that one day, a commonly used drug may be able to stop dementia from progressing. It might even be shown that treating this metabolic state in the brain may help in the regeneration of tissue, thus giving a tantalizing [sic] hint that reversal of dementia may one day be possible.”

The authors noted that gaining a better understanding of the cause of high urea levels will be a key point of future studies, according to the study.

“More research, however, is needed to discover the source of the elevated urea in [Huntington’s disease], particularly concerning the potential involvement of ammonia and a systemic metabolic defect,” Dr Cooper said. “This could have profound implications for our fundamental understanding of the molecular basis of dementia, and its treatability, including the potential use of therapies already in use for disorders with systemic urea phenotypes.”