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Ca bon Dioxide–Calcium C oss alk in Alzheime ’s Disease: A Mechanis ic
Model o Neu odegene a ion
Abdel azak Mansou Ali1*, Radwa Abdel azak Ali2, Mohamed Abdel awab Ib ahim3, Mohga
Abdel awab Ba ba 4
1P o esso D . (MD, PhD), Co esponding Au ho , P o esso o Pedia ics, In e na ional Cen e o Popula ion
S udies and Resea ch, Al-Azha Uni e si y, Cai o, Egyp
2Associa e Resea che , B.Sc. in Neu oscience (Geo ge Mason Uni e si y), M.Sc. (Uni e si y o Vi ginia),
Na ional Ins i u es o Heal h, Depa men o Resea ch, USA
3Doc o o Medicine (MD), Minis y o Heal h, Gene al Di ec o o Ma sa Alam Hospi al, and Quali y
Managemen Consul an , Egyp
4Mohga Abdel awab Ba ba , B.Sc. and M.Sc., Ag icul u al Resea ch Cen e , Minis y o Ag icul u e, Egyp
Ci a ion: Abdel azak Mansou Ali, Radwa Abdel azak Ali, Mohamed Abdel awab Ib ahim, Mohga Abdel awab
Ba ba . Ca bon Dioxide–Calcium C oss alk in Alzheime ’s Disease: A Mechanis ic Model o
Neu odegene a ion. In Clinc Med Case Rep Jou . 2025;4(11):1-20.
Recei ed Da e: 11 No embe 2025; Accep ed Da e: 17 No embe 2025; Published Da e: 19 No embe 2025
*Co esponding au ho : Abdel azak Mansou Ali, P o esso D . (MD, PhD), Co esponding Au ho , P o esso
o Pedia ics, In e na ional Cen e o Popula ion S udies and Resea ch, Al-Azha Uni e si y, Cai o, Egyp
Copy igh : © Abdel azak Mansou Ali, Open Access 2025. This a icle, published in In Clinc Med Case Rep
Jou (ICMCRJ) (A ibu ion 4.0 In e na ional), as desc ibed by h p://c ea i ecommons.o g/licenses/by/4.0/
ABSTRACT
Backg ound: The incidence o Alzheime ’s disease has isen in pa allel wi h inc easing a mosphe ic ca bon
dioxide (CO₂) le els o e he pas cen u y.
Objec i e: To in es iga e whe he ele a ed CO₂ le els a e associa ed wi h Alzheime ’s disease.
Design: A case-con ol s udy conduc ed a e ia y hospi als in Egyp .
Me hods: A o al o 78 pa ien s diagnosed wi h Alzheime ’s disease and 45 age- and sex-ma ched con ols (65–
76 yea s old) we e en olled. All pa icipan s unde wen clinical examina ion and comple ed a s anda dized
ques ionnai e collec ing demog aphic in o ma ion, including age, sex, occupa ion, smoking s a us, amily
his o y, and his o y o ch onic espi a o y disease o occupa ional CO₂ exposu e, in acco dance wi h he
Na ional Ins i u e o Occupa ional Sa e y and Heal h c i e ia (Augus 1976). Rec ui men occu ed be ween
No embe 2023 and Oc obe 2024. A e ial blood gas analysis was pe o med o all pa icipan s, and selec ed
pa ien s unde wen addi ional e alua ions o con i m he diagnosis o Alzheime ’s disease, whe e applicable.
PaCO₂ le els we e analyzed using wo independen s a is ical me hods o assess signi icance.
Resul s: The mean PaCO₂ (± SD) was 46.20 ± 2.26 mmHg in pa ien s wi h Alzheime ’s disease compa ed o
43.73 ± 3.02 mmHg in con ols, wi h a s anda d e o (SE) o 0.518 and a 95% con idence in e al o 1.44–3.50
(P < 0.0001). Ele a ed PaCO₂ was obse ed in 54 (69.2%) cases and 9 (20.0%) con ols (P < 0.00001).
Conclusion: This s udy demons a es a signi ican associa ion be ween ele a ed CO₂ le els and Alzheime ’s
disease. The unde lying mechanisms may in ol e CO₂-induced al e a ions in cell memb ane in eg i y, calcium
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homeos asis, and in acellula signaling pa hways. CO₂- ela ed acidi ica ion may impai β-amyloid–clea ing
enzymes by dis up ing zinc-binding his idine esidues, he eby p omo ing Aβ accumula ion, while i s
he mogenic e ec may accele a e mic o ubule deg ada ion and neu onal ins abili y. These indings highligh
CO₂-associa ed pa hways as po en ial he apeu ic a ge s, including s a egies o limi CO₂ accumula ion o
di usion and he use o hype ba ic oxygen he apy o mi iga e CO₂-d i en ecep o modula ion and
neu oin lamma ion.
.Keywo ds: CO2; Ca2+; Alzheime ’s disease; Amyloid; Calcium
INTRODUCTION
The incidence o neu odegene a i e diso de s has ma kedly inc eased o e ecen decades. Neu ological
diso de s a e now he leading cause o physical and cogni i e disabili y wo ldwide, a ec ing app oxima ely
15% o he global popula ion. The absolu e numbe o pa ien s has isen subs an ially o e he pas 30 yea s [1].
This end pa allels he escala ing isks associa ed wi h ca bon dioxide (CO₂) emissions and clima e change
ecognized as signi ican h ea s o humani y’s u u e [2]. While he en i onmen al impac s o CO₂ ha e been
widely discussed and s udied—pa icula ly hei economic consequences— hei e ec s on human heal h ha e
ecei ed a less a en ion and emain insu icien ly in es iga ed. This wo k aims o ale he scien i ic
communi y by p esen ing e idence ha elucida es he heal h isks o CO₂ exposu e, he eby opening a la gely
unde explo ed esea ch ield.
Fu u e CO₂- ela ed esea ch should ocus on elucida ing he unde lying pa hophysiology, de eloping s a egies
o disease p e en ion, modi ica ion, and ea men , and iden i ying no el bioma ke s o enable ea ly diagnosis,
de ec subclinical disease p og ession, and moni o he apeu ic esponses. Enhancing demen ia sc eening,
de ec ion, and diagnosis emains a key p io i y o his mission.
Epidemiology. Alzheime ’s disease (AD) is he mos common cause o demen ia in olde adul s (≥65 yea s) and
ep esen s a majo global heal h challenge. The wo ldwide bu den o AD is e iden om ising p e alence,
incidence, and mo ali y a es. Mild cogni i e impai men (MCI) due o AD o en p og esses o demen ia, wi h
es ima es o AD- ela ed demen ia among MCI pa ien s anging om 40% o 75%, depending on he popula ion
s udied and he diagnos ic c i e ia used [3]. AD accoun s o app oxima ely 60–80% o demen ia cases globally.
Age is he s onges isk ac o : ea ly-onse AD (<65 yea s) is a e and ep esen s <5% o cases, while
p e alence oughly doubles e e y i e yea s beyond age 65. Women ace a highe isk, pa ly due o hei longe
li e expec ancy and po en ially due o biological ac o s.
Global S a is ics. As o 2023, an es ima ed 55 million people li e wi h demen ia, o whom 60–80% ha e AD.
This numbe is p ojec ed o each app oxima ely 139 million by 2050 [4–6].
Pa hology o Alzheime ’s Disease. Neu odegene a i e diseases sha e common pa hological and clinical
ea u es, including selec i e ulne abili y o speci ic b ain egions and agg ega ion o mis olded p o eins [7]. In
AD, pa hology is cha ac e ized by ex acellula amyloid plaques and in acellula neu o ib illa y angles
(NFTs), o en su ounded by ac i a ed immune cells, pa icula ly mic oglia. Clinically, AD mani es s as
p og essi e cogni i e decline [8]. The p incipal componen o amyloid plaques is amyloid be a (Aβ), gene a ed
by abno mal clea age o amyloid p ecu so p o ein (APP). NFTs consis o hype phospho yla ed au, a
mic o ubule-associa ed p o ein. While Aβ and au accumula ion a e cen al o AD pa hology, he p ecise
mechanisms d i ing hei o ma ion emain incomple ely unde s ood [9]. Aβ deposi ion begins in he p eclinical
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phase, and indi iduals may ha bo Aβ plaques o mo e han a decade be o e symp om onse [10]. Tau
pa hology gene ally de elops downs eam o Aβ accumula ion [9]. Deposi ed Aβ is hough o ac as a damage-
associa ed molecula pa e n (DAMP), engaging ecep o s such as oll-like ecep o s (TLRs), he ecep o o
ad anced glyca ion end p oduc s (RAGE), and nucleo ide-binding oligome iza ion domain-like ecep o s
(NLRs). This in e ac ion ac i a es mic oglia, igge ing he elease o cy okines and chemokines and ec ui ing
addi ional glial cells o he si e o Aβ deposi ion [11].
Mic oglia and as ocy es can phagocy ose Aβ ia mul iple ecep o s o p o ec neu ons [12]. Howe e ,
ine icien clea ance leads o ch onic in lamma ion and he elease o p o-in lamma o y and neu o oxic
media o s, including cy okines, chemokines, eac i e oxygen species (ROS), and ni ic oxide (NO), which
exace ba e neu onal damage [10,13]. O he cen al ne ous sys em (CNS) cell ypes, such as neu ons,
oligodend ocy es, ascula endo helial cells, and pe icy es, also con ibu e o sus aining his in lamma o y
mic oen i onmen [14,15]. Ac i a ed mic oglia may u he p omo e Aβ plaque o ma ion by inc easing Aβ
agmen sec e ion, inducing in e e on-induced ansmemb ane p o ein 3 (IFITM3, a γ-sec e ase modula o y
p o ein), o eleasing me als such as coppe ha enhance Aβ agg ega ion [15–17]. Because mic oglial ac i a ion
p ecedes au agg ega ion and p omo es au hype phospho yla ion, i ul ima ely d i es NFT o ma ion [18].
Accumula ed au angles dis up neu onal unc ion, igge apop osis, and p omo e immune cell ac i a ion [19]
(Figu e 1).
NFTs a e also spa ially associa ed wi h neu oin lamma ion in human AD b ain samples [20,21]. Meng e al.
demons a ed ha hype phospho yla ed au can dis up memb ane bilaye s and ac i a e human mac ophages ia
TLR4 [22]. Mo e ecen ly, Weliko i ch e al. epo ed ha neu ons laden wi h soluble and oligome ic Aβ
display a dis inc i e in lamma o y signa u e. This neu on-speci ic in lamma o y esponse may p ecede he
o ma ion o insoluble Aβ plaques and au angles, sugges ing ha in aneu onal Aβ accumula ion is an ea ly
pa hological e en wi h a subs an ial immunological componen [23].
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Figu e 1: In eg a ed Model o In lamma o y Signaling in Neu odegene a ion
In lamma o y ecep o s on he su ace o immune cells, pa icula ly glial cells, ac as senso s ha de ec
abno mali ies in he human body. S imula ion o hese ecep o s by damage-associa ed molecula pa e ns
(DAMPs) o pa hogen-associa ed molecula pa e ns (PAMPs)—such as p o ein agg ega es, i uses, o
bac e ia—ac i a es in acellula signal ansduce s, which in u n s imula e ansc ip ion ac o s. These
ansc ip ion ac o s p omo e he sec e ion o in lamma o y media o s, he eby ampli ying he in lamma o y
esponse [10].
The Rela ionship Be ween Ca bon Dioxide (CO₂) and Alzheime ’s Disease (AD). This is an eme ging esea ch
a ea, especially conside ing ecen indings ela ed o ce eb al blood low, neu oin lamma ion, and acid–base
imbalance.
1. CO₂, Ce eb al Blood Flow, and Hypoxia. Ele a ed a e ial CO₂ (hype capnia) causes ce eb al asodila ion.
Howe e , ch onic CO₂ ele a ion can impai ce eb al au o egula ion and oxygen deli e y. Hype capnia also
al e s blood–b ain ba ie (BBB) pe meabili y and may exace ba e hypoxia-induced neu onal inju y. Impai ed
ce eb al pe usion con ibu es o ascula demen ia and inc eases he isk o AD [24,25].
2. CO₂ and B ain pH (Acidosis). CO₂ eac s wi h wa e o o m ca bonic acid, lowe ing b ain pH. Acidosis
a ec s:
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Enzyme unc ion, inc easing amyloid β-p o ein (Aβ) exp ession in hippocampal neu ons and
p omo ing Aβ accumula ion [24].
Tau phospho yla ion and agg ega ion [25].
3. CO₂ and Neu oin lamma ion. Ele a ed CO₂ has been linked o ac i a ion o in lamma o y signaling,
including in e leukin-1β p oduc ion. The NF-κB and NLRP3 in lammasome pa hways a e ac i a ed unde
hype capnic condi ions [26–28]. While mic oglia play a p o ec i e ole in clea ing Aβ plaques du ing he ea ly
s ages o AD, hei ch onic ac i a ion can ha e de imen al consequences, such as exace ba ing au pa hology
and p omo ing neu onal apop osis [29].
4. CO₂, P o ein Agg ega ion, and Clea ance. CO₂-induced acidosis impai s p o ein clea ance mechanisms.
Al e a ions in endosomal and lysosomal pH, along wi h global b ain acidi ica ion, a e associa ed wi h inc eased
amyloid-β agg ega ion and educed solubili y [30].
5. Expe imen al Models Linking CO₂ o AD-like Changes. Animal s udies sugges ha CO₂ exposu e can
di ec ly in luence AD pa hology. Ch onic hype capnia in oden models has been shown o inc ease APP
exp ession, p omo e Aβ accumula ion, and enhance au phospho yla ion [31].
Summa y
Ca bon dioxide may con ibu e o Alzheime ’s disease h ough mul iple in e connec ed mechanisms:
Dis up ion o ce eb al blood low and oxygena ion.
B ain acidosis leads o al e ed calcium signaling and enzyme ac i i y.
Ac i a ion o neu oin lamma o y pa hways.
Impai ed clea ance and inc eased agg ega ion o amyloid-β and au p o eins.
Me hods
To ou knowledge, his is he i s s udy o in es iga e he ole o CO₂ in he pa hogenesis o Alzheime ’s
disease. I is impo an o no e ha , due o he p esence o uncon olled ex aneous a iables, his s udy can
sugges a possible associa ion bu canno es ablish causali y. The assessmen o a e ial pa ial p essu e o CO₂
(PaCO₂) has long been conside ed a gold s anda d in clinical e alua ion. These measu emen s a e pa icula ly
ele an in he con ex o clima e change and indoo ai quali y, as hey in o m en ila ion s anda ds.
Fu he mo e, calcula ions in ol ing CO₂ p oduc ion and oxygen consump ion yield me abolic indices ha can
be u he explo ed in a ious ields [30]. Based on exclusion c i e ia designed o minimize con ounding, CO₂
exposu e was selec ed as a p ima y a iable in bo h he s udy design and assessmen .
S udy Design. This case-con ol s udy employed pa icipan selec ion based on es ablished ma ching c i e ia
linked o known associa ions wi h he ou come o in e es .
Se ing and Pa icipan s. The s udy was app o ed by he adminis a i e boa ds o Hu ghada, Ma sa Alam, and
Nasse Ins i u e Hospi als in Cai o, Egyp . In o med consen o labo a o y es ing was ob ained om all
pa icipan s in acco dance wi h hospi al egula ions. The s udy p o ocol adhe ed o he e hical s anda ds o he
1975 Decla a ion o Helsinki.
Va iables. Cases and con ols we e ma ched o po en ial con ounde s and ec ui ed om he same geog aphic
and demog aphic popula ion. Pa ame e s such as age, sex, u baniza ion le el, socioeconomic s a us, and
como bidi ies we e balanced be ween g oups. Demog aphic da a we e collec ed ia ques ionnai e, including
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age, sex, occupa ion, smoking s a us, amily his o y, and his o y o ch onic espi a o y illness o occupa ional
CO₂ exposu e, in acco dance wi h he c i e ia se by he Na ional Ins i u e o Occupa ional Sa e y and Heal h
(Augus 1976). Indi iduals wo king in a ming, mining, o CO₂- ela ed indus ies we e excluded.
Da a Sou ces and Measu emen . Cases we e iden i ied om pa ien os e s a pa icipa ing hospi als, while
con ols we e d awn om he same sou ce popula ion. Bo h g oups we e ma ched by sociodemog aphic ac o s.
Eligible cases we e ec ui ed om bo h ou pa ien and inpa ien se ings. A e ial blood gases we e measu ed
using he ABL90 FLEX PLUS analyze o de e mine Pa CO₂ le els. Pa icipan s we e s a i ied based on
whe he hei PaCO₂ alues we e abo e o below he median. The s anda d e e ence ange o PaCO₂ was 35–
45 mmHg.
Sample Size and Bias. Be ween Oc obe 2024 and June 2025, 78 cases (40 males, 38 emales) and 45 con ols
(24 males, 21 emales), aged 65–76 yea s, we e en olled. While he g oup sizes di e ed, he p ima y ocus was
on he pe cen age o e en occu ence and he compa a i e s eng h o associa ion, bo h o which a e app op ia e
indica o s in case–con ol s udies. The analysis was es ic ed o CO₂ exposu e and alida ed using wo
s a is ical me hods: pe cen age o e en occu ence and mean ± s anda d de ia ion.
Quan i a i e Va iables. Pa icipan s we e sc eened o exclude condi ions a ec ing PaCO₂, such as
ca diopulmona y diseases, obs uc i e sleep apnea, c i ical illness, and mul isys em o gan ailu e. Diagnos ic
es ing o Alzheime ’s disease was conduc ed when clinically indica ed.
S a is ical Analysis. Da a we e ei he no mally dis ibu ed o he sample size was su icien o he Cen al Limi
Theo em o apply. Independen g oup compa isons we e pe o med using manual calcula ions equi alen o he
ollowing so wa e ools: IBM SPSS 29, R ( 4.3.1), and Py hon’s SciPy module (s a s. es _ind wi h
equal_ a =False). Demog aphic cha ac e is ics we e compa ed using - es s, adjus ed odds a ios, 95%
con idence in e als (CIs), and p- alues.
Alzheime ’s Disease Diagnos ic C i e ia:
G adual onse (o e mon hs o yea s).
P og essi e cogni i e decline, ypically beginning wi h memo y impai men and po en ially a ec ing
language, isuospa ial skills, and execu i e unc ion.
In e e ence wi h daily unc ioning.
No explained by o he causes (e.g., s oke, dep ession, o o he demen ias).
Suppo i e ea u es (no equi ed):
Bioma ke s (CSF, PET) indica ing amyloid and au pa hology.
MRI showing medial empo al lobe a ophy.
Diagnos ic Ca ego ies:
A. P obable AD demen ia: Typical p esen a ion wi h unc ional impai men .
B. Possible AD demen ia: A ypical p esen a ion o mixed pa hology.
C. Mild Cogni i e Impai men due o AD: Memo y decline wi hou comple e loss o independence [33–
35].
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RESULTS
Table 1: Demog aphic cha ac e is ics o cases and con ols.
Va iable
Cases No. (%)
(n =78),
Con ols No. (%)
(n =45),
Odds a io, o Mean di e ence
(95% CI), P alue
Sex ( emale)
33 (42.3)
20(44.4)
OR=0.92 [0.44, 1.92]
p ≈ 0.82
Age, mean
(S.D.), yea s
71.29 ±1.63
70.84 ± 2.17
MD = 0.45 [-0.28, 1.18]
P ≈ 0.23
To al annual
ou come, $
≤ 12000.
12000 – 30000
≥ 30000
47 (60.3)
25 (32)
6 (7.7%)
27 (60.0)
14 (31.1)
4 (8.9)
Smoke s
16 (20.5)
8 (17.8)
1.19 [0.46, 3.05], P ≈ 0.72
No s a is ically signi ican associa ion be ween case/con ol s a us and smoking (p > 0.05).
The e was no s a is ically signi ican di e ence in age be ween cases and con ols. Simila ly,
no signi ican di e ence was obse ed in he odds o being emale be ween he wo g oups (p
> 0.05). Addi ionally, smoking s a us was no signi ican ly associa ed wi h case/con ol
classi ica ion (p > 0.05).
Table 2: Compa ison o mean pa ial p essu e o ca bon dioxide (Pa CO
₂
) in a e ial blood
be ween cases and con ols
G oup
N
Mean Value o PaCO2
SD
SE, 95% C I
P alue
Cases
78
46.20
2.26
0.518, (1.44, 3.50)
< 0.0001
Con ol
45
43.73
3.02
No e: Pa CO₂ = pa ial p essu e o ca bon dioxide in a e ial blood. The e was a highly
signi ican di e ence in Pa CO₂ be ween cases and con ols.
Table 3: Compa ison o ele a ed Pa CO
₂
a es be ween cases and con ols
G oup
No. (%) wi h ele a ed
PaCO2
No. (%) wi hou
ele a ed PaCO2
To al
Cases
54 (69.2)
24 (30.8)
78
Con ols
9 (20.0)
36 (80.0)
45
To al
63
60
123
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The p- alue o a wo- ailed es was < 0.00001, indica ing an ex emely signi ican
di e ence in he p opo ion o subjec s wi h ele a ed Pa CO₂ be ween cases and con ols.
Ca ego ies 1&2
Figu e 2: Blue columns ep esen cases. B own columns ep esen con ols.
Ca ego y 1: Ra e o inc ease in Pa CO₂.
Ca ego y 2: Mean Pa CO₂ alues.
DISCUSSION
The wo ld is cu en ly acing an unp eceden ed and li e-al e ing challenge in esponse o clima e change. The
unique physicochemical p ope ies o ca bon dioxide (CO₂) signi ican ly in luence cellula elec ical po en ial,
pH egula ion, he mal capaci y o abso b and e-emi in a ed adia ion, gas-like di usi i y, and liquid-like
sol a ing powe .
This s udy is he i s o elucida e he associa ion be ween ca bon dioxide (CO₂) and he inc eased incidence o
Alzheime ’s disease (AD). Ou indings indica e ha he pa ial p essu e o a e ial CO₂ (PaCO₂) is di ec ly
p opo ional o he numbe o AD cases. Al hough no p io esea ch has documen ed his ela ionship, we
iden i y mul iple pa hogenic mechanisms implica ed in AD e iology. These appea o be media ed h ough
downs eam pa hways igge ed by CO₂’s di ec e ec s on Tau–mic o ubule unc ional in eg i y, al e a ions in
he enzyma ic clea ance o β-amyloid, and CO₂-media ed dis up ion o calcium channels and in acellula
signaling.
Gi en ecen ad ances in calcium (Ca²⁺) signaling esea ch and he g owing p e alence o neu odegene a i e
diseases, we explo ed CO₂’s po en ial ole in he pa hogenesis o such diso de s, p ima ily AD. We p opose a
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mechanis ic model in eg a ing CO₂, Ca²⁺ signaling, calcium channels, seconda y messenge s, and AD
p og ession. This model is suppo ed by e idence o a p ecise link be ween CO₂ and Ca²⁺ signaling. No ably,
Ca²⁺ signals encode in o ma ion ia hei equency, kine ics, ampli ude, and spa ial dis ibu ion, enabling
complex in a- and in e cellula communica ion.
CO₂’s mul i ace ed ac ions may con ibu e o neu odegene a ion h ough in e connec ed pa hways in ol ing
memb ane ecep o s, cy okines, in e leukins, genes, and messenge RNAs. Collec i ely, ou esul s suppo he
hypo hesis ha CO₂ can ini ia e, s abilize, and sus ain AD pa hogenesis. Kuma e al. ecen ly highligh ed he
link be ween cy okine-media ed diso de s and an ioxidan -based he apies [36]. CO₂ possesses dis inc i e
physicochemical ai s—such as becoming a supe c i ical luid abo e i s c i ical empe a u e and p essu e,
exhibi ing bo h gas-like di usi i y and liquid-like sol a ing powe , and demons a ing high aqueous
solubili y— ha make i a compelling esea ch a ge [37]. I s capaci y o abso b and e-emi in a ed adia ion
unde lies i s cen al ole in an h opogenic clima e change. Gi en i s long a mosphe ic li e ime and cumula i e
adia i e o cing, CO₂ emains he p ima y a ge o global emission educ ion and ca bon cap u e s a egies
[38].
In aqueous en i onmen s, CO₂ o ms ca bonic acid (H₂CO₃), which apidly equilib a es wi h bica bona e and
ca bona e ions [39]. Ele a ed empe a u es p omo e wa e au oioniza ion and shi acid–base equilib ia in
acco dance wi h Le Cha elie ’s p inciple, lowe ing solu ion pH—a phenomenon well es ablished bo h
heo e ically and expe imen ally [40]. We sugges ha his acidi ica ion could con ibu e o AD pa hogenesis by
al e ing p o ein con o ma ion, enzyme ac i i y, and neu onal mic oen i onmen s. P elimina y e idence also
sugges s a po en ial associa ion be ween CO₂ and au oimmune diso de s [41,42], wi h ecen mechanis ic
insigh s p o ided by Abdel azak e al. [43]. Inc easing ecogni ion o immune dys egula ion in
neu odegene a ion—suppo ed by he disco e y o immune- ela ed gene ic isk ac o s—has spu ed in e es in
a ge ing neu oin lamma ion o p e en cen al ne ous sys em damage [10].
We u he p opose ha CO₂-d i en acidi ica ion may p o ona e his idine esidues, leading o imidazole ing
ioniza ion and con o ma ional shi s ha ac i a e he e o ime ic G p o eins, inc ease in acellula cAMP, and
modula e signaling. This pH- esponsi e beha io o his idine is ele an o he acidic b ain en i onmen s
obse ed in AD [44–46].
Ou indings also sugges ha mechanical and he mally induced memb ane luc ua ions can modi y subcellula
ecep o opology, in luencing cellula signaling and p o ein olding. CO₂ may exace ba e p o ein mis olding
ia:
In acellula Acidosis — des abilizing hyd ogen bonds, elec os a ic in e ac ions, and disul ide b idges
[48].
P o ein Ca bamyla ion — al e ing p o ein cha ge and s uc u e h ough non-enzyma ic CO₂ eac ions
[49].
Chape one Dys unc ion — impai ing HSP-media ed olding unde hype capnic s ess [50].
Endoplasmic Re iculum S ess — ac i a ing he un olded p o ein esponse, leading o apop osis [51].
Addi ionally, ecep o opology changes may impai immune-media ed β-amyloid clea ance [52], while ele a ed
empe a u es can des abilize mic o ubules and collapse hei ne wo ks [53–55]. Acidic condi ions may also
In e na ional Clinical and Medical Case Repo s Jou nal
Resea ch A icle (ISSN: 2832-5788)
In Clinc Med Case Rep Jou (ICMCRJ) 2025 | Volume 4 | Issue 11
ECE = Endo helin-Con e ing Enzyme
MMPs = Ma ix Me allop o einases
VGCCs = Vol age-Ga ed Calcium Channels
Acknowledgmen s
We hank Ahmed Ali, an expe in in o ma ion sys ems, and Shehab Ali, an expe in compu e science, o hei
aluable discussions and assis ance wi h his s udy.
Disclosu e o Con lic o In e es
The au ho s decla e ha hey ha e no known compe ing inancial in e es s ha could ha e in luenced he wo k
epo ed in his pape .
Funding
The au ho s con i m ha hey did no ecei e any inancial suppo om indi iduals o o ganiza ions o his
s udy.
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