Dementia Management Act and Death Toll by Dementia Drug

The Dementia Management Act (DMA) came into effect on August 04, 2011, in South Korea. Medical data on the correlation between Alzheimer's disease (AD) and anti-AD drug (AAD) groups were observed from 2010 to 2019. This study investigated the increase and decrease in deaths and AAD used to treat AD. It is known that psychotropic medicines should not be administered for dementia patients because they increase all-cause mortality. This study demonstrated that acetylcholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonist also increase the death toll when used to treat dementia. the only functional subtype found within the muscarinic 1 and both dilation and constriction in the vasculature 50

If the independent variables are AAD, Donepezil, Rivastigmine, Memantine, Risperidone, Fluoxetine, Olanzapine, Sertraline, Quetiapine, Aripiprazole, Escitalopram, and the others, the dependent variable is Lee's hidden data. It makes to calculate the F-ratio value and the p-value by One-Way Repeated Measures ANOVA Calculator (Fig. 5).
The population is all Koreans. The number of deaths is the independent variable. If the independent variables are ve (AAD, Donepezil, Rivastigmine, Memantine, Risperidone), the dependent variable is Lee's hidden data. The output of the ANOVA Calculator is pretty signi cant. The F-ratio value is 3.2028. The p-value is .023868. (The result is signi cant at p < .05.) (Supplement Section 3. Statistics Table 19-1, One-Way Repeated Measures ANOVA Calculator) We used AAD as the reference line. Although rivastigmine was rapidly increased and decreased, it was the drug that increased the death rate (Fig. 6).
Memantine did not increase the number of deaths compared to the increase of users. However, when the hidden equation was used, memantine also increased the rate of deaths (Fig. 7).

Discussion
ChEIs and memantine do not lower the progression rate to Alzheimer's disease 9 10 11 12 13 . AD patients who received ChEIs and memantine took them longer, were more functionally impaired, and showed more signi cant cognitive decline than those who received ChEIs only 14 . Amnestic mild cognitive impairment is associated with increased mortality 15 . The cohort's mortality was more signi cant in the galantamine group than in the placebo group in the original perprotocol assessment 13 . Conversely, there have been reports of the duration, and the dose of donepezil or galantamine are not related to an increase in mortality 16 . 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 actively 18 . 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 introduced 20 . The "War against Dementia" was announced, and the First National Dementia Plan in 2008 21 . 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 services 20 . 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 nding a cure for dementia.  24 . They strengthened the dementia management programs that administer AAD to mild cognitive impairments or delirium as a preventive and treatment [25][26][27][28][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 countries 26  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 con rmed that antipsychotic drugs should not be administered to dementia patients because of the risk of seizures and all-cause mortality 35 . Deprescribing psychotropic medications are feasible to most people experiencing no withdrawal symptoms in long-term care 36 37 . Life expectancy is signi cantly 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 salivation 40 . When connected with the Sorokdo National Hospital's EDI database, we could evaluate AAD prescriptions for fteen years 41 . Three ChEIs are approved for use in mild-to-moderate AD, and their symptomatic bene t in AD has been con rmed 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 su ciently estimated.
Memantine did not show a signi cant 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 symptoms 38 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 bene ciaries were observed, with donepezil being associated with better survival than memantine and oral and transdermal forms of rivastigmine 43 . 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, ve 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 brain 47 48 .
The non-neuronal cholinergic systems are involved in the pathophysiology of diseases 49 . 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 vasculature 50 .
When a patient taking dapsone, mainly used in clinical studies on in ammasome competitors 41 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 abnormalities 40 .
AADs administered to the elderly are closely related to health insurance policies. If the elderly die early, health insurance companies will bene t. However, health insurance policies have been implemented to improve the health of the elderly 53 . Long-term administration of ChEIs to patients with dementia has increased mortality. The effects of ChEIs on cardiovascular systems should be analyzed and studied.

Experimental Design
According to the O cial Information Disclosure Act in Korea, the Seoul study analyzed AD and anti-Alzheimer's disease drug (AAD) use in Hansen subjects. We searched all medical records of the National Health Insurance Service (NHIS) in Korea when the Korean Government computerized the International Classi cation of Diseases (ICD)-9 (10) code and Electronic Data Interchange (EDI). We also connected the medical record database of the Sorokdo National

Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download.