Incurable disease early-stage Alzheimer's treatment will be launched in KoreaProfessor Park Ki-hyung of Gachon University Gil Hospital

What exactly is Alzheimer's?

Alzheimer's disease was announced in 1907 when Dr. Alois Alzheimer, a German psychiatrist, performed an autopsy on the brain of a housewife who died four years after exhibiting abnormal behavior, and found a protein called "amyloid."

It is normal for amyloid to be present in the brain, but when it does not leave the body when you sleep and becomes sticky, the brain kills nerve cells and the resulting amyloid builds up. In addition, Alzheimer's disease occurs due to the deposition of tau protein in nerve cells.

Former President Reagan also suffered from the disease, and the average life expectancy after diagnosis is about 10.3 years, and one of the symptoms, Alzheimer's dementia, is the most common form of degenerative dementia.

Alzheimer's disease is not matrilineal, and familial Alzheimer's disease is so rare that it is reported in the paper.

What happens to the brain when Alzheimer's occurs?

When Alzheimer's occurs, the shape of the brain becomes wrinkled and shrivelled. However, if the brain wrinkles according to the results of imaging tests, it is not necessarily Alzheimer's dementia, and it is often elderly, and in order to know whether it is Alzheimer's disease, it must be comprehensively judged by cognitive tests, blood tests, and imaging tests.

When you look at the results of PET imaging of Alzheimer's patients, the accumulated amyloid appears red and has a somewhat atrophied shape compared to the normal group. That's why Alzheimer's disease can be detected 20 years before the onset of dementia symptoms.

This is because the state of Alzheimer's disease without symptoms persists for 15~20 years, when tau protein and amyloid accumulate most explosively, and if it continues untreated, it will lead to Alzheimer's disease, mild cognitive impairment, and dementia. Many drugs are being developed to treat dementia before it is diagnosed and to prevent symptoms from appearing.

How is Alzheimer's treated?

First of all, the prevention method of Alzheimer's progression is divided into 1~3 stages. The asymptomatic period, when amyloid explosively accumulates, is the primary preventive stage, a process that lowers the production of amyloid beta, which leads to the death of neurons, nerve cells, and the formation of amyloid clumps. The most important thing is to eat quality food and exercise properly.

The second stage of prevention is when there are no symptoms or only the initial symptoms. The goal is to delay the onset of cognitive decline in individuals with evidence of Alzheimer's pathology. It is a phase that degrades beta-amyloid and tau protein deposition and inhibits neurodegeneration with neuroprotective agents. Most of the drugs currently in development are for secondary prevention.

The third stage of prevention is when you come to the hospital because you already feel the discomfort caused by Alzheimer's. Its purpose is to delay the onset of dementia or the exacerbation of the disease. Treatments are performed to protect nerves to prevent nerve loss and increase neurotransmitters.

How do clinical studies of Alzheimer's drugs work?

The phases of Alzheimer's drug clinical research are as follows:

Preclinical: Animal Studies

Phase 1 clinical trial: Safety testing, confirmation of side effects

Phase 2 Clinical Trial: Indication and Optimal Dose Determination

Phase 3 Clinical Trial: Confirmation of Drug Availability at Scale

Phase 4 Trial: Real-World Patient Identification Stability and Validation

What are the drugs for Alzheimer's?

As described above, the main purpose of developing Alzheimer's drugs is to prevent Alzheimer's disease without symptoms or with only early symptoms.

First, we need to know the pathological mechanism of Alzheimer's disease. Amyloid is soluble in water under normal conditions, so it should be excreted from the body such as urine, but when it denatures, it becomes sticky and cannot be excreted, and attacks brain cells. Neuroinflammatory reactions occur in brain cells and nerves degenerate. The tau proteins that maintain the nerve bones are damaged and the nerves are lost. The lost nerve becomes clenched, producing abnormal tau protein, which eventually leads to nerve degeneration.

Therefore, as an early Alzheimer's drug, amyloid-targeted therapies that block amyloid production are being developed first. There are aducanumab, lecanemab, and donanemab.

First, aducanumab received the first partial approval from the US FDA in 2021. The reason for the "partial" approval is that this drug lowers amyloid to a meaningful range but does not have a clinical cognitive improvement effect. It must have a clinically effective effect on improving cognitive function in order to be meaningful as a medicine. In addition, one of the problems is that the cost of the drug is very high, and side effects such as cerebral edema and cerebral hemorrhage can occur.

Second, lecanemab is the first drug to receive full approval from the US FDA in January 2023, and it is a drug that significantly lowers amyloid and has been proven to be clinically effective. At 18 months, normal cognitive function can be maintained for another 7.5 months.

Third, donanemab was also announced at the World Alzheimer's Congress this summer as having a good clinical effect and successfully lowering amyloid, and is currently under FDA review.

In South Korea, the above drugs are expected to be approved by next year.