'Dementia, the No.1 Disease Feared by the Elderly, Will a Cure Emerge Within 10 Years? [Reading Science]'

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[Asia Economy Reporter Kim Bong-su] "'Dementia, known as the most cruel farewell,' when will a treatment be available?"

This is not an easy question. Dementia is a major concern not only for individuals but also for families and society as a whole in the era of population aging. Early diagnosis is difficult. The exact causes and mechanisms have not yet been identified, so it remains an 'incurable disease.' As of 2019, the number of dementia patients in South Korea reached approximately 790,000 and is rapidly increasing every year, with projections to surpass 3 million by 2050. Families with one dementia patient must spend about 20 million KRW annually on care costs. This also places a heavy burden on welfare finances. As of 2019, the national dementia management cost was 16.5 trillion KRW, expected to rise to 63.1 trillion KRW by 2040. This means more than 10% of the national budget will be required.

Accordingly, major countries worldwide are accelerating research on dementia treatment. South Korea launched the Dementia Overcoming Research and Development Project Group (KDRC) in August 2020, planning to support a total of 198.7 billion KRW by 2028 for the development of dementia diagnostic technologies and treatments. The specific goals are 'delaying dementia onset by 5 years and reducing the annual increase rate of dementia patients by 50%,' with efforts to initiate clinical phase 3 trials for treatment development. With concentrated national investment, advances in medical science, and integration of cutting-edge ICT technologies, there have been revolutionary improvements in research methodologies. Due to limitations of animal model experiments, research using organoids and human-derived tissues is actively pursued. Efforts continue to complement existing research results to enable accurate diagnosis and prescription. Experts predict that groundbreaking results for fundamental treatment may emerge within 10 to 20 years.

The following is a Q&A that can help clarify questions about dementia. With the assistance of the National Research Foundation of Korea, a written interview was conducted with Professor Seo Young-ho of Seoul National University College of Medicine and then organized and supplemented.

◇ Why is dementia frightening?

Dementia refers to a condition where a person who was living normally experiences impairments in various cognitive functions, including memory loss, making it difficult to live independently. Causes can include various diseases such as Alzheimer's type dementia, cerebrovascular disease, Lewy body dementia, frontotemporal degeneration, and normal pressure hydrocephalus, but Alzheimer's type dementia is the most representative. In 1906, Dr. Alois Alzheimer (1864-1915) treated a 51-year-old female patient named Auguste Deter who showed symptoms such as short-term memory loss in 1901. Five years after the patient's death, brain autopsy revealed neurofibrillary tangles inside nerve cells and amyloid plaques outside nerve cells in the cerebral cortex. Since then, this disease has been called Alzheimer's disease. The main component of the amyloid plaques found in Dr. Alzheimer's autopsy was later identified as beta-amyloid peptide, and the main component of neurofibrillary tangles as tau protein. To this day, the hypothesis that cognitive impairment is caused by neuronal death due to deposition of beta-amyloid and tau proteins is widely accepted as the cause of dementia.

Dementia is frightening because memory decline makes independent living difficult. Unlike skin cells, nerve cells cannot regenerate; once nerve cells die, they cannot be restored. This means that by the time dementia is diagnosed, a significant number of nerve cells have already died, and the disease inevitably progresses gradually. Moreover, cognitive functions such as language and judgment also decline. Changes in sleep patterns, mood, personality, and behavior make communication and normal daily life difficult. Each year, new research and treatments deepen scientific understanding of dementia and increase social interest, so with appropriate support, an active and healthy life can be maintained.

◇ Do we still not know the cause of dementia?

Dementia occurs due to the death of cerebral cortex nerve cells, but the cause is the problem. (Beyond the existing beta-amyloid + tau protein deposition hypothesis,) recently, scientific hypotheses have been proposed that nerve cells die due to dysfunction of microglia or astrocytes. Microglia are immune cells in the central nervous system that activate in response to inflammation, infection, or injury in the brain, similar to macrophages in peripheral organs. They protect nerve cells by removing dying neurons and tissue debris and secreting survival factors. Astrocytes support nerve cells by supplying nutrients, removing waste, and regulating ion and neurotransmitter concentrations, thus maintaining homeostasis.

Recent research indicates that microglia and astrocytes can regulate the development of synapses in nerve cells. Microglia, astrocytes, and oligodendrocytes are types of glial cells, which are about four times more numerous than nerve cells and constitute about 80% of cells in the human brain. Therefore, the hypothesis that abnormalities in these glial cells (even if nerve cells themselves are normal) can lead to nerve cell death is plausible. However, like the chicken and egg debate, there are still many hypotheses and controversies about the primary cause of dementia, and much new research is ongoing.

◇ Why are dementia patients rapidly increasing recently, and what are the prevention methods?

Dementia is not simply an elderly disease that naturally occurs with aging, but age is the biggest risk factor for dementia. In other words, as average life expectancy has increased compared to the past, the incidence of dementia patients has also increased. Besides genetic predisposition, lifestyle-related risk factors that increase dementia risk include lack of exercise, obesity, smoking, hypertension, hypercholesterolemia, and diabetes. These are similar to risk factors for heart disease. Therefore, regular exercise, a healthy diet low in saturated fats, avoiding excessive drinking, and controlling and treating hypertension, diabetes, and hypercholesterolemia are helpful. Social interaction, reading, light dancing, board games, artistic activities, and playing musical instruments are also known to help prevent dementia.

◇ What is the most difficult challenge in dementia treatment research?

By the time of diagnosis, a significant number of nerve cells have already died and cannot be restored. Early detection is important. Also, currently, there is no clear method (fundamental treatment) to dramatically halt the progression of dementia. The causes and mechanisms are complex and vary among patients, making it difficult to develop fundamental treatments targeting the onset mechanisms.

Based on existing research, amyloid plaques and neurofibrillary tangles exhibit neurotoxicity and can cause nerve cell death, so many attempts have been made to remove them to halt disease progression. Recently, monoclonal antibody drugs targeting beta-amyloid removal, such as Biogen's Aducanumab approved by the U.S. Food and Drug Administration (FDA), Eli Lilly's 'Donanemab' under approval application, and Biogen/Eisai's 'Lecanemab,' are being developed for this purpose.

◇ The need for new research methodologies is being raised

A significant portion of Alzheimer's dementia research results have been based on animal models. However, recently, scientists increasingly believe that mouse models, due to their short lifespan (2 years) and other factors, are quite distant from actual human dementia. Animal models do not adequately reflect the complex biological changes occurring during dementia onset and progression, and treatments effective in animals often fail to show efficacy in humans.

Therefore, there is a trend to produce brain organoids using human-derived induced pluripotent stem cells for experiments. These have the same genetic background and can include not only nerve cells but also glial cells. This creates an environment most similar to the actual patient's brain and can be used as a standard platform for dementia research. The U.S. National Institutes of Health (NIH) has launched the INDI project to establish and distribute induced pluripotent stem cell lines with dementia gene mutations. Domestic experts also emphasize the necessity of this approach.

Recently, a research team at GIST (Gwangju Institute of Science and Technology) reported that applying 40Hz ultrasonic vibrations for 2 hours a day to a mouse model resulted in a reduction of dementia-causing substances and improvement of symptoms. Image courtesy of GIST.

◇ When will dementia treatments be developed?

Under the Moon Jae-in administration, the National Responsibility System for Dementia was implemented. Although public attention waned somewhat due to COVID-19, the Dementia Overcoming Research and Development Project Group was launched in August 2020. Significant resources and efforts are being devoted to dementia research and treatment development. Many neuroscientists worldwide, including in South Korea, are striving to develop dementia treatments, so while it will not be easy, good results can be anticipated.

However, dementia is generally a degenerative disease that progresses slowly over 8 to 10 years. Therefore, research requires substantial time and cost. A system must be established to facilitate researchers' easy access to dementia research resources and testing of treatment targets.

Meanwhile, the Dementia Overcoming Research and Development Project Group plans to start clinical phase 1 trials for treatments within this year and enter clinical phase 3 by 2028, along with goals to commercialize early diagnosis and disseminate prevention programs.