This study was conducted from 2005 to 2020 based on the medical records of Sorokdo National Hospital. However, this study was initiated in February 1962 by Sister Marianne Stoeger and Sister Margaritha Pissarek. They left Sorok island on November 21, 2005, returned to their homeland. They stayed for 40 years with exceptional compassion for their patients. However, the average life expectancy of HD patients began to decline overall in the four groups from 2005 after they left (Fig. 6). The life expectancy of HD patients was longer than that of Koreans because of taking dapsone6-10. Even more embarrassing, the group's life expectancy taking AAD (red and black) was higher than that of the group not taking AAD (blue and green), and all four groups tended to decrease. Groups that were not taking dapsone (green) live longer than groups taking dapsone (blue). After President Dae-Jung Kim came to power in 1998, they were guaranteed freedom. As more and more became smokers, as in a typical rural village, respiratory infectious diseases increased19. It is natural for people with stronger hearts and health to live longer, and AD was more prevalent in those who lived longer. The control group on Sorok Island, created by the two sisters for 40 years, shows that death tolls are more important than life expectancy for studying AAD and deaths. The AD2000 Collaborative Group's research already reported the following results in 2004.
Donepezil is not cost-effective, with benefits below minimally relevant thresholds20. There were no significant results: between donepezil and placebo in adverse events or deaths, formal care costs, unpaid caregiver time, carer psychopathology, behavioural and psychological symptoms. There was also no significant difference between 5 mg and 10 mg donepezil. More effective treatments than cholinesterase inhibitors are needed to treat AD. ChEIs and memantine do not reduce the progression rate of Alzheimer's disease21-25. AD patients who received ChEIs and memantine took them for longer, were more functionally impaired, and showed more significant cognitive decline than those who only received ChEIs26. When we assess the hazard of death in persons with and without amnestic mild cognitive impairment (MCI), MCI is associated with increased mortality27. They tended to take ChEIs more than without amnestic MCI persons. The DMA reinforced the socialisation of elder care, and the enduring fear of dependency in old age forced Koreans to cooperate in diagnostic tests and treatments for dementia actively28. It is well understood that individual Koreans are very active in the prevention of SARS-CoV-229.
Korean Government's Legislative Process and Medical Staff Medication
The Korean government has established national policies for dementia care, and compulsory long-term care insurance for older people was introduced30. The 'War against Dementia' and the First National Dementia Plan was announced in 200831. It facilitates the socialisation of long-term care services at a national level. The DMA was legislated in August 2011. The government announced the DMA as a reform plan, emphasising changes such as increasing coverage and improving the quality of services30. The DMA intended to lighten its burden on society and help enhance national health by establishing and implementing comprehensive policies on preventing dementia, supporting dementia patients, and researching finding a cure for dementia.
As a result of the election in May 2017, the new president announced the National Duty for Dementia32. The proportion of elderly over 65 years exceeded 14% of the entire population in 201833, and dementia care became a major national issue. The DMA was strengthened on June 12, 2018. The Korean government installed Community Dementia Reassurance Centers successively at all Community Health Centers to establish a community-based dementia management system according to the National Duty for Dementia. Psychiatrists or neurologists of medical institutions engaged in medical diagnosis and treatment under the Medical Service Act34. They strengthened the dementia management programs that administer AAD to MCI or delirium as a preventive and treatment35-39. They insisted that the 1-year persistence rate of ChEIs for AD patients should be specially monitored to optimise treatment persistence because patients are less likely to remain on therapy than those in other countries36. The no improvement results of clinical studies on AAD were already published in 2005–200921-26. In Korea, medical staff started to publish clinical studies of ChEIs and memantine as significant but modest therapeutic improvement in the year 200935,40,41.
Furthermore, the media interviewed medical staff on whether the administration of AAD is essential to slow down and treat dementia42,43. By Article 12 (1) of the DMA, the government and local governments provided support for the treatment and diagnosis of dementia in consideration of the economic burden of dementia patients. NHIS began to reduce the cost of AAD drugs for dementia patients, and the drugs became almost free. From 2010 to June 2019, policymakers and medical staff increased the diagnosis of patients with MCI or AD by 3.26 times and AAD prescriptions by 4.65 times in Korea.
The Neurological Side Effects of ChEIs for AD Patients
The percentage of new users was 2.5% across hospitalizations for Alzheimer's medication44. Neuropsychiatric symptoms and adverse drug reactions were associated with significantly increased prevalence of further psychotropic medication use45, and hospital stays due to dementia and the need of care were predictors for new use of psychotropic medication46. All studies from many countries have already confirmed that antipsychotic drugs should not be administered to dementia patients because of the risk of seizures and all-cause mortality47,48. Deprescribing psychotropic medications are feasible for most people experiencing no withdrawal symptoms in long-term care49,50. Life expectancy is significantly different between AD and AAD groups 1 and 2 for 2018 - 2019 in the Sorokdo National Hospital (Fig. 1). It is suspected because the patients were hospitalised in the psychiatric ward, but the life expectancy of AAD group 1 is also decreased. Adverse events of ChEIs were reported by 81.2% of 196 participants in the Comparative Research of Alzheimer's Disease Drugs51. However, the neurological side effects of ChEIs for AD patients are similar to the neurological symptoms of AD patients. Few specialists can distinguish the side effects caused by dementia or donepezil drugs: dizziness, delusions, dream abnormalities, ataxia, convulsive seizures, hemiplegia, hypertonia, and salivation52,53. While monitoring the AD patient's condition, acetylcholine precursor was prescribed in the hospital's intensive care unit to the patient who had a stroke but medical staffs were not aware of the neurological symptoms caused by the acetylcholine precursor’ side effects (Fig. 7). If AAD itself was not staged as a biomarker (D), the patient was bound to a bed, and making the patient's condition worse54. When connected with the Sorokdo National Hospital's EDI database, we could evaluate AAD prescriptions for fifteen years55. Three ChEIs are approved for use in mild to moderate AD, and their symptomatic benefit in AD has been confirmed via meta-analyses assessing both cognitive performance and global functioning56. However, the data analysis on the number of people who took four FDA-approved therapeutics (three ChEIs and memantine) and the number of fatalities revealed that the number of deaths increased as the number of prescriptions increased. NHIS did not separately provide the number of users and deaths of galantamine because of the pharmaceutical company's request, but it could be sufficiently estimated. Memantine did not show a significant increase in the number of deaths than the increase in users, but the death toll increased in the hidden equation graph (Fig. 5).
We Should Re-Examine the Life Expectancy of Dementia Patients Treated by AAD
We re-evaluated the effects of long-term accumulation of four FDA-approved therapeutics. ChEIs' neurological side effects are very similar to AD neurologic symptoms52-54. Many unique ethical issues arise when treating AD, and psychiatrists are prone to pharmacological prescriptions for their ease of management of late-stage AD patients57. Today, patients with Alzheimer’s disease (AD) tend to have more drugs prescribed and much older and frailer than some decades ago. According to the “evidence-based medicine issue”, pushing clinical trials to anticipate its detection even before the appearance of its clinical manifestations may overshadow the person’s values and priorities58. Donepezil, which most patients have taken, increased more patients with neurological abnormalities with heart failure53,59. Patients with neurological abnormalities are classified as severe AD because violence and abnormal behaviour are increased54. Clinicians promptly administer the AAD group 2 with restraining the patient, and the number of deaths from AAD group 2 replaces the number of deaths from donepezil like Figs. 1 and 6. It may explain why the mortality from donepezil relatively seems low when cognitive function is maintained partly by their cognitive effects by ChEIs60. We watched the report of donepezil initiation associated with better survival benefit than other AD medications (memantine and oral and transdermal forms of rivastigmine) from AD medication groups in a US national sample of Medicare beneficiaries61. But patients who caused side effects by donepezil was not recorded because they went to the ward to treat evolving neurological symptoms or heart failure with AAD group 2 or other managements, this study elucidates the direct effects of AD medications on mortality in real-world settings.
Dapsone has been mainly used in clinical studies on inflammasome competitors. When a patient taking dapsone stopped dapsone for stroke treatment and took acetylcholine precursors for dementia care, the patient's courses were rapidly exacerbated to severe hypertension and neurologic abnormalities62-64.
Many Toxins are Cholinesterase Inhibitors
However, many toxins are cholinesterase inhibitors, and these toxins can cause death if given at high enough dosages. There is no known cumulative effect on AD patients who have taken ChEIs or memantine consistently for long periods. Botulinum toxin blocks the release of acetylcholine hormone from the presynaptic terminal by preventing acetylcholine release65. Black widow spider venom is thought to be associated with a wide release of neurotransmitters, especially norepinephrine and acetylcholine, due to spider envenomation. If widow venom exhausts all acetylcholine supplies as the opposite effect of botulinum toxin, paralysis occurs66,67.
Acetylcholine performs various physiologic functions through cholinergic muscarinic receptors; five different types of muscarinic receptors, M1, M2, M3, M4, and M5. The muscarinic receptor M1 is in the cerebral cortex, salivary glands, and gastric glands. The muscarinic receptor M2 is present in smooth muscle as well as cardiac tissue. The muscarinic receptor M3 is found in smooth muscle cells, particularly of the bronchioles, iris, bladder, and small intestines. The muscarinic receptors M4 and M5 have a less clear distribution but have been found in the hippocampus, substantia nigra, and other locations within the brain68,69.
The non-neuronal cholinergic systems are involved in the pathophysiology of diseases70. The cardiovascular system determines generalised vasodilation, negative chronotropic effects, and negative inotropic effects. It has a less pronounced negative dromotropic effect in the specialised tissue of the sinoatrial and atrioventricular nodes at the ventricular level than other organs. Muscarinic receptor 2 is not the only functional subtype found within the heart, and muscarinic receptors 1 and 3 mediate both dilation and constriction in the vasculature71.
When a patient taking dapsone, mainly used in clinical studies on inflammasome competitors19,55,72, stopped it for stroke treatment and administered acetylcholine precursors for dementia care, the patient's courses were rapidly progressed to severe hypertension and neurologic abnormalities54.
AADs administered to the elderly are closely related to health insurance policies. If the elderly die early, health insurance companies will benefit. However, health insurance policies have been implemented to improve the health of the elderly73. Long-term administration of ChEIs to patients with dementia has increased mortality. The effects of ChEIs on cardiovascular systems should be analysed and studied.