The study of whether acquired Mendelian diseases are the origin of Alzheimer’s disease from viral respiratory diseases.

doi:10.21203/rs.3.rs-3238261/v1

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The study of whether acquired Mendelian diseases are the origin of Alzheimer’s disease from viral respiratory diseases.

https://doi.org/10.21203/rs.3.rs-3238261/v1

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We must study viral RNA infection, sustained interferon response, acetylcholine excess, and developing Alzheimer’s disease (AD). We analyzed viral respiratory disease (VRD) (+)/(−) and dapsone (DDS) (+)/(−) groups. ANOVA calculator, logistic regression analysis, and Mann-Whitney U Test Calculator were used to examine the association of VRDs, COPD, and anti-AD drugs (AADs) with AD. A total of 107 subjects from 2005 to 2021 developed COPD. The DDS (+) AAD (-) and DDS (-) AAD (+) groups were strongly positively correlated with all COPD subjects. COPD develops into AD without dapsone, and AAD exacerbates AD through COPD. Ten AD among ninety-three non-COPD patients occurred in 2010 since the endemic. Viral infections set a direct pathway into AD directly without COPD. The endemic causes bronchitis, COPD, and AD. Acquired Mendelian up-regulation might set a direct pathway into AD as an origin.

Biological sciences/Cell biology/Cell death

Biological sciences/Cell biology/Post translational modifications

Biological sciences/Cell biology/Senescence

Health sciences/Diseases/Immunological disorders/Inflammatory diseases/Autoinflammatory syndrome

Health sciences/Diseases/Neurological disorders/Dementia/Alzheimers disease

Alzheimer’s disease

Anti-Alzheimer’s disease drugs

COPD

Interferonopathies

Mendelian up-regulation

Viral respiratory disease

Can Alzheimer’s disease (AD) develop after viral infections? Leprosy patients have a low prevalence of VRDs with dapsone. After the endemic, viral infection induces AD directly. In a previous study, the bronchitis/COPD group strongly correlated with acetylcholine excess, and in this study, COPD developed AD, and AAD exacerbated AD in COPD patients. The endemic causes bronchitis, COPD, and AD. Viral interferonopathy sets a direct pathway into AD as an origin.

Sorokdo National Hospital, dedicated to treating leprosy patients, separated the group taking dapsone from those not taking dapsone among Alzheimer’s disease (AD) patients from January 2005 to June 2020. This study demonstrates that the effects of dapsone are mixed with the viral interferonopathy in the Japanese sanatoria autopsy series ¹ ² ³. AD patients increased in the DDS (-) group for fifteen years. As a result, data for Sanatoria in 1991 and Sorok Island for 2005-2006 are similar ⁴ ⁵ ⁶. Based on the AD prevalence in patients, dapsone had a preventive effect against AD ⁴. Their observations were scientific.

This study was conducted on the potential clinical impact of continuing AD and related medicines (anti-AD drug, AAD) on elderly care in a real-life setting. The Dementia Management Act (DMA) in South Korea was enacted in August 2011 after declaring the "Warning against Dementia in 2008". From 2012 to 2019, Donepezil, rivastigmine, risperidone and quertiapine increased the number of deaths based on R² > 0.75 ⁷. Acetylation and excess acetylcholine (ACh) affect viral respiratory diseases (VRDs), bronchitis, and chronic obstructive pulmonary disease (COPD) ¹. ACh excess might inhibit ACh receptors for interferon (IFN) production against virus invasion. Some AADs exacerbate viral respiratory inflammatory diseases, but acetylation drugs treat VRDs ⁸ ⁹ ¹⁰. The downstream IFN-stimulated cascade should attenuate the overactive immune-mediated respiratory inflammatory response in the onset stages ⁹ ¹⁰ ¹¹ ¹² ¹³. In a randomized controlled trial (RCT) study of the acetylation effect of dapsone in antihistamine refractory chronic idiopathic urticaria, viral respiratory infections occurred less in the trial group than in the placebo group ¹⁴.

We have observed progressive dementia as a complication of VRDs but have remained ambiguous ¹⁵. Choline esterase inhibitors (ChEIs) have frequent side effects, such as pharyngitis, pneumonia, increased cough, and bronchitis ¹⁶; Anti-psychotic drug uses increase mortality in dementia patients ⁷ ¹⁷. Mendelian disorders demonstrated key up-regulation of IFN or IFN stimulating gene (ISG) expression ¹⁸. The constitutive involvement of IFN is an attractive thesis to the acquired interfernopathies by VRDs or COVID-19. We analyzed the effects of dapsone to decide whether the Mendelian upregulation should induce AD or not from 2005 to 2019 in the Sorok Island cohort.

All methods were carried out in accordance with relevant guidelines and regulations. All experimental protocols were approved by the Korea National Institute for Bioethics Policy (KoNIBP) as the institutional and/or licensing committee. The KoNIBP approved this study for the Management of Life-sustaining Treatment and certified that this study was managed properly (approval number P01-202007-22-006). Informed consent was obtained from all subjects and/or their legal guardians.

STUDY STRATEGY

Influenza A virus (IAV) and SARS-CoV dysregulate human innate immune responses. Severe influenza exhibits distinct cytokine patterns similar to SARS-CoV-2’s ability to suppress immune responses ¹⁹. We analyzed diverse relationships with immune-mediated VRDs, pneumonia, COPD, and AD through national health electronic data interchange (EDI) systems. The Korean government has established compulsory long-term care insurance, and the 'War against Dementia' was announced in 2008. It accelerates the socialization of dementia care services at a national level ²⁰ ²¹. Due to the DMA, psychiatrists - neurologists diagnosed and treated patients under the Medical Service Act ²². As randomized by DMA, they bolstered dementia management and administered AADs as therapeutics to mild cognitive impairment (MCI) or AD patients ²³ ²⁴. DMA randomized the dapsone-prescribing (+) group from the dapsone-non-prescribing (-) group due to mental psychiatric examinations ⁷ ²⁵. Medical staff prescribed AADs to treat MCI or AD. The War Against Dementia and DMA encouraged the prescription of AAD. It randomized the EDI code-based cohort studies, tested the cohort in a completely blinded state, and provided definite causality ⁷.

ELIGIBILITY CRITERIA

According to the Infectious Disease Control and Prevention Act, all Hansen subjects on Sorok Island have been registered at Sorokdo National Hospital. The cohort consisted of leprosy patients, dapsone, respiratory diseases, and AD in all Hansen subjects, according to the data received from Sorokdo National Hospital by South Korea's Official Information Disclosure Act. Therefore, we searched all medical records of the Sorokdo National Hospital with ICD-10 codes. (Table S1, S2, S3)

DDS(+):VRD(+) group (T1), DDS(-):VRD(+) group (T2), DDS(+):VRD(-) group (T3), and DDS(-):VRD(-) group (T4) were arranged. The T1:T3, T1:T4, T2:T3, and T2:T4 tests indicate that in approximately 2010, the group with dapsone and without dapsone were separated, and the group taking dapsone was less susceptible to VRD infection. The relationship between VRD and DDS each year was analyzed using the chi-square test. The p value was insignificant from 2006 to 2009 or 2011 to 2013 when the p value was considered significant at < 0.05. Thus, we separated two DDS (+/-) groups and classified VRD (+) patients with ICD-10 codes from 2012 to 2019. According to the One-way ANOVA Calculator, the f-ratio value is 116.07984. The p value is <.00001. The result is significant at p <.05. Tukey's honestly significant difference (HSD) procedure facilitates pairwise comparisons within T1:T2, T1:T3, T1:T4, T2:T3, and T2:T4. (Table S4, S5)

DATA COLLECTION

Medical data on the correlation between DDS and VRDs were analyzed by the International Classification of Diseases (ICD)-10 codes of viral respiratory infectious diseases. We archived data from January 2005 to June 2019 with the ICD codes of respiratory diseases (RDs). (Table S6, S7)

According to the ICD-10 codes for AD: F00, F01, F02, F03, F04, F05, F06, F07, F08, F09, and G30 (Table S1), AD drugs for symptomatic relief are donepezil, rivastigmine, galantamine, and memantine. The AD drugs for psychological symptoms are haloperidol, Risperidone, Quetiapine, Olanzapine, Aripiprazole, Oxcarbazepine, fluvoxamine, Escitalopram, Trazodone, Sertraline, Escitalopram, and Fluoxetine. We used the object-oriented database management system (ORDBMS) and Google spreadsheet for R² analysis, linear equations, and SPSS. We again applied the linear equation and R².

DEMOGRAPHY

HD patients would spend their whole lives on Sorok Island. According to the request to disclose health checkup information from 2005 to 2020 on October 27, 2020, 2186 people (1152 males, 1034 females) resided. The average age was 83.7 years (median (M) 84, interquartile range (IQR) 76.8–91.2, standard deviation (SD) 10.8, 95% confidence interval (CI): 0.45, 83.6–84.5).

STUDY SELECTION

Study Setting for the ICD Code of Korean Diseases and Medicines

For VRD

Acute nasopharyngitis [common cold] J00, acute pharyngitis J02, acute pharyngitis unspecified J02.9, acute tonsillitis J03, acute tonsillitis unspecified J03.9, acute laryngitis J04.0, acute laryngopharyngitis J06.0, acute upper respiratory infection unspecified J06.9, influenza due to identified zoonotic or pandemic influenza virus J09, influenza with other manifestations seasonal influenza virus identified J10.8, viral pneumonia unspecified J12.9, acute bronchitis unspecified J20.9. (Table S6)

For Respiratory Diseases

Immune-related: Asthma J45, Predominantly allergic asthma J45.0, Nonallergic asthma J45.1, Asthma unspecified J45.9, Status asthmaticus J46, Vasomotor rhinitis J30.0, Allergic rhinitis, unspecified J30.4, Chronic rhinitis J31.0, Chronic sinusitis J32, Chronic maxillary sinusitis J32.0, Chronic pansinusitis J32.4, Other chronic sinusitis J32.8, Chronic sinusitis, unspecified J32.9, Chronic laryngitis J37.0, Chronic nasopharyngitis J31.1, Chronic pharyngitis J31.2, Abscess furuncle and carbuncle of nose J34.0, Deviated nasal septum J34.2, Other specified disorders of nose and nasal sinuses J34.8, Chronic tonsillitis J35.0, Peritonsillar abscess J36, Retropharyngeal and parapharyngeal abscess J39.0
Bronchitis: Acute Bronchitis unspecified J20.9, Bronchitis, not specified as acute or chronic J40, Unspecified chronic bronchitis J42,
Pneumonia: Bacterial Pneumonia NEC J15, Other bacterial pneumonia J15.8, Bacterial Pneumonia unspecified J15.9, Pneumonia in bacterial diseases classified elsewhere J17.0, Other Pneumonia organism unspecified J18.8, Pneumonia unspecified J18.9,
COPD: Pneumonitis due to food and vomit J69.0, Other chronic obstructive pulmonary disease J44, Chronic obstructive pulmonary disease, unspecified J44.9, Bronchiectasis J47
End stage: Pulmonary edema J81, Abscess of lung with pneumonia J85.1, Pleural effusion NEC J90, Pneumothorax J93, Hemothorax J94.2, Chronic pulmonary insufficiency following surgery J95.3, Acute respiratory failure J96.0, Pulmonary collapse J98.1, Other specified respiratory disorders J98.8, Respiratory disorder, unspecified J98.9. (Table S7)

RISK OF BIAS ASSESSMENT

The Korean National Assembly unanimously passed the DMA in 2012 and diagnosed and treated all Hansen subjects without exception ²⁶. Medical staff treated patients with VRD, while no one knew dapsone's ability to compete with inflammasomes. All were in complete-blinded states. Randomization was unrestricted (no blocking or stratification), and the study's data team analyzed the ICD codes in the EMR databases of Sorokdo National Hospital. (Complete Blinded Study & Randomization)

DMA made all medical staff of Sorokdo National Hospital investigate dementia for all HD patients. AAD was prescribed for Hansen subjects, and dapsone was not for inactive HD patients. DMA administered dapsone to the trial group beginning in 2012. Therefore, we classified dapsone-unprescribed subjects as the control group.

STATISTICAL ANALYSIS

Significance was evaluated based on a p value of 0.05 from 2005 to 2021. We used the software programs Object-Relational DBMS and Google spreadsheet with SPSS, ANOVA calculator, and post hoc Tukey HSP (honestly significant difference) test. In addition, a t test was performed among T1, T2, T3, T4, or T5.

We investigated 93 subjects who survived non-COPD patients with AD in 2022. There were 62 females, the average age was 83.5 years, hypertension was present in 66 patients, no obesity or cancer was present, diabetes was present in 21 patients, and dapsone was taken in 38 patients. AD occurred in six patients (Number 10. 19, 45, 51, 62, 87) in 2007, four (Number 12, 31, 59, 76) in 2008, 1 (Number 88) in 2009, and ten (Number 33, 53, 54, 55, 57, 63, 69, 77, 84, 89) in 2010 since the endemic. AD patients increase without COPD. (Table S8, S9) Ten in 2010 is evidence that the endemic could directly induce AD.

Immune-related viral respiratory diseases, COPD, and Alzheimer’s disease

COPD increased slowly from 2008 to 2011, rapidly increased in 2012 and 2013, and decreased ¹. Acute bronchitis quickly rose from 2012 to 2014 and then dropped ¹. Pneumonia increased sharply in 2013 compared to previous years ¹. The longitudinal analysis of all COPD subjects presents vital results. A total of 107 subjects from 2005 to 2021 developed COPD. There were 71 males and 36 females. The population's average age was 87.6 years (M 88.1, IQR 80-93.9, SD 9.55, 95% CI: 0.19, 87.4-87.8). The minimum age was 55.6 years, and the highest was 106.8 years. There were 44 patients with hypertension, no obesity patients, 4 patients with cancer, 17 patients with diabetes mellitus, 26 patients with dapsone, and 31 patients with dementia. We analyzed the DDS (+)/(−) group, dementia diagnosed (+)/undiagnosed (-) group, and COPD group from 2005 to 2021 with the ANOVA calculator. The f-ratio value is 7.94. The p value is.000019. (Significant at p<.05) (Table S10)

We investigated 24 subjects who survived COPD in 2022. Twenty subjects took dapsone, four of which had AD, and sixteen patients did not. The other four subjects did not take dapsone, of which three patients had AD and one patient did not have AD: DDS (+) 20, AD (+) 4, AD (-) 16/DDS (-) 4, AD (+) 3, and AD (-) 1. Dapsone-non-taking COPD survivors were more likely to suffer from AD than dapsone-taking COPD survivors, X² (1, N = 24) = 4.9, p =.027. (Table S11)

COPD has exacerbated AD.

The number of AD patients in the COPD patient group was 1 in 2005, 0 in 2006, 3 in 2007, 0 in 2008, 0 in 2009, 0 in 2010, 1 in 2011, 3 in 2012, 4 in 2013, 0 in 2014, 1 in 2015, 2 in 2016, 5 in 2017, 0 in 2018, 0 in 2019, 2 in 2020, 2 in 2021, 0 in 2022. (Table S12)

Dapsone was proposed as a treatment for MCI and AD ⁴ ⁶ ¹⁶ ²⁷. The post hoc Tukey HSD (honestly significant difference) procedure indicated pairwise comparisons of the DDS (+) AAD (+) group (T1) with the COPD group (T5), DDS (+) AAD (-) (T2) with T5, and DDS (-) AAD (+) (T3) with T5. (Calculator S1)

Supplement Calculator (C) 1: T1 and T5 were moderately correlated, r(17) =.72, p =.0012.

C2: T1 association would be considered statistically significant. (Calculator S2)

C1: T2 and T5 were strongly positively correlated, r(17) =.75, p = 0.00052.

C2: T2 association was considered statistically significant. (Calculator S3)

C1: T3 and T5 were strongly positively correlated, r(17) =.91, p <.00001.

C2: T3 association would be considered statistically significant. (Calculator S4)

T1 is data of AD treated by dapsone and evolving AD. T1 has a modest correlation with T5. The modest correlation could explain why COPD would induce AD against dapsone. T2 explains the strong correlation with T5 between the prevalence of AD treated by dapsone from exacerbated AD in the COPD group. T3 correlates highest with T5. COPD without dapsone developed into AD, and AAD exacerbated COPD during medication for AD.

This study elucidates the correlation between COPD and AD and paradoxically reports that ACh excess positively affects the clinical prevalence of exacerbated AD in treating COPD. Dapsone treats and prevents AD, but COPD worsens AD despite dapsone treatment.

DMA enrolled a total of 9649 participants in the completely blinded state.

4772 subjects were randomized from 2012 to 2020 on Sorok Island. (Fig. S1)

VRD (+) subjects (sum (S) = 4156, M = 519.50, SD = 61.98; 95% CI, 517.62–521.38) consisted of T1: VRD (+) DDS (+) (S = 1702, M = 212.75, SD = 36.76) and T2: VRD (+) DDS (−) (S =2454, M = 306.75, SD = 88.70).

VRD (−) subjects (S = 616, M = 41.07, SD = 55.46) consisted of T3 VRD (-) DDS (+) (S = 170, M = 21.2, SD = 33.2) and T4 VRD (-) DDS (−) groups (S = 446, M = 55.7, SD = 24.3).

The values of f and p were calculated using an ANOVA calculator. Four groups were defined for the T test: T 1: VRD (+) DDS (+), T 2: VRD (+) DDS (−), T 3: VRD (−) DDS (+), and T 4: VRD (−) DDS (−). The f-ratio value in the one-way ANOVA calculator for dependent measures is 116.08, and the p value is <.00001. The result is significant at p < 0.05. The comparisons (T1:T2, T1:T3, T1:T4, T2:T3, and T2:T4) were applicable except for T3:T4. (Table S5)

The T1: T2 graph shows that patients with dapsone have a relatively low prevalence among patients with VRD. (Fig. S2) By Mann-Whitney U Test Calculator, the z-score is -2.88808. The p-value is .00386. The result is significant at p < .05.

The T1:T3 graph shows that patients with dapsone have a decreased prevalence of VRD. (Fig. S3) By Mann-Whitney U Test Calculator, the z-score is 3.30816. The p-value is .00094. The result is significant at p < .05.

T1:T4 demonstrate that the VRD (+) DDS (+) group has conversely shown almost the décalcomnie pattern with the VRD (-) DDS (-) group. This proves that this study is scientific. (Fig. S4) By Mann-Whitney U Test Calculator, the z-score is 3.30816. The p-value is .00094. The result is significant at p < .05.

The T2:T3 graph shows that patients with dapsone have a very low prevalence of VRD. (Fig. S5) By Mann-Whitney U Test Calculator, the z-score is 3.30816. The p-value is .00094. The result is significant at p < .05.

T2:T4 demonstrated that the VRD (+) and VRD (-) groups without dapsone had a constant prevalence, and dapsone was the decisive factor in preventing most VRD exacerbations. (Fig. S6) By Mann-Whitney U Test Calculator, the z-score is 3.30816. The p-value is .00094. The result is significant at p < .05.

SUMMARY OF FINDINGS AND RECOMMENDATIONS

The endemic in 2008 caused bronchitis, COPD, and AD. Viral infection induces AD directly. AAD exacerbates VRDs and leads to the development of COPD in the previous study ¹. COPD developed into AD. VRDs and COPD positively cause AD and AAD indirectly contributes to AD’s development in treating COPD.

Safety

All leprosy patients have lived there with national medical support.

This study included only leprosy patients.

The risk of COPD exacerbation may increase in the first 90 days of ChEI therapy in patients with dementia ²⁸. Viral infection and interferon treatment decrease muscarinic (M)2 receptor gene expression on parasympathetic nerve endings by causing the release of IFN-gamma, which inhibits M2 receptor gene expression. VRDs and IFN treatment decreased M2 receptor gene expression by causing the release of IFN-gamma. IFN-gamma inhibits M2 receptor gene expression on parasympathetic nerve endings ²⁹. ACh excess inhibits ACh receptors for IFN production against virus invasion because the genesis of the ACh receptor requires IFN ³⁰. The muscarinic and nicotinic receptors play critical roles in controlling immune function ³¹. A previous study revealed the correlation between donepezil and ACh with VRDs. The ACh excess by AAD might negatively affect ACh receptor gene expression ¹. Chemo genetic concerns predict drugs modulating microglial functions. Tau protein induces substantial changes in microglial-immune signaling and early interferon-driven immune suppression. ³². This clinical approach clearly defines the origin of AD as another origin from amyloidosis or tau accumulation ³³.

Ion Gresser et al. reported in 1980 that the possibility that indecent exposure to IFN-1 might be harmful to the mammalian system and IFN excess should cause adverse reactions in the host. Human diseases were associated with IFN up-regulation. Mendelian up-regulation is inborn human interferonopathies. Systemic lupus erythematosus (SLE) and Aicardi–Goutières syndrome (AGS) are innate Mendelian up-regulation diseases ³⁴. COPD was associated with incident nonamnestic MCI, and the danger of COPD exacerbation in patients with AD and COPD may increase in the first 90 days of ChEI therapy ³⁵ ²⁸. VRDs and IFN treatment decreased M2 receptor gene expression by causing the release of IFN-gamma. IFN-gamma inhibits M2 receptor gene expression on parasympathetic nerve endings ²⁹. ACh excess inhibits ACh receptors for IFN production against virus invasion because the genesis of the ACh receptor requires IFN ³⁰. The muscarinic and nicotinic receptors play critical roles in controlling immune function ³¹. A previous study revealed the correlation between donepezil and ACh with VRDs. The ACh excess by AAD might negatively affect ACh receptor gene expression ¹.

Neuropilin 1 (NRP1) is a receptor that connects essential pattern recognition receptors and the immune response. It is engaged in developing the heart, vasculature, and neuronal system and establishes primarily a cellular receptor for various molecules ³⁶. The brain with AIDS has direct dementia effects from the retrovirus ³⁷. SARS-CoV-2 uses it as a coreceptor with ACE2 ³⁸ ³⁹. NRP1 serves as the principal receptor mediating astrocyte entry of SARS-CoV-2 ⁴⁰. It plays a complex role in the secondary CD8 T-cell response to control VRDs and tumors ⁴¹. NRP1 maintains protein complexes at cell-to-cell junctions in endothelial cells. The NRP1 deficiency was associated with larger plaque sizes in mice ⁴². Group 3 innate lymphoid cells (ILC3s) are present in patients with COPD. ILC3s with NRP1 (NRP1⁺ ILC3s) show higher levels of cytokines than NRP1^- ILC3s, and NRP1⁺ ILC3s play a potential role in inflammation ⁴³ ⁴⁴. We define this up-regulation as acquired Mendelian up-regulation. NRP1⁺ ILC3s constitute the inflammatory cascade pathway with IFN1 or cGAS-STING through acetylation-deacetylation ⁹.

The cGAS-STING-IFN-I axis in AD pathogenesis by VRDs

The factor in the AA equation consisted of the dapsone-taking group and the AAD-taking AD group ⁷. Through its acetylation capacity, dapsone inhibits the activation of both IFN-1 and NF-κB by targeting cyclic GMP-AMP synthase (cGAS) ⁴⁵. The cGAS-stimulator of interferon genes (STING) and RNA sensing pathway has triggered innate immune responses such as COVID-19 ⁴⁶ ⁴⁷. COVID-19 has a broad spectrum of diseases and has resulted in unprecedented rates of pneumonia, acute respiratory distress syndrome (ARDS), and death ⁴⁸. The IFN-1 system drives excessive inflammation and immunopathology ⁴⁹ ⁵⁰. The cGAS-STING-IFN-I axis promotes the clearance of aberrant DNA and RNA viruses from the gut microbiota found in circulation ⁵¹ ⁵².

The interferonopathy of VRDs induces bronchitis, COPD, and AD.

The endemic in 2008 might induce innate immune responses ¹. Pandemic patients who required intensive care had higher risks of persistent symptoms and higher COPD assessment test scores ⁵³. SARS-CoV-2 can target granular neurons ⁵⁴. Immune-to-brain communication occurs as glia, microglia, and astrocytes interpret and propagate inflammatory signals, influencing physiological and behavioral changes ⁵⁵ ⁵⁶. In addition, activating the peripheral immune system affects physiological and clinical responses by the immunological memory engram pathway ⁹. Jacqueline et al. reported a relatively high incidence of cognitive impairment in processing speed, category fluency, executive functioning, memory encoding, and recall several months after hospitalization in COVID-19 patients. This dysexecutive syndrome after COVID-19 has considerable implications for occupational, psychological, and functional outcomes ⁵⁷. These findings are generally consistent with other viruses' alterations in cognitive and emotional behaviors (e.g., influenza A). VRDs cause AD even if it is not from COPD ⁵⁸.

Dapsone as a baseline treatment for exacerbated Mendelian diseases

Acetylation inhibits cGAS-mediated interferon production ⁵⁹. The acetylation of dapsone showed genetic polymorphism and reproducible individual characteristics. Acetylation of dapsone and deacetylation of monoacetyl dapsone occurred concurrently. Plasma ratios acetylated to the parent drug reached constant states but were characteristic for the individual ⁶⁰. Dapsone is used to treat an IFN-1 overproduction for SLE, lupus erythematosus profundus, cutaneous lupus erythematosus, and familial Mediterranean fever ⁶¹ ⁶² ⁶³ ⁶⁴ ⁶⁵. AGS is also related to upregulated IFN-1 production with slight differences across numerous triggering endogenous nucleotide sensors ⁶⁶ ⁶⁷. Based on the relative prevalence in leprosy patients, dapsone had a preventive effect against AD ⁴. Therefore, it is necessary to set a prospective cohort for the leprosy patients of Sorok Island after stopping prescribing the AAD. Moreover, RCT studies are needed around the world. (Fig. S7)

The endemic causes bronchitis, COPD, and AD. Viral interferonopathy might set a direct pathway into AD as an origin.

Acknowledgments

This study was not supported by any institute. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author.

Conflict Of Interest Statement

The authors have no conflicts of interest to disclose.

Funding

None

Author contributions

Conceptualization, J.H.L. ; methodology, J.H.L. ; investigation, J.H.L. ; resources, J.H.L. ; data curation, J.H.L. ; writing—original draft, J.H.L. ; editing, J.H.L. : review, all; supervision, J.H.L. ; project administration, J.H.L. All authors have read and agreed to the published version of the manuscript.

Data and materials availability

"All data are available in the main text or the supplementary materials." Additional data supporting this study's findings are available from the corresponding author upon reasonable request. In addition, the complete detailed survey is provided as a separate file. LEE, JONG HOON (2023): Data on Viral Respiratory Diseases and Alzheimer's Diseases on Sorok Island in South Korea. figshare. Journal contribution. https://doi.org/10.6084/m9.figshare.22817060.v1

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Table 1. Sanatoria data in Japan in 1991 and Sorok Island data in South Korea from 2005 to 2020

Year	*Treated Total	AD	%	*Untreated Total	AD	%
^***1991*	2031	71	0.035	1761	110	0.062
^***2005	308	18	0.058	436	19	0.044
^***2006	322	20	0.062	400	37	0.093
^***2007	339	22	0.065	383	51	0.133
^***2008	332	22	0.066	370	58	0.157
^***2009	319	19	0.060	349	66	0.189
^***2010	295	25	0.085	368	82	0.223
^***2011	290	35	0.121	366	98	0.268
^***2012	277	39	0.141	376	135	0.359
^***2013	229	34	0.148	420	172	0.410
^***2014	197	25	0.127	426	190	0.446
^***2015	193	26	0.135	410	242	0.590
^***2016	187	33	0.176	404	255	0.631
^***2017	180	37	0.206	383	268	0.700
^***2018	177	45	0.254	379	292	0.770
^***2019	160	46	0.288	374	334	0.893
^***2020	141	32	0.227	356	352	0.989

*For five years, dapsone-treated or -untreated **Japanese Sanatoria data, Intermitteently treated data (Table S14) was summed up as treated data for comparison with Korean data ⁵ ⁶ ***The AD data among a summed number of dapsone users of Sorok Island in South Korea (Table S15) ⁴

Table 2. All COPD patients from 2005 to 2021.

year	COPD patients					Non-COPD patients
*	T1:DDS (+) AD (+)	T2:DDS (+) AD (-)	T3:DDS (-) AD (+)	T4:DDS (-) AD (-)	T5:All	AD (+)
2005	1	2	4	10	17	35
2006	0	0	0	0	0	2
2007	0	2	1	3	6	6
2008	0	0	0	4	4	4
2009	0	1	2	1	4	1
2010	0	0	0	2	2	10
2011	0	1	2	7	10	1
2012	1	2	7	10	20	2
2013	2	3	3	7	15	3
2014	0	3	0	4	7	4
2015	0	1	0	1	2	1
2016	0	1	0	1	2	4
2017	1	3	6	4	14	4
2018	0	0	0	0	0	5
2019	0	0	0	0	0	5
2020	1	0	0	1	2	3
2021	0	1	0	1	2	1

*Four groups (T1, T2, T3, and T4) were classified: DDS-prescribed (+) subjects, DDS-unprescribed (-) subjects, dementia-diagnosed (+) subjects, and dementia-undiagnosed (-) subjects.

Table 3. T1:T2:T3:T4 study of the prevalence of viral respiratory diseases (VRDs) on Sorok Island of South Korea.

year	VRD (+)	T1^*	T2^*	VRD (-)	T3^*	T4^*	Sum	Mean	SD^f	95% CI^g	[CI^g	CI^g]
2012	448	237	211	205	103	102	653	163.25	70.95	10.97	152.28	234.20
2013	618	269	349	31	8	23	649	162.25	172.68	26.79	135.46	334.93
2014	585	236	349	38	6	32	623	155.75	164.85	26.16	129.59	320.60
2015	552	227	325	51	7	44	603	150.75	150.82	24.33	126.42	301.57
2016	526	207	319	65	4	61	591	147.75	142.63	23.25	124.50	290.38
2017	494	193	301	69	14	55	563	140.75	131.44	21.96	118.79	272.19
2018	481	178	303	75	15	60	556	139	129.14	21.66	117.34	268.14
2019	452	155	297	82	13	69	534	133.5	123.66	21.21	112.29	257.16
Sum	4156	1702	2454	616	170	446
Mean	519.50	212.75	306.75	41.07	21.25	55.75
SD	61.98	36.76	43.69	55.46	33.28	24.31
95% CI	1.88	1.75	1.73	4.39	5.04	2.26
	517.62	211.00	305.02	36.68	16.21	53.49
	521.38	214.50	308.48	45.46	26.29	58.01

^*Four groups were classified: T1 group is DDS-prescribed (+) with VRD-diagnosed (+) subjects, T2 group is DDS-unprescribed (-) with VRD-diagnosed (+) subjects, T3 group is DDS-prescribed (+) with VRD-undiagnosed (-) subjects, and T4 group is DDS-unprescribed (-) with VRD-undiagnosed (-) subjects. VRD: Viral Respiratory Disease ^**chi-square, e indicates a p value < 0.05, f Standard deviation (SD), g Confidence interval (CI).

No competing interests reported.

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The study of whether acquired Mendelian diseases are the origin of Alzheimer’s disease from viral respiratory diseases.

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