Carbon Dioxide–Calcium Crosstalk in Alzheimer's Disease: A Mechanistic Model of Neurodegeneration

International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11 Carbon Dioxide–Calcium Crosstalk in Alzheimer’s Disease: A Mechanistic Model of Neurodegeneration Abdelrazak Mansour Ali1*, Radwa Abdelrazak Ali2, Mohamed Abdeltawab Ibrahim3, Mohga Abdeltawab Barbar4 1Professor Dr. (MD, PhD), Corresponding Author, Professor of Pediatrics, International Center for Population Studies and Research, Al-Azhar University, Cairo, Egypt 2Associate Researcher, B.Sc. in Neuroscience (George Mason University), M.Sc. (University of Virginia), National Institutes of Health, Department of Research, USA 3Doctor of Medicine (MD), Ministry of Health, General Director of Marsa Alam Hospital, and Quality Management Consultant, Egypt 4Mohga Abdeltawab Barbar, B.Sc. and M.Sc., Agricultural Research Center, Ministry of Agriculture, Egypt Citation: Abdelrazak Mansour Ali, Radwa Abdelrazak Ali, Mohamed Abdeltawab Ibrahim, Mohga Abdeltawab Barbar. Carbon Dioxide–Calcium Crosstalk in Alzheimer’s Disease: A Mechanistic Model of Neurodegeneration. Int Clinc Med Case Rep Jour. 2025;4(11):1-20. Received Date: 11 November 2025; Accepted Date: 17 November 2025; Published Date: 19 November 2025 *Corresponding author: Abdelrazak Mansour Ali, Professor Dr. (MD, PhD), Corresponding Author, Professor of Pediatrics, International Center for Population Studies and Research, Al-Azhar University, Cairo, Egypt Copyright: © Abdelrazak Mansour Ali, Open Access 2025. This article, published in Int Clinc Med Case Rep Jour (ICMCRJ) (Attribution 4.0 International), as described by http://creativecommons.org/licenses/by/4.0/ ABSTRACT Background: The incidence of Alzheimer’s disease has risen in parallel with increasing atmospheric carbon dioxide (CO₂) levels over the past century. Objective: To investigate whether elevated CO₂ levels are associated with Alzheimer’s disease. Design: A case-control study conducted at tertiary hospitals in Egypt. Methods: A total of 78 patients diagnosed with Alzheimer’s disease and 45 ageand sex-matched controls (65– 76 years old) were enrolled. All participants underwent clinical examination and completed a standardized questionnaire collecting demographic information, including age, sex, occupation, smoking status, family history, and history of chronic respiratory disease or occupational CO₂ exposure, in accordance with the National Institute for Occupational Safety and Health criteria (August 1976). Recruitment occurred between November 2023 and October 2024. Arterial blood gas analysis was performed for all participants, and selected patients underwent additional evaluations to confirm the diagnosis of Alzheimer’s disease, where applicable. PaCO₂ levels were analyzed using two independent statistical methods to assess significance. Results: The mean PaCO₂ (± SD) was 46.20 ± 2.26 mmHg in patients with Alzheimer’s disease compared to 43.73 ± 3.02 mmHg in controls, with a standard error (SE) of 0.518 and a 95% confidence interval of 1.44–3.50 (P < 0.0001). Elevated PaCO₂ was observed in 54 (69.2%) cases and 9 (20.0%) controls (P < 0.00001). Conclusion: This study demonstrates a significant association between elevated CO₂ levels and Alzheimer’s disease. The underlying mechanisms may involve CO₂-induced alterations in cell membrane integrity, calcium International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11 homeostasis, and intracellular signaling pathways. CO₂-related acidification may impair β-amyloid–clearing enzymes by disrupting zinc-binding histidine residues, thereby promoting Aβ accumulation, while its thermogenic effect may accelerate microtubule degradation and neuronal instability. These findings highlight CO₂-associated pathways as potential therapeutic targets, including strategies to limit CO₂ accumulation or diffusion and the use of hyperbaric oxygen therapy to mitigate CO₂-driven receptor modulation and neuroinflammation. .Keywords: CO2; Ca2+; Alzheimer’s disease; Amyloid; Calcium INTRODUCTION The incidence of neurodegenerative disorders has markedly increased over recent decades. Neurological disorders are now the leading cause of physical and cognitive disability worldwide, affecting approximately 15% of the global population. The absolute number of patients has risen substantially over the past 30 years [1]. This trend parallels the escalating risks associated with carbon dioxide (CO₂) emissions and climate change recognized as significant threats to humanity’s future [2]. While the environmental impacts of CO₂ have been widely discussed and studied—particularly their economic consequences—their effects on human health have received far less attention and remain insufficiently investigated. This work aims to alert the scientific community by presenting evidence that elucidates the health risks of CO₂ exposure, thereby opening a largely underexplored research field. Future CO₂-related research should focus on elucidating the underlying pathophysiology, developing strategies for disease prevention, modification, and treatment, and identifying novel biomarkers to enable early diagnosis, detect subclinical disease progression, and monitor therapeutic responses. Enhancing dementia screening, detection, and diagnosis remains a key priority of this mission. Epidemiology. Alzheimer’s disease (AD) is the most common cause of dementia in older adults (≥65 years) and represents a major global health challenge. The worldwide burden of AD is evident from rising prevalence, incidence, and mortality rates. Mild cognitive impairment (MCI) due to AD often progresses to dementia, with estimates of AD-related dementia among MCI patients ranging from 40% to 75%, depending on the population studied and the diagnostic criteria used [3]. AD accounts for approximately 60–80% of dementia cases globally. Age is the strongest risk factor: early-onset AD (<65 years) is rare and represents <5% of cases, while prevalence roughly doubles every five years beyond age 65. Women face a higher risk, partly due to their longer life expectancy and potentially due to biological factors. Global Statistics. As of 2023, an estimated 55 million people live with dementia, of whom 60–80% have AD. This number is projected to reach approximately 139 million by 2050 [4–6]. Pathology of Alzheimer’s Disease. Neurodegenerative diseases share common pathological and clinical features, including selective vulnerability of specific brain regions and aggregation of misfolded proteins [7]. In AD, pathology is characterized by extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs), often surrounded by activated immune cells, particularly microglia. Clinically, AD manifests as progressive cognitive decline [8]. The principal component of amyloid plaques is amyloid beta (Aβ), generated by abnormal cleavage of amyloid precursor protein (APP). NFTs consist of hyperphosphorylated tau, a microtubule-associated protein. While Aβ and tau accumulation are central to AD pathology, the precise mechanisms driving their formation remain incompletely understood [9]. Aβ deposition begins in the preclinical International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11 phase, and individuals may harbor Aβ plaques for more than a decade before symptom onset [10]. Tau pathology generally develops downstream of Aβ accumulation [9]. Deposited Aβ is thought to act as a damageassociated molecular pattern (DAMP), engaging receptors such as toll-like receptors (TLRs), the receptor for advanced glycation end products (RAGE), and nucleotide-binding oligomerization domain-like receptors (NLRs). This interaction activates microglia, triggering the release of cytokines and chemokines and recruiting additional glial cells to the site of Aβ deposition [11]. Microglia and astrocytes can phagocytose Aβ via multiple receptors to protect neurons [12]. However, inefficient clearance leads to chronic inflammation and the release of pro-inflammatory and neurotoxic mediators, including cytokines, chemokines, reactive oxygen species (ROS), and nitric oxide (NO), which exacerbate neuronal damage [10,13]. Other central nervous system (CNS) cell types, such as neurons, oligodendrocytes, vascular endothelial cells, and pericytes, also contribute to sustaining this inflammatory microenvironment [14,15]. Activated microglia may further promote Aβ plaque formation by increasing Aβ fragment secretion, inducing interferon-induced transmembrane protein 3 (IFITM3, a γ-secretase modulatory protein), or releasing metals such as copper that enhance Aβ aggregation [15–17]. Because microglial activation precedes tau aggregation and promotes tau hyperphosphorylation, it ultimately drives NFT formation [18]. Accumulated tau tangles disrupt neuronal function, trigger apoptosis, and promote immune cell activation [19] (Figure 1). NFTs are also spatially associated with neuroinflammation in human AD brain samples [20,21]. Meng et al. demonstrated that hyperphosphorylated tau can disrupt membrane bilayers and activate human macrophages via TLR4 [22]. More recently, Welikovitch et al. reported that neurons laden with soluble and oligomeric Aβ display a distinctive inflammatory signature. This neuron-specific inflammatory response may precede the formation of insoluble Aβ plaques and tau tangles, suggesting that intraneuronal Aβ accumulation is an early pathological event with a substantial immunological component [23]. International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11 Figure 1: Integrated Model of Inflammatory Signaling in Neurodegeneration Inflammatory receptors on the surface of immune cells, particularly glial cells, act as sensors that detect abnormalities in the human body. Stimulation of these receptors by damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs)—such as protein aggregates, viruses, or bacteria—activates intracellular signal transducers, which in turn stimulate transcription factors. These transcription factors promote the secretion of inflammatory mediators, thereby amplifying the inflammatory response [10]. The Relationship Between Carbon Dioxide (CO₂) and Alzheimer’s Disease (AD). This is an emerging research area, especially considering recent findings related to cerebral blood flow, neuroinflammation, and acid–base imbalance. 1. CO₂, Cerebral Blood Flow, and Hypoxia. Elevated arterial CO₂ (hypercapnia) causes cerebral vasodilation. However, chronic CO₂ elevation can impair cerebral autoregulation and oxygen delivery. Hypercapnia also alters blood–brain barrier (BBB) permeability and may exacerbate hypoxia-induced neuronal injury. Impaired cerebral perfusion contributes to vascular dementia and increases the risk of AD [24,25]. 2. CO₂ and Brain pH (Acidosis). CO₂ reacts with water to form carbonic acid, lowering brain pH. Acidosis affects: International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11  Enzyme function, increasing amyloid β-protein (Aβ) expression in hippocampal neurons and promoting Aβ accumulation [24].  Tau phosphorylation and aggregation [25]. 3. CO₂ and Neuroinflammation. Elevated CO₂ has been linked to activation of inflammatory signaling, including interleukin-1β production. The NF-κB and NLRP3 inflammasome pathways are activated under hypercapnic conditions [26–28]. While microglia play a protective role in clearing Aβ plaques during the early stages of AD, their chronic activation can have detrimental consequences, such as exacerbating tau pathology and promoting neuronal apoptosis [29]. 4. CO₂, Protein Aggregation, and Clearance. CO₂-induced acidosis impairs protein clearance mechanisms. Alterations in endosomal and lysosomal pH, along with global brain acidification, are associated with increased amyloid-β aggregation and reduced solubility [30]. 5. Experimental Models Linking CO₂ to AD-like Changes. Animal studies suggest that CO₂ exposure can directly influence AD pathology. Chronic hypercapnia in rodent models has been shown to increase APP expression, promote Aβ accumulation, and enhance tau phosphorylation [31]. Summary Carbon dioxide may contribute to Alzheimer’s disease through multiple interconnected mechanisms:  Disruption of cerebral blood flow and oxygenation.  Brain acidosis leads to altered calcium signaling and enzyme activity.  Activation of neuroinflammatory pathways.  Impaired clearance and increased aggregation of amyloid-β and tau proteins. Methods To our knowledge, this is the first study to investigate the role of CO₂ in the pathogenesis of Alzheimer’s disease. It is important to note that, due to the presence of uncontrolled extraneous variables, this study can suggest a possible association but cannot establish causality. The assessment of arterial partial pressure of CO₂ (PaCO₂) has long been considered a gold standard in clinical evaluation. These measurements are particularly relevant in the context of climate change and indoor air quality, as they inform ventilation standards. Furthermore, calculations involving CO₂ production and oxygen consumption yield metabolic indices that can be further explored in various fields [30]. Based on exclusion criteria designed to minimize confounding, CO₂ exposure was selected as a primary variable in both the study design and assessment. Study Design. This case-control study employed participant selection based on established matching criteria linked to known associations with the outcome of interest. Setting and Participants. The study was approved by the administrative boards of Hurghada, Marsa Alam, and Nasser Institute Hospitals in Cairo, Egypt. Informed consent for laboratory testing was obtained from all participants in accordance with hospital regulations. The study protocol adhered to the ethical standards of the 1975 Declaration of Helsinki. Variables. Cases and controls were matched for potential confounders and recruited from the same geographic and demographic population. Parameters such as age, sex, urbanization level, socioeconomic status, and comorbidities were balanced between groups. Demographic data were collected via questionnaire, including International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11 age, sex, occupation, smoking status, family history, and history of chronic respiratory illness or occupational CO₂ exposure, in accordance with the criteria set by the National Institute for Occupational Safety and Health (August 1976). Individuals working in farming, mining, or CO₂-related industries were excluded. Data Sources and Measurement. Cases were identified from patient rosters at participating hospitals, while controls were drawn from the same source population. Both groups were matched by sociodemographic factors. Eligible cases were recruited from both outpatient and inpatient settings. Arterial blood gases were measured using the ABL90 FLEX PLUS analyzer to determine Pa CO₂ levels. Participants were stratified based on whether their PaCO₂ values were above or below the median. The standard reference range for PaCO₂ was 35– 45 mmHg. Sample Size and Bias. Between October 2024 and June 2025, 78 cases (40 males, 38 females) and 45 controls (24 males, 21 females), aged 65–76 years, were enrolled. While the group sizes differed, the primary focus was on the percentage of event occurrence and the comparative strength of association, both of which are appropriate indicators in case–control studies. The analysis was restricted to CO₂ exposure and validated using two statistical methods: percentage of event occurrence and mean ± standard deviation. Quantitative Variables. Participants were screened to exclude conditions affecting PaCO₂, such as cardiopulmonary diseases, obstructive sleep apnea, critical illness, and multisystem organ failure. Diagnostic testing for Alzheimer’s disease was conducted when clinically indicated. Statistical Analysis. Data were either normally distributed or the sample size was sufficient for the Central Limit Theorem to apply. Independent group comparisons were performed using manual calculations equivalent to the following software tools: IBM SPSS v29, R (v4.3.1), and Python’s SciPy module (stats.ttest_ind with equal_var=False). Demographic characteristics were compared using t-tests, adjusted odds ratios, 95% confidence intervals (CIs), and p-values. Alzheimer’s Disease Diagnostic Criteria:  Gradual onset (over months to years).  Progressive cognitive decline, typically beginning with memory impairment and potentially affecting language, visuospatial skills, and executive function.  Interference with daily functioning.  Not explained by other causes (e.g., stroke, depression, or other dementias).  Supportive features (not required):  Biomarkers (CSF, PET) indicating amyloid and tau pathology.  MRI showing medial temporal lobe atrophy. Diagnostic Categories: A. Probable AD dementia: Typical presentation with functional impairment. B. Possible AD dementia: Atypical presentation or mixed pathology. C. Mild Cognitive Impairment due to AD: Memory decline without complete loss of independence [33– 35]. International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11 RESULTS Table 1: Demographic characteristics of cases and controls. Variable Cases No. (%) (n =78), Controls No. (%) (n =45), Odds ratio, or Mean difference (95% CI), P value Sex (female) 33 (42.3) 20(44.4) OR=0.92 [0.44, 1.92] p ≈ 0.82 Age, mean (S.D.), years 71.29 ±1.63 70.84 ± 2.17 MD = 0.45 [-0.28, 1.18] P ≈ 0.23 Total annual outcome, $ ≤ 12000. 12000 – 30000 ≥ 30000 47 (60.3) 25 (32) 6 (7.7%) 27 (60.0) 14 (31.1) 4 (8.9) Smokers 16 (20.5) 8 (17.8) 1.19 [0.46, 3.05], P ≈ 0.72 No statistically significant association between case/control status and smoking (p > 0.05). There was no statistically significant difference in age between cases and controls. Similarly, no significant difference was observed in the odds of being female between the two groups (p > 0.05). Additionally, smoking status was not significantly associated with case/control classification (p > 0.05). Table 2: Comparison of mean partial pressure of carbon dioxide (Pa CO ₂ ) in arterial blood between cases and controls Group N Mean Value of PaCO2 SD SE, 95% C I P value Cases 78 46.20 2.26 0.518, (1.44, 3.50) < 0.0001 Control 45 43.73 3.02 Note: Pa CO₂ = partial pressure of carbon dioxide in arterial blood. There was a highly significant difference in Pa CO₂ between cases and controls. Table 3: Comparison of elevated Pa CO ₂ rates between cases and controls Group No. (%) with elevated PaCO2 No. (%) without elevated PaCO2 Total Cases 54 (69.2) 24 (30.8) 78 Controls 9 (20.0) 36 (80.0) 45 Total 63 60 123 International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11 The p-value for a two-tailed test was < 0.00001, indicating an extremely significant difference in the proportion of subjects with elevated Pa CO₂ between cases and controls. Categories 1&2 Figure 2: Blue columns represent cases. Brown columns represent controls. Category 1: Rate of increase in Pa CO₂. Category 2: Mean Pa CO₂ values. DISCUSSION The world is currently facing an unprecedented and life-altering challenge in response to climate change. The unique physicochemical properties of carbon dioxide (CO₂) significantly influence cellular electrical potential, pH regulation, thermal capacity to absorb and re-emit infrared radiation, gas-like diffusivity, and liquid-like solvating power. This study is the first to elucidate the association between carbon dioxide (CO₂) and the increased incidence of Alzheimer’s disease (AD). Our findings indicate that the partial pressure of arterial CO₂ (PaCO₂) is directly proportional to the number of AD cases. Although no prior research has documented this relationship, we identify multiple pathogenic mechanisms implicated in AD etiology. These appear to be mediated through downstream pathways triggered by CO₂’s direct effects on Tau–microtubule functional integrity, alterations in the enzymatic clearance of β-amyloid, and CO₂-mediated disruption of calcium channels and intracellular signaling. Given recent advances in calcium (Ca²⁺) signaling research and the growing prevalence of neurodegenerative diseases, we explored CO₂’s potential role in the pathogenesis of such disorders, primarily AD. We propose a International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11 mechanistic model integrating CO₂, Ca²⁺ signaling, calcium channels, secondary messengers, and AD progression. This model is supported by evidence of a precise link between CO₂ and Ca²⁺ signaling. Notably, Ca²⁺ signals encode information via their frequency, kinetics, amplitude, and spatial distribution, enabling complex intraand intercellular communication. CO₂’s multifaceted actions may contribute to neurodegeneration through interconnected pathways involving membrane receptors, cytokines, interleukins, genes, and messenger RNAs. Collectively, our results support the hypothesis that CO₂ can initiate, stabilize, and sustain AD pathogenesis. Kumar et al. recently highlighted the link between cytokine-mediated disorders and antioxidant-based therapies [36]. CO₂ possesses distinctive physicochemical traits—such as becoming a supercritical fluid above its critical temperature and pressure, exhibiting both gas-like diffusivity and liquid-like solvating power, and demonstrating high aqueous solubility—that make it a compelling research target [37]. Its capacity to absorb and re-emit infrared radiation underlies its central role in anthropogenic climate change. Given its long atmospheric lifetime and cumulative radiative forcing, CO₂ remains the primary target of global emission reduction and carbon capture strategies [38]. In aqueous environments, CO₂ forms carbonic acid (H₂CO₃), which rapidly equilibrates with bicarbonate and carbonate ions [39]. Elevated temperatures promote water autoionization and shift acid–base equilibria in accordance with Le Chatelier’s principle, lowering solution pH—a phenomenon well established both theoretically and experimentally [40]. We suggest that this acidification could contribute to AD pathogenesis by altering protein conformation, enzyme activity, and neuronal microenvironments. Preliminary evidence also suggests a potential association between CO₂ and autoimmune disorders [41,42], with recent mechanistic insights provided by Abdelrazak et al. [43]. Increasing recognition of immune dysregulation in neurodegeneration—supported by the discovery of immune-related genetic risk factors—has spurred interest in targeting neuroinflammation to prevent central nervous system damage [10]. We further propose that CO₂-driven acidification may protonate histidine residues, leading to imidazole ring ionization and conformational shifts that activate heterotrimeric G proteins, increase intracellular cAMP, and modulate signaling. This pH-responsive behavior of histidine is relevant to the acidic brain environments observed in AD [44–46]. Our findings also suggest that mechanical and thermally induced membrane fluctuations can modify subcellular receptor topology, influencing cellular signaling and protein folding. CO₂ may exacerbate protein misfolding via:  Intracellular Acidosis — destabilizing hydrogen bonds, electrostatic interactions, and disulfide bridges [48].  Protein Carbamylation — altering protein charge and structure through non-enzymatic CO₂ reactions [49].  Chaperone Dysfunction — impairing HSP-mediated folding under hypercapnic stress [50].  Endoplasmic Reticulum Stress — activating the unfolded protein response, leading to apoptosis [51]. Additionally, receptor topology changes may impair immune-mediated β-amyloid clearance [52], while elevated temperatures can destabilize microtubules and collapse their networks [53–55]. Acidic conditions may also International Clinical and Medical Case Reports Journal Research Article (ISSN: 2832-5788) Int Clinc Med Case Rep Jour (ICMCRJ) 2025 | Volume 4 | Issue 11 ECE = Endothelin-Converting Enzyme MMPs = Matrix Metalloproteinases VGCCs = Voltage-Gated Calcium Channels Acknowledgments We thank Ahmed Ali, an expert in information systems, and Shehab Ali, an expert in computer science, for their valuable discussions and assistance with this study. Disclosure of Conflict of Interest The authors declare that they have no known competing financial interests that could have influenced the work reported in this paper. Funding The authors confirm that they did not receive any financial support from individuals or organizations for this study. References 1. Van Schependom J, D'haeseleer M. 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