Conquering the Enemy of an Aging Society, 'Dementia': How Much Time Is Left? [Reading Science]

Development of Fundamental Therapeutics, Aducanumab Approval Leading Full-Scale R&D
152 Candidate Therapeutics Under Global Trials, 85% Aimed at Fundamental Treatment
Urgent Need for New Methodologies and Advanced Technologies to Overcome Existing Experimental and Research Limitations with Government Focused Support

[Asia Economy Reporter Kim Bong-su] "I have been taking care of my father, who has been suffering from Alzheimer's dementia for 10 years, alone, separated from the family. Every time I see my father becoming more violent and turning into a child, I have extreme thoughts. Please tell me when a cure will be available." (Family member A of a domestic dementia patient)

This is the true face of dementia, nicknamed 'the cruelest farewell.' Dementia refers to symptoms of degenerative behavior caused by the death of brain cells due to various diseases. In particular, Alzheimer's dementia is the most common, accounting for the majority (74.9%) of dementia patients aged 65 and older in Korea. Other types include vascular dementia caused by stroke, Lewy body dementia (Parkinson's disease), and secondary dementia (sequelae of various diseases). Alzheimer's dementia, which accounts for most dementia cases, is considered to be close to 'conquest.' Currently, 'fundamental treatments' that can remove causative substances and improve symptoms are being actively researched worldwide. Experts expect groundbreaking progress within 10 to 20 years.

◇Current Status of Existing Drug Development

The exact cause and mechanism of Alzheimer's dementia have not yet been clarified. Currently, drug therapies that regulate neurotransmitters in the brain are used under the approval of the U.S. Food and Drug Administration (FDA) for symptom improvement. The acetylcholinesterase inhibitors (ACEIs), approved by the FDA in 1993, are representative. In normal individuals, the neurotransmitter acetylcholine is properly secreted from brain nerve cells, maintaining memory and learning. However, in the brains of Alzheimer's dementia patients, the synthesis and metabolism of this substance are significantly reduced. Accordingly, three drugs with acetylcholinesterase inhibitory effects?Donepezil, Rivastigmine, and Galantamine?are used. When used in early to middle stages, they are known to slow progression for about 6 to 24 months and show some effects, but there is no precise statistical evidence.

Memantine, an NMDA receptor antagonist that can inhibit glutamate, a neurotransmitter hypothesized to cause nerve cell damage and death when excessively activated, is also used. It is known to prevent nerve cell death and restore physiological function of remaining nerve cells, improving symptoms mainly in moderate to severe patients rather than mild cases. Antioxidants are also used as adjunct drugs, but their efficacy remains controversial.

◇Will a Fundamental Treatment Emerge?

Recently, with advances in medicine and science, treatments are being developed by more specifically identifying the causative substances and mechanisms of Alzheimer's dementia. The hypothesis that beta-amyloid and tau proteins accumulate in the form of neuritic plaques or neurofibrillary tangles, causing nerve cell death and neurodegeneration leading to cognitive decline, is considered a representative cause and a target for drug development. Globally, 126 candidate substances (as of January last year) are undergoing 152 clinical trials. Among them, 28 candidates have reached phase 3 with 41 clinical trials ongoing. There are also 74 candidates (87 trials) in phase 2 and 24 candidates (24 trials) in phase 1. Of the total 126 candidates, 104 (82.5%) are fundamental treatments aimed at slowing or stopping dementia progression and improving disease pathology itself. Among these, 16 (15.4%) target beta-amyloid, and 11 (10.6%) target tau protein.

Aducanumab (brand name Aduhelm), approved by the FDA in June last year, was developed as an antibody against beta-amyloid. It is designed to remove beta-amyloid deposits and improve cognitive function. It was the first FDA-approved drug aimed at 'fundamental treatment' rather than merely alleviating symptoms, causing a major stir. However, controversy over its therapeutic effect remains. In a 2019 clinical trial involving 3,482 participants, a reduction in beta-amyloid deposits was observed, but no evidence of cognitive improvement was found, leading to the discontinuation of phase 3 trials. However, some patient groups receiving high doses showed effects, and the FDA approved it on the condition that post-marketing studies prove clinical benefits. Due to controversy over the high annual cost of about 60 million KRW, the developer, U.S. biotech company Biogen, halved the price earlier this year.

An official from the Basic Research Division of the National Research Foundation of Korea explained, "Aducanumab remains controversial due to the unclear status of the beta-amyloid deposition hypothesis as the exact cause of Alzheimer's disease, potential side effects such as temporary brain edema and headaches with high doses, and its high price."

◇Seeking Alternatives

The approval of Aducanumab is regarded as a signal flare for the development of fundamental treatments for Alzheimer's dementia. However, the revealed limitations and challenges are significant. Although success was achieved in removing beta-amyloid, previously known as the causative substance of dementia, the lack of clear cognitive improvement has posed new challenges for dementia researchers.

Professor Minjae Lee of Seoul National University College of Medicine said, "Considering that previous studies using mouse models have not shown effectiveness in humans, the introduction of new research methodologies and active use of human-based research techniques are essential to directly develop new drugs and expect effective clinical outcomes. Biochemical studies on the actions of beta-amyloid and tau proteins, utilization of patient-derived cells, meticulous analysis of big data based on sequencing and large-scale epidemiological studies, and next-generation imaging methods for actual human studies should be core components in dementia drug development research."

Also, Professor Young-ho Seo of Seoul National University College of Medicine emphasized the importance of support for dementia research. Professor Seo said, "Testing whether researchers' ideas or treatment targets discovered in vitro are effective requires much more resources and time compared to other research, making it difficult to easily engage in treatment target testing. If there were institutions like a central dementia research center to provide support, it could accelerate the development of dementia treatments."