Nabbing the Genetic Culprit in Asian dementia

The discovery of an Asian variant of the NOTCH3 gene opens the doors for a precision medicine approach to young-onset dementia.

Have you ever been teased by your friends because you left your earphones at home or you forgot someone’s birthday? You must be getting old, they joke. While forgetfulness is often dismissed as merely a sign of ageing, in younger adults, it could hint at a more serious medical condition: dementia.

Caused by a lack of blood flow to the brain, vascular dementia refers to a broad class of symptoms that affect mental ability, leading to impaired memory, logic and attention, sometimes even triggering volatile moods that affect social interactions. While generally a condition of old age, several forms of vascular dementia, particularly those that are genetic and heritable, can arise in younger adults.

In Singapore, an increasing number of young people in their 40s and 50s have been diagnosed with vascular dementia. In a 2020 interview1 with SingHealth, Associate Professor Nagaendran Kandiah, Senior Consultant at the National Neuroscience Institute’s Department of Neurology, said that genes play a bigger role in young-onset dementia, explaining some 20 to 30 percent of cases, as opposed to only five percent in the elderly.

Because it combines the traditional factors of family history, brain imaging and blood chemistry with cutting-edge genetic analysis, precision medicine could potentially facilitate the early detection of dementia in young adults. But the lack of studies in Asians leaves precision medicine with few genetic culprits to look for.

A genetic suspect

In a recent study2, a group of researchers created their own custom-designed screening panel containing 200 neurodegeneration-related genes, in hopes of finally pinning down a potential genetic explanation for young-onset dementia in a subset of this population.

Led by Dr Adeline Ng of the National Neuroscience Institute, the team, which included investigators from Lee Kong Chian School of Medicine, A*STAR, and SingHealth Duke-NUS Institute of Precision Medicine, recruited adults of Southeast Asian descent suspected to have an inherited form of vascular dementia.

By combining their custom gene panel with magnetic resonance brain imaging, they found that 20 of the 45 participants—most of whom were predominantly Chinese—indeed had tiny alterations in their genes that were either disease-causing or predicted to have a similar effect. This translated to a diagnostic yield of 44.4 percent, meaning that of 10 young adults coming into the clinic with signs of possible genetic dementia, at least four will leave with a definitive diagnosis.

Surprisingly, 17 of the 20 genetic diagnoses were of CADASIL, a rare form of vascular dementia caused by mutations to the NOTCH3 gene. As they looked deeper into these mutations, the researchers saw that 76.5 percent of their CADASIL patients harboured a particular variant of NOTCH3 called R544C, a mutation predominantly seen in East Asians.

“We found that CADASIL remains the most common cause of inherited vascular dementia in Singapore, and that the most common variant seen in our CADASIL cases was the ‘East Asian’ NOTCH3 R544C variant,” Ng said. “This changes practice as we now have a specific target we can look at for detecting vascular dementia early.”

The identification of this specific variant of interest opens up the possibility of a precision medicine approach to dementia in young Asian adults, which will allow doctors detect these conditions earlier and help scientists come up with specific and more effective treatments.

Catching community carriers

Not only is CADASIL genetically distinct in Asians, but Ng and her team also showed that the unique NOTCH3 R544C variant led to notable differences in how the disease progressed.

For example, whereas Western CADASIL patients typically suffer from erosion in the anterior temporal regions of the brain—the parts responsible for memory and language—this phenomenon was markedly less common in Asian counterparts.

The research team noticed clear differences in warning signs, too. Thirty-five percent of participants with genetically confirmed CADASIL had abnormalities in their movement and motor skills, a set of symptoms collectively called parkinsonism. In three patients, parkinsonism was even the very first symptom to manifest. In contrast, parkinsonism is seen as a hallmark of advanced CADASIL in Western patients; rarely manifesting early in the course of the disease.

But pinning down a potential genetic cause and delineating racial differences underlying young-onset dementia in Asians is only the first step, Ng said. After all, the ultimate goal of precision medicine is to translate deeper and more context-specific knowledge of diseases into better care and outcomes for patients.

To this end, her team has started establishing a national baseline by measuring just how widespread the Asian NOTCH3 variant is in Singapore. Looking farther ahead, Ng added, “We need resources to determine if these carriers in the community can be screened for vascular cognitive impairment through clinical evaluation and neuroimaging, as well as given appropriate genetic counselling and treatment plans.” In the future, as precision medicine becomes embedded in Singapore’s clinics, screening for genetic dementia could become routine practice, ensuring early detection for all.

References:

1 More here diagnosed with young onset dementia, says NNI [Online]. https://www.singhealth.com.sg/news/tomorrows-medicine/more-here-diagnosed-with-young-onset-dementia-says-nni

2 Chen, Z., Tan, Y.J., Lian, M.M., Tandiono, M., Foo, J.N., et al. High Diagnostic Utility Incorporating a Targeted Neurodegeneration Gene Panel With MRI Brain Diagnostic Algorithms in Patients With Young-Onset Cognitive Impairment With Leukodystrophy. Frontiers in Neurology 12:631407 (2021).