ChEIs and memantine do not lower the progression rate to Alzheimer's disease9 10 11 12 13. AD patients who received ChEIs and memantine took them longer, were more functionally impaired, and showed more significant cognitive decline than those who received ChEIs only14. Amnestic mild cognitive impairment is associated with increased mortality15. The cohort's mortality was more significant in the galantamine group than in the placebo group in the original per-protocol assessment 13. Conversely, there have been reports of the duration, and the dose of donepezil or galantamine are not related to an increase in mortality16. ChEIs' role remains unclear in acute myocardial infarction and heart failure remediation 17.
The DMA reinforced the socialization of elder care, and enduring fear of dependency in old age forced Koreans to cooperate in diagnostic tests and treatments for dementia actively18. It is well understood that individual Koreans are very active in the prevention of SARS-CoV-2 19.
Korean government's legislative process and medical staff medication
The Korean Government has continuously established national policies for dementia care, and compulsory long-term care insurance for older people was introduced20. The "War against Dementia" was announced, and the First National Dementia Plan in 200821. It facilitates the socialization 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, emphasizing changes such as increasing coverage and improving the quality of services20. 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 Dementia22. The proportion of elderly over 65 years exceeded 14% of the entire people in 201823, 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 Act24. They strengthened the dementia management programs that administer AAD to mild cognitive impairments or delirium as a preventive and treatment25-29. They insisted that the 1-year persistence rate of ChEIs for AD patients should be specially monitored to optimize treatment persistence because patients are less likely to remain on therapy than those in other countries26. The no improvement results of clinical studies on AAD were already published in 2005-20099 10 11 12 30 14, but in Korea, medical staff started to publish clinical studies of ChEIs and memantine as significant but modest therapeutic improvement the year 200925 31 32.
Furthermore, they interviewed the media that the administration of AAD is essential to slow down and treat dementia 33 34. 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 became almost free. From 2010 to June 2019, policymakers and medical staffs increased the diagnosis of patients with MCI or AD by 3.26 times and AAD prescription by 4.65 times in Korea.
We should re-examine the life expectancy of dementia patient treated by AAD
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 mortality35. Deprescribing psychotropic medications are feasible to most people experiencing no withdrawal symptoms in long-term care 36 37. Life expectancy is significantly different between AD and AAD groups 1 and 2 in the Sorokdo National Hospital (Fig 1. between 2018 and 2019). It is suspected because the patients were hospitalized in the psychiatric ward, but the life expectancy of AAD group 1 is also decreased.
The neurological side effects of ChEIs for AD patients are similar to neurological symptoms of AD patients. Treated patients had increased disinhibited or compulsive acts, which abated with discontinuation of the ChEIs 38 39. Few specialists can distinguish whether they are side effects caused by dementia or donepezil drugs: dizziness, delusions, dream abnormalities, ataxia, convulsive seizures, hemiplegia, hypertonia, and salivation40. When connected with the Sorokdo National Hospital's EDI database, we could evaluate AAD prescriptions for fifteen years41. 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 functioning 42. However, the data analysis on the number of peo
ple 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, but it can 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. 6).
We re-evaluated the effects of long-term drug accumulation of four FDA-approved therapeutics. Since ChEIs' neurological side effects are similar to AD symptoms38 39,40, it can be assumed that patients take AAD group 2 quickly when admitted to the hospital. AD medication groups in a US national sample of Medicare beneficiaries were observed, with donepezil being associated with better survival than memantine and oral and transdermal forms of rivastigmine43. This study elucidates the underlying causes of mortality and hospitalization to determine the direct effects of AD medications on mortality in real-world settings.
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 release 44. 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 occurs 45 46.
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 brain47 48.
The non-neuronal cholinergic systems are involved in the pathophysiology of diseases49. The cardiovascular system determines generalized vasodilation, negative chronotropic effects, and negative inotropic effects. It has a less pronounced negative dromotropic effect in the specialized 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 vasculature50.
When a patient taking dapsone, mainly used in clinical studies on inflammasome competitors41 51 52, stopped it for stroke treatment and administered acetylcholine precursors for dementia care, the patient's courses were rapidly progressed to severe hypertension and neurologic abnormalities40.
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 elderly53. Long-term administration of ChEIs to patients with dementia has increased mortality. The effects of ChEIs on cardiovascular systems should be analyzed and studied.