Cognitive Health of the Asian Population
The prevalence of poor mental health in Singapore has increased from 13.4% in 2020 to 17% in 20221, according to the National Population Health Survey 2022. In another survey by the National University of Singapore in 2022, findings revealed that about one in three youth in Singapore has reported internalising mental health symptoms such as sadness, anxiety and loneliness2. Amidst this growing concern, Singapore launched a national mental health and well-being strategy on 4 October 2023, which adopted a multi-pronged approach to tackle mental health issues3.
At the frontline of cognitive genomic precision medicine is Assistant Professor Max Lam, Deputy Science Director for Precision Health Research, Singapore (PRECISE)’s PRECISE-SG100K study4, and the Principal Investigator of the COgnitive functioN in psyChiatric IllnesSEs (CONCISE) mental health study at Institute of Mental Health. Also leading the PRECISE-SG100K Cognitive Health Flagship Project, Dr Lam and his team are looking to contribute towards the field through introducing novel treatment strategies for cognitive-related disabilities and identifying segments of patients amenable to specific treatment strategies.
Challenges in Studying Cognitive Genetics
Dr Lam shared, “During my early years as a psychologist working with patients and their families, I noticed that many patients faced significant cognitive challenges. While psychiatric medications were effective in managing symptoms, they often did not improve cognitive function. This observation highlighted a critical gap in treatment and inspired me to explore solutions that could better address cognitive difficulties in psychiatric patients.”
Dr Lam’s search for a solution led him to deep dive into the biology underpinning these issues, and ultimately, the emerging field of genetics. Dr Lam said, “In 2010, large-scale precision medicine efforts were nascent. Hence, while our research effort was considered ambitious then, it was modest by the standards of precision medicine today. More importantly, it was clear that if we want to answer the question ‘Are there any drug targets that can help address cognitive issues?’, we would need to look into the genetic architecture of psychiatric illness as well as how genetics might be associated with cognitive function in the normal population.”
It proved to be challenging to study cognition in clinical populations because findings could be impacted by clinical interventions such as medicine and treatments. “To overcome the problem, we studied healthy people instead. We looked at their cognitive function and how their genetics predict cognitive function. Concurrently, we also studied the genetics of psychiatric illness. By merging both research streams and locating the intersection for these two groups, we have found some genes that are likely associated with cognition and illness. The next step would be to identify, within this smaller subset of genes, which would make good drug targets for rescuing cognitive function in mental illness,” Dr Lam explained.
The Case for Large-scale Cognitive Genomics Analyses
Despite making positive progress, Dr Lam's journey is far from nearing its end. He said, “We are just about to drill into the exciting part. Unlike medical conditions like Huntington’s disease or Spinal Muscular Atrophy (SMA) where clear genetic signals exist, the genetic architecture of psychiatric illnesses is much more complex. That means no one biomarker or gene is solely responsible for the disease—it’s likelier that hundreds or even thousands of genes are relevant. With the PRECISE-SG100K study and the large number of phenotype data points we are getting from each consented participant, we can begin to develop and examine the use of genetic risk scores in cognitive and mental health for the first time.”
The availability of a polygenic risk score not only holds the promise of opportunities for early disease intervention and prevention but also reduces healthcare costs for both the patient and the healthcare system. Dr Lam elaborated, “Present treatment guidelines for schizophrenia do not differentiate patient profiles, but some patients do not respond to first- and second-line antipsychotic treatments—they are generally more ill with more disability and have a higher rate of hospitalisations. Recently, we found that polygenic risk scores are potentially helpful in identifying patients with treatment resistance. We are now trying to validate this finding.”
The Importance of Translating Knowledge into Clinical Practice
Having been in psychiatric research for over a decade, Dr Lam knows that groundbreaking research findings matter only when translated into clinical practice. “The development and findings from these large-scale studies are not translating fast enough into the clinical settings. Rather than treating patients symptomatically with drugs, if we could leverage genetics to impact therapy strategy and treatment outcomes, we would gain an extra arsenal in our battle against mental illnesses,” said Dr Lam.
The potential impact is substantial, offering benefits to both the healthcare system and patients. Dr Lam noted, “Clinicians are highly skilled in diagnosing conditions like schizophrenia and depression, but additional insights into how a patient might respond to specific treatments or their likely diagnostic journey over time would be invaluable. For example, understanding whether a patient initially presenting with anxiety disorder might develop other conditions such as severe depression, early psychosis, or bipolar disorder, could greatly enhance personalised treatment plans. While some patients may experience a stable clinical trajectory, these predictive insights are currently limited for many clinicians.”
Dr Lam continued, “The answers however could be found in genetics. That is why we are hoping to put together a mental health study (CONCISE) of 10,000 individuals using parallel technologies that PRECISE-SG100K is using so that we can carry out data comparison and scale it alongside the National Precision Medicine (NPM) programme. We are also exploring the possibility of monitoring cognition fluctuations in real time through wearables—then mapping this information back to genetics to see if there are any genetic predictors for cognition profiles.”
The Future of Cognitive Disorders in the Asian Population
Dr Lam notes that PRECISE-SG100K is the only large-scale Asian national effort systematically collecting cognitive data. He elaborated, “None of the Asian biobanks or precision medicine cohorts is collecting cognitive and whole genome sequencing data at this scale; with PRECISE-SG100K, there is a huge opportunity for Singapore to lead in the field.”
“In addition, there is increasing evidence that cognitive function is linked to other health ailments like diabetes and cardiometabolic health. Given that we are collecting detailed and comprehensive data on other health variables and phenotypes in PRECISE-SG100K, we are in a strong position to systematically delve into how physical health, psychopathology, cognition, and genetics interface with one another. With that understanding, we can then treat and prevent diseases in a more holistic manner,” said Dr Lam.
Dr Lam said, “Years on—I am still passionate about finding the answer
to my first question, ‘Do we have drugs or therapy to rescue ability-related
cognitive problems?’ I hope that the first drug for rescuing cognitive
function could be discovered in Singapore.”
[1] National Population Health Survey 2022
[3] S’pore launches national mental health and well-being strategy (The Straits Times, 6 Oct 2023)
[4] PRECISE-SG100K