Kettunen et al. Journal of Neuroinflammation
https://doi.org/10.1186/s12974-024-03139-y(2024) 21:152

Journal of Neuroinflammation

Open Access

REVIEW

Contribution of CNS and extra‑CNS
infections to neurodegeneration: a narrative
review
Pinja Kettunen1, Jari Koistinaho1* and Taisia Rolova1

Abstract
Central nervous system infections have been suggested as a possible cause for neurodegenerative diseases, particularly sporadic cases. They trigger neuroinflammation which is considered integrally involved in neurodegenerative processes. In this review, we will look at data linking a variety of viral, bacterial, fungal, and protozoan infections
to Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis and unspecified dementia.
This narrative review aims to bring together a broad range of data currently supporting the involvement of central
nervous system infections in the development of neurodegenerative diseases. The idea that no single pathogen
or pathogen group is responsible for neurodegenerative diseases will be discussed. Instead, we suggest that a wide
range of susceptibility factors may make individuals differentially vulnerable to different infectious pathogens
and subsequent pathologies.
Keywords Neuroinflammation, CNS infection, Neurodegeneration, Brain infections, Alzheimer’s disease, Parkinson’s
disease, Amyotrophic lateral sclerosis, Multiple sclerosis
BackgroundCentral nervous system (CNS) infections have been suggested to act as a possible trigger for neurodegenerative
diseases such as Alzheimer’s disease (AD), Parkinson’s
disease (PD), amyotrophic lateral sclerosis (ALS) andmultiple sclerosis (MS). They are particularly interesting
when trying to explain the high prevalence of sporadic
neurodegenerative diseases which genetic factors alone
are unable to explain.
For a while, the field of neurodegeneration has
been dominated by the idea that neurodegenerative
diseases are caused by the pathological accumulation of toxic aggregating proteins such as amyloid-β(AD), α-synuclein (PD). However, the processes that
*Correspondence:
Jari Koistinahojari.koistinaho@helsinki.fi
1
Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finlandtrigger protein accumulation in various brain areas arestill poorly understood, apart from rare familial cases
where the accumulation is caused by dominantly inherited mutations. Since research targeting aggregating proteins has been limited in its ability to produce effective
treatments, many researchers have turned towards complementary hypotheses [1].
The ‘infection hypothesis’ suggests that infections canpush the system to pathology by direct harm caused by
the infection or by triggering neuroinflammation [1–3].
As we will later see, microbes can harm the host organism in multiple ways, such as via toxic molecules, inhibition of host immune function, disruption of tissue
tight junctions, induction of proteotoxic stress, or bydirectly killing host cells. On the other hand, they trigger
an immune response which can be detrimental to hostcells (‘bystander effect’) especially if the inflammatory
state becomes chronic. However, not all infections leadto neurodegeneration, and genetic susceptibility factors© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
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regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of thislicence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Kettunen et al. Journal of Neuroinflammation(2024) 21:152

may help explain why some people are more vulnerable
to the detrimental effects of infections than others. Furthermore, infections are only one possible cause for neuroinflammation alongside other factors such as traumatic
injury, ischemic injury, autoimmunity, metabolic disease,and lifestyle (diet, sleep, exercise, stress, smoking) which
we will not cover here.
To assess whether infections are involved in neurodegeneration, we need to determine (a) whether patients
suffering from neurodegeneration have a history of CNS
infections, (b) whether non-CNS infections can cause
neurodegeneration without direct CNS invasion, (c)whether infections increase risk of neurodegeneration,and (d) whether infections are able to induce neuroinflammation and neurodegeneration-related changes atthe cellular and tissue level, possibly even after infection
clearance. It would also be important to know whether
pathogen infections and known risk factors for neurodegenerative diseases interact, and whether eradicating
infections is an effective treatment and/or prevention
strategy for neurodegenerative diseases. Since aggregating proteins are integral to neurodegenerative diseases,
we will look at how aggregating proteins and infections
could fit into the same picture.

Main text
Prevalence of CNS infections in the global population

Neurological symptoms such as fatigue, headache, sensory changes, cognitive changes, psychosis, seizures,paresis, and coma are common symptoms of many
infectious diseases [4]. For example, around 20–30% of
all Covid-19 patients have been reported to have neurological symptoms such as fatigue or cognitive impairment even months after acute respiratory infection [5].
It is often difficult to know whether the neurologicalsymptoms are secondary to the systemic disease state orcaused by direct infection of the CNS. However, a varietyof pathogens from viruses and bacteria to fungi and protozoa have been detected in the CNS using histochemical and molecular biology methods [6]. In fact, many
globally significant diseases, such as malaria, borreliosis/
Lyme disease, HIV, diphtheria, tuberculosis, candidiasis,and syphilis have neurological presentations where theotherwise systemic infection enters the brain [4].
Differences in target tissues, infection routes, replication, and release patterns are likely to affect theoutcome of the infection [7]. Some CNS-infiltrating
pathogens specifically target brain cells such as neurons or glia. For example, rabies virus, Zika virus, tickborne encephalitis virus and herpes viruses specificallytarget neurons. They often cause severe disturbance of
the CNS homeostasis, such as encephalitis or meningitis, which can cause death or disability. Such severe

Page 2 of 30

infections are associated with many disorders including
neurodegeneration in survivors [8–12].
Other pathogens are more likely to enter the CNS
during disturbance such as immunodeficiency, inflammation, blood–brain barrier (BBB) breakdown, trauma,
neurosurgical procedures or other infections. Suchpathogens include Candida yeasts, Cryptococcus andMycorales fungi, the protozoan parasite Toxoplasma
gondii, as well as the bacteria Streptococcus pneumoniae, Staphylococcus aureus and Mycoplasma sp. [13].
These microbes can cause encephalitis in immunocompromised patients, but such severe representations arerare in otherwise healthy individuals.
Certain pathogens, such as Helicobacter pylori, periodontal bacteria, and gut microbes, have been linked
to neuropathology without a direct infection of the
CNS. In fact, changes of the gut-brain axis, such as gut
dysbiosis (imbalance of the gut microbiome), are very
common in patients of neurodegenerative diseases[14]. It is thought that systemic inflammation caused byextra-CNS infections can jump across the CNS barriers (most notably the BBB) via proinflammatory factors
such as cytokines, extracellular vesicles, and small lipid
mediators, which triggers neuroinflammation [15–20].
Interestingly, this jump can occur prior to BBB disruption [21] which suggests that systemic infections could
disturb BBB function from both sides. Furthermore,changes in the gut-brain axis can affect the CNS also
via the secretion of neurotransmitters, vitamins, important fatty acids such as butyrate, and amyloid proteins
by gut microbes [14].
Finally, most neurodegenerative disease patients do
not have a history of severe CNS pathologies such as
encephalitis or meningitis. Thus, common pathogens
that cause milder infections have gained the interest ofscientists. For example, most of us carry latent infections (Table 1) which means that such infections could
potentially explain common diseases such as dementias.
Latent infections are characterized by alternating active
and quiescent periods, where the pathogens hide fromthe immune system only to reactivate under favorable
conditions such as stress-induced immunosuppression.
To do this, they use immunomodulatory molecules [22,23], biofilms [24], cysts [25], encapsulation [23], and integration to the host genome (viruses) [26]. While the reactivation of latent infections can lead to severe pathology
such as encephalitis [11], majority of these infections are
mild or asymptomatic. However, the chronic presenceof these pathogens in the CNS is thought to cause long
lasting or reoccurring neuroinflammation [25, 27, 28].
In fact, latent infections have been linked to severe conditions such as cancer [29–31] and neurodegenerative
diseases.

Kettunen et al. Journal of Neuroinflammation(2024) 21:152

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Table 1 Examples of common pathogens that cause chronic latent infections and their prevalence in different adult humanpopulations
Virus

Abbreviation Associated disease

Immunoglobulin G prevalence,adult(females, males or pooled)

Known toenter the
CNS

Refs.

Human herpesviruses
Herpes simplex virus 1/Human
herpesvirus 1

HSV-1

Cold sores, encephalitis UK: 71%, 69% (female, male)
Latin America & the Caribbean: 88%(pooled)Middle East & North Africa: 92%(pooled)
Sub-Saharan Africa: 96% (pooled)
Asia: 77% (pooled)
East Asia (Japan): 63%, 55% (female,
male)

Yes

[32–36]

Herpes simplex virus 2/Human
herpesvirus 2

HSV-2

Genital herpes

Europe: 11%, 5% (females, males)
Eastern Mediterranean: 8%, 3%(females, males)
UK: 17%, 15% (females, males)
Americas: 24%, 12% (females, males)
Latin America & Caribbean: 25%, 14%(females, males)
Africa: 44%, 25% (females, males)
South-East Asia: 10%, 7% (females,
males)
East Asia (Japan): 7%, 9% (females,
males)
Western Pacific: 15%, 7% (females,
males)

Yes[32, 33, 37, 38]

Varicella zoster virus/Human
herpesvirus 3

VZV, HHV-3

Chicken pox, Varicella,
Shingles,Herpes zoster

UK: 91%, 94% (females, males)
Western Europe (Netherlands): 95%,
93% (females, males)
US: 98% (pooled)
Middle East (Iran): 78% (pooled)
East Asia (South Korea): 93% (males)Yes[32, 39–42]

Epstein-Barr virus/Human herpesvirus 4

EBV, HHV-4

Mononucleosis

UK: 96%, 93% (females, males)
US: 89% (pooled)
Middle East (Qatar): 100%, 96%(females, males)
Sub-Saharan Africa (Nigeria): 20%(pooled)East Asia (China): 90%(pooled, > 8-year-olds)
Australia: 89%, 96% (females, males)Yes[32, 43–46]

Cytomegalovirus/Human herpesvirus 5

CMV, HHV-5

Europe: 45–95%, 35–44% (females,
Yes
males)
UK: 59%, 96% (females, males)
North America: 24–81%, 48% (females,
males)
Latin America: 58–94% (females)
Africa: 55–97% (pooled)
East Asia (Japan): 60% (females)[32, 47, 48]

Human (beta)herpesvirus 6

HHV-6

UK: 91%, 90% (females, males)
Northern Europe (Finland): 86%(pooled)Western Europe (France): 76%(females)US: 98% (pooled)
Middle East (Qatar): 93%, 71%(females, males)
South America (Brazil, Ecuador):
91–92%, 90% (females, males)
Northern Africa (Morocco): 20%(females)Sub-Saharan Africa: 60–90% (females)
East Asia (Japan): 79% (pooled)[32, 49–53]

Yes

Kettunen et al. Journal of Neuroinflammation(2024) 21:152

Page 4 of 30

Table 1 (continued)
Virus

Abbreviation Associated disease

Immunoglobulin G prevalence,adult(females, males or pooled)

Known toenter the
CNS

Refs.

Human (beta)herpesvirus 7

HHV-7

UK: 96%, 93% (females, males)
Central America (Mexico): 98%(pooled)South Africa: 99% (pooled)
East Asia (Japan): 44% (pooled)
Germany/Israel/Poland/Australia/US:
75–85% (pooled)Yes[32, 54, 55]

Kaposi’s sarcoma-associated herpesvirus/Human herpesvirus 8

HHV-8

UK: 8%, 9% (females, males)
Southern Europe (Spain): 7%, 6%(females, males)
Middle East (Iran): 15% (females)
US: 3–5% (pooled)
Sub-Saharan Africa: 40% (pooled)
The Caribbean: 3% (pooled)
South-East Asia: 4% (pooled)No[32, 56–60]

Anogenital cancers

Among asymptomatic individuals:
Africa: 21–23%, 17% (females, males)
Eastern Africa: 35%, 38% (females,
males)
North America: 5–14%, 9–45%(females, males)
South America: 14–17%, 9–34%(females, males)
Central America: 21%, 26% (females,
males)
Europe: 7–10%, 7–31% (females,
males)
Eastern Europe: 29%
Asia: 8–11%, 3% (females, males)
Eastern Asia: 19%, 15% (females,
males)

No[61–64]

Toxoplasmosis

Europe: 30% (females)
Northern Europe (Finland): 14%, 20%(females, males)
UK: 27%, 29% (females, males)
Eastern Europe (Serbia): 45%, 55%(females, males)
Eastern Mediterranean: 40% (females)
USA & Canada: < 10% (females)
Latin America: 45% (females)
Africa: 31–40%, 30% (females, males)
South-East Asia: 25% (females)
Western Pacific: 11% (females)Yes[32, 65–69]

Human papillomaviruses
Human papillomaviruses

HPV

Parasites
Toxoplasma gondii

General mechanisms of microbe‑induced pathology
in the brain

Potential mechanisms for microbial neuropathology are
diverse. Many of them are secondary to the microbe’s
attempt to infect, survive and replicate inside the host.
For example, many viruses and intracellular parasites lyse
the host cell as part of their reproductive cycle to release
the newly produced pathogens. However, there are otherways in which pathogens are harmful. For example, many
molecules that microbes use to survive can be toxic to
the host [70]. Furthermore, the infiltration of pathogens

into host tissues via pore formation [71], modulation ofadhesion proteins [72], and hijacking of the host endocytosis [73] can disrupt important host cell-to-cell contacts[74, 75], cause the fusion of adjacent cells (syncytia) [75–78], and cause leakage of molecules across host barriers
such as the BBB [75].
Similarly, by hijacking the host protein synthesis
machinery, cytoskeleton, and intracellular transportsystem, the pathogen facilitates its own replication andspread. Simultaneously, it can also disrupt the homeostatic function of the host cell, such as normal protein

Kettunen et al. Journal of Neuroinflammation(2024) 21:152

synthesis and axonal transport [79, 80]. This can lead toproblems such as proteotoxic stress [81]— a common
occurrence in neurodegenerative diseases [82].
Furthermore, the immunomodulatory and immunosuppressive tactics utilized by pathogens to evade thehost immune system [22, 23, 83] can lead to secondary
infections, or to the disruption of homeostatic functions
performed by the immune cells, e.g. waste clearance performed by microglia.
Finally, host immune response to pathogen surface
structures or secreted products can become as detrimental as the infection itself. For example, cytokines,
antimicrobial molecules, reactive oxygen species (ROS),
nitric oxide, phagocytosis, and forced cell death are usedby immune cells to destroy pathogens [84]. These samemechanisms can be harmful to nearby host cells if there
is no balance between optimal pathogen clearance andexcessive inflammatory response [75, 84].

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its effect on lipid membranes, APOE is involved in manycellular functions, including the regulation of immune
cells such as microglia [87, 88].
Many other risk mutations for AD are enriched in
microglia, including mutations in TREM2, ABI3, ABCA7,
CD33, and CR1 [89–91]. For example, triggering receptor
expressed on myeloid cells 2 (TREM2) regulates microglial functions such as phagocytosis, microglial activation, and inflammatory responses, which are crucial for
CNS immunity. Rare mutants of TREM2, such as the single nucleotide mutation R47H, have been associated withincreased risk of AD and other dementias [92, 93].
Parkinson’s disease

World Health Organization estimates that around 55 million people are affected by dementia around the world
and the number is thought to increase to 139 million
by 2050 [85]. Dementia itself is not a disease but a syndrome (a collection of symptoms) which describes thedecline of cognitive abilities such as memory, learning,
concentration, planning, motivation, language processing, reasoning, and thinking. It also affects mood and cancause anxiety, depression, or aggression. The most common causes for dementia are AD (70% of all cases), frontotemporal dementia, vascular dementia, and dementia
with Lewy bodies. All of them have slightly different
main symptoms and disease dynamics, but the overlap
between diseases is considerable. Determining which disease causes dementia in each patient is difficult and often
based on symptoms alone. Thus, many studies handle
dementia as a collective unit.

PD is the second most common neurodegenerative disease after AD. In 2019 it was estimated to have affected
over 8.5 million individuals globally [94]. PD is the mostcommon cause of parkinsonism, a motor disorder characterized by tremors, rigidity, bradykinesia, and posturechanges. PD also causes a variety of gastrointestinal (GI)symptoms. The symptoms are a result of the progressive
loss of dopaminergic neurons of substantia nigra. The
process is associated with neuroinflammation and theaccumulation of amyloid-like α-synuclein.
Many important PD risk genes are involved in endosomal (LRRK2, SNCA) and lysosomal (GBA, TMEM175,
CTSB) function, mitophagy (PINK1, PARK2), autophagy(SNCA, KAT8), RNA processing (TARDBP), and antigen
presenting (HLA-DRB6, HLA-DQA1) [95]. Many of thesefunctions are important for immune response. Thus,
mutations in these pathways can make an individual
susceptible to the negative effects associated with infections. For example, the PD risk mutation p.G2019S in the
LRRK2 gene lead to higher reovirus mortality in mutant
mice compared to wildtype animals. The effect seems to
be caused by heightened inflammatory response [96, 97].
Interestingly, the LRRK2 p.G2019S mice were better atcontrolling septic Salmonella typhimurium infection [96]which hints at a pathogen-specific effect.

Alzheimer’s disease

Amyotrophic lateral sclerosis (ALS) and ALS‑like syndromes

AD causes around 60–70% of all dementia cases [85]. It
is characterized by progressive degeneration of the brain
parenchyma and the accumulation of proteinaceous
amyloid-β and tau inclusions. The pathology is associatedwith neuroinflammation, glial activation, and dysfunction of the BBB and the brain blood circulation.
Apolipoprotein E (APOE) ξ4 allele is the most prevalent genetic risk factor for late-onset AD (begins after
the age of 65). It increases the risk of AD ~ threefold inheterozygotes and ~ 15-fold in homozygotes [86]. APOE
is a lipid carrier molecule that facilitates the traffickingof cholesterol and phospholipids between cells. Due toAmyotrophic lateral sclerosis, also known as Lou Gehrig’s
Disease, is a fatal motor neuron disease characterized byprogressive degeneration of upper and lower motor neurons. It leads to muscle weakness and the loss of motor
control, which leads to death when it spreads to respiratory muscles. Intracellular aggregation of proteins suchas transitive response DNA-binding protein 43 (TDP43), fused in sarcoma (FUS) and superoxide dismutase 1(SOD1) are common.
Noncoding hexanucleotide GGG​
GCC​repeat expansion in C9orf72 is the most common genetic mutation
found in ALS patients (40–50% of familial cases, 5–10%

A brief introduction of discussed neurodegenerative
diseases
Dementia (unspecified)Kettunen et al. Journal of Neuroinflammation(2024) 21:152

of sporadic cases) and frontotemporal dementia [98]. The
gene is involved in many cellular functions including lysosomal function, stress granule formation and immune
function. Several gain-of-function and loss-of-function
mechanisms have been suggested to explain how mutations in C9orf72 increase ALS risk [99, 100].
Several mutations in SOD1 explain around 2% of all
ALS cases and 20% of familial cases. SOD1 is an important antioxidant enzyme that protects cells from ROS,
which is secreted by immune cells during pathogen infections [101]. A combination of infection and genetic susceptibility to ROS could make an individual vulnerable toneurodegeneration [102].
Multiple sclerosis

MS is the most common inflammatory demyelinating
disease in the brain and spinal cord. It affects around
2.8 million people worldwide [103]. It is characterized
by defects in sensory, motor, and autonomic functions.
The most common clinical course involves alternating
relapses and remissions where flare-ups of symptoms arefollowed by periods of full or partial recovery. Common
histopathological findings include focal demyelinatedplaques or lesions surrounded by activated T-cells andmyeloid cells such as microglia. The leading theory is that
MS is caused by autoimmunity against host myelin-producing cells. In fact, many MS risk genes are involved in
autoimmunity, such as the human leukocyte antigen class
II allele HLA-DBR1*15:01 and the interleukin 2 receptor
subunit alpha (IL2RA) [104]. The possible role of infections in MS remains unknown. On the one hand, microbial molecular mimics of myelin-associated proteins suchas the myelin basic protein (MBP) could trigger autoimmunity [105, 106]. On the other hand, it has been suggested that excessive hygiene in modern societies leads to
deficient training of immune cells which can cause themto attack host tissues (‘the hygiene hypothesis’).
Role of pathogens in neurodegenerative diseases

Many CNS-infiltrating pathogens have been found in
neurodegenerative disease patients using histological and
PCR-based methods. Many of them show positive associations with neurodegeneration in population level studies(often around 1.3–3.0-fold increase in risk, see Table 2).
The strength of these associations is of the same magnitude as other commonly accepted neurodegenerationassociated factors such as cardiovascular disease, stroke,and sleep disorders [107–112].
Furthermore, in vitro cell culture studies and in vivo
animal models have shown that many pathogens can
induce neuroinflammation and neurodegenerationrelated changes, such as glial activation, leukocyte infiltration, cytokine production, BBB dysfunction, and thePage 6 of 30

accumulation of neurodegeneration-related aggregating
proteins.
The diversity of pathogens that have been implicated inneurodegenerative diseases is striking, even though noneof the connections have been conclusively proven. For
example, Sipilä et al. screened the association of hospital-treated pathogen infections (925 International Classification of Diseases-10 codes) with dementia using the
medical records of over 700 000 participants in Finnish
and United Kingdom databanks. The dataset included
pathogens of all classes: viruses, bacteria, fungi, and protozoan parasites, and both CNS and non-CNS infections.
All types of infections increased the risk of dementia
which suggests that there is no single pathogen or infection type that would be solely responsible for dementia. Furthermore, multiple simultaneous or subsequent
infections increased the risk of dementia more than single infections (adjusted hazard ratio (aHR) 5.08 vs. 3.04
respectively), particularly in the case of combined virus
and bacterial infections (aHR 8.15, 95% CI: 4.73–14.05)[116]. Similar results have since been published by Bohn
et al. [139]. However, there may be disease-specific differences. For example, Fang et al. found no association
between CNS infections and ALS in a study of 4000 ALS
patients and 20 020 matched controls [140].
Below, we will continue exploring this diversity byreviewing the data that supports the involvement of CNS
infections by herpesviruses, enteroviruses, HIV, SARSCoV-2, spirochete bacteria, bacterial pneumonia, fungi,
and T. gondii in unspecified dementia, AD, PD, ALS,
and MS (Fig. 1). We will also briefly mention extra-CNS
infections that have strong link to neurodegeneration,
namely periodontal disease, H. pylori infections, and gut
dysbiosis. Simultaneously, we will discuss the importanceof individual susceptibility, which may explain why neurodegeneration is triggered in some individuals whilemost are left unaffected. The final section of this review
discusses the idea that neurodegeneration-related aggregating proteins could function as innate immune proteinsthat bind microbes and repress their replication while
activating antimicrobial immune pathways.
Herpesviruses

The family of human herpes viruses includes herpes simplex virus 1 and 2 (HSV-1 and HSV-2), varicella-zoster
virus/human herpes virus 3 (VZV/HHV-3), Epstein-Barrvirus/human herpes virus 4 (EBV/HHV-4), cytomegalovirus/human herpes virus 5 (CMV/HHV-5) and humanherpes viruses 6, 7 and 8 (HHV-6, HHV-7, HHV-8). They
cause common ailments such as cold sores of the mouthand genitals (HSV-1 and HSV-2), chickenpox/shingles(VZV), and mononucleosis/ ‘the kissing disease’ (EBV).

Herpesvirus

HSV-1

VZV

1. HSV-1
2. VZV

PooledVZV

VZV

1. CMV2. EBV

CMV

1. HSV-1
2. CMV
3. EBV
4. VZV

CMV

HSV-1

HSV-1

DiseaseDementia

Dementia

Dementia

Dementia

Dementia

Dementia

Cognitive decline

Dementia

Cognitive decline

Cognitive decline

Alzheimer’s disease

Alzheimer’s diseaseaHR 1.12, 95% CI: 1.05–1.19

aHR 2.35, 95% CI: 1.38–3.98

1. aHR 1.18, 95% CI: 1.16–1.20,
p < 0.001
2. aHR 1.09, 95% CI: 1.07–1.11,
p < 0.001

HR 1.94, 95% CI: 0.78–4.80

aHR 1.18, 95% CI: 0.83–1.68

OR/HR/RR, 95% CI, p-value

IgG and IgM positive vs. negative
APOE ε4 carriers

Seropositive vs. Seronegative

Seropositive vs. Seronegative

IgG positive vs. Negative

Positive vs. negative
1. Age 40–59
2. Age 60–79
3. Age > 80

Seropositive vs. Seronegative

aHR 3.68, 95% CI: 1.08–12.55,
p = 0.04

aHR 1.13, 95% CI: 0.77–1.66

p = 0.425

1. p = 0.018
2. p = 0.011
3. p = 0.128
4. p = 0.187

1. OR 11.7, 95% CI: 2.5–49.4
2. OR 1.8, 95% CI: 1.1–3.2
3. OR 1.3, 95% CI: 0.5–2.8

1. HR 1.74, 95% CI: 0.12–15.0
2. HR 2.24, 95% CI: 0.36–16.4

1. Herpes zoster patients vs. control 1. aHR 1.11, 95% CI: 1.04–1.17
2. Antivirals vs. no treatment in her- 2. HR 0.55, 95% CI: 0.4–0.77
pes zoster patients

Herpes zoster patients vs. control

Persistent herpesvirus infection vs.
no infection

Infection vs. No infection

Herpes zoster CNS infection vs.
no infection

Seropositive vs. Seronegative

Comparison

CohortIncreased risk of AD in HSV-1 positive APOE ε4 carriers, but not in
non-carriers

No association between HSV-1
and decline in global cognition

No association between CMV
and cognitive decline in individuals age 40–70 year using multivariate testing

Poisson regression model
supported the association
between HSV-1, CMV and cognitive decline. No association
with EBV or VZVAssociation between CMV
and dementia

No association between cognitive
decline and CMV or EBV

Herpes zoster mildly increased
the risk of dementia
Antiviral therapy reduced the riskof dementia in herpes zoster
patients

Herpes zoster mildly increased
the risk of dementia

Persistent herpesvirus infection
increased the risk of dementia

Mild association between dementia and HSV-1 or VZV

No association between herpes
zoster and dementia

[114]

[113]

Refs.

[116]

Bordeaux-3c prospective cohort

Rotterdam StudyUK Biobank

Baltimore ECA cohort

Korea National Health Insurance
Database

Finnish Health 2000 Survey

Taiwan National Health Insurance
Research Database

[123]

[113]

[122]

[121]

[120]

[119]

[118]

South Korea National Health Insur- [117]ance Service

3 Finnish cohorts
UK biobank

South Korea National Health Insur- [115]ance Service

Danish nationwide

No association between dementia Rotterdam Studyand HSV-1. HSV-1 increased the riskof decline in global cognition

Conclusion/Additional info

Table 2 An overview of studies investigating the association between herpesviruses and dementia, AD, PD, ALS, or MS

Kettunen et al. Journal of Neuroinflammation(2024) 21:152
Page 7 of 30

Herpesvirus

pooledHSV-1

1. CMV
2. HSV-1

1. HSV
2. VZV

HSV-1

VZV

VZV

HSV-1

HSV-1

DiseaseAlzheimer’s disease

Alzheimer’s disease

Alzheimer’s disease

Parkinson’s disease

Parkinson’s disease

Parkinson’s disease

Parkinson’s disease

Parkinson’s disease

Parkinson’s disease

Table 2 (continued)

1. OR 0.79, 95% CI: 0.73–0.86,
p < 0.001
2. OR 0.88, 95% CI: 0.83–0.92,
p < 0.001

1. RR 2.15, 95% CI: 1.42–3.27,
p < 0.001
2. RR 0.84, 95% CI: 0.62–1.16,
p < 0.001

1. OR 4.55, 95% CI: 1.29–16.06,
p = 0.02
2. OR 2.35, 95% CI: 1.21–4.56,
p = 0.01

aHR 0.85, 95% CI: 0.75–0.96,
p = 0.009

OR/HR/RR, 95% CI, p-value

IgG titer in patients vs. Healthy
controls

IgG titer in patients vs. healthy
controls

herpes zoster vs. Control

herpes zoster vs. ControlNA

p < 0.001

aHR 1.17, 95% CI: 1.1–1.25

HR 1.50, 95% CI: 1.16–1.93

IgG titer with infection vs. no infec- p = 0.045
tion

1. Infection vs. no infection
2. Herpes zoster vs. control

Seropositive vs. Seronegative

1. IgG positive + APOE ε4 vs. negative controls
2. IgG positive + risk score vs. negative controls

Systemic antiherpetic drug vs.
untreated

Comparison

CohortRush Memory and Aging Project,
The Religious Orders Study,The
Minority Aging Research Study

Medical Biobank in UmeåTaiwan National Health Insurance
Research Database

Taiwan National Health Insurance
Research Database

IRCCS Santa Maria Nascente, Don
Gnocchi Foundation

Increased level of antibodies
against HSV-1 capsid, envelope,and excreted antigen in PD
patients

52 patients

Increased level of HSV-1 antibodies 40 patientsin’PD patients

Mild increase in PD risk in herpes
zoster patients

Association between PD and herpes zoster

HSV-1 antibody prevalence
and titer were slightly higher in’PD
patients. CMV and HHV-6 prevalence or IgG levels not altered.
Protective’AD protective mutationin PILRA was not associatedwith HSV-1 in’PD

Inverse association between PD
Medicare beneficiaries
and HSV, and PD and VZVAntiherpetic treatment reduced
the risk of PD. Included drugs: Acyclovir, Valacyclovir, Valganciclovir,
Famciclovir, Ganciclovir, Penciclovir

Association between CMV and AD
irrespective of race, HSV-1 status,or APOE ε4 status
No association between HSV_1
and AD

Increased risk of AD in HSV-1
positive APOE ε4 heterozygotes
but not in APOE ε4 non-carriers.
Risk also increased by a risk scorethat was calculated using nine
genes: ABCA7, BIN1, CD33, CLU,
CR1, EPHA1, MS4A4E, NECTIN2
and PICALM

Systemic antiherpetic drugs
French medico-administrative
reduced the risk of AD
database
Included drugs: Aciclovir, Famciclovir, Valaciclovir, Valganciclovir

Conclusion/Additional info

[132]

[131]

[130]

[129]

[128]

[127]

[126]

[125]

[124]

Refs.

Kettunen et al. Journal of Neuroinflammation(2024) 21:152
Page 8 of 30

pooled

HHV-8

HHV-7, HHV-8 Presense of viral material
in patients vs. controls

Multiple sclerosis

Multiple sclerosis

Multiple sclerosis

Amyotrophic lateral sclerosis 1. HHV-6
2. HHV-8

EBV

Multiple sclerosis

OR 2.07, 95% CI: 1.8–2.37

1. HR 26.5, 95% CI: 3.7–191.6,
p = 0.001
2. HR 32.4, 95% CI: 4.3–245.3,
p < 0.001

p < 0.005 for capsid antibodies
p < 0.001 for envelope
and excreted antibodies

OR/HR/RR, 95% CI, p-value

Seropositive vs. Seronegative

1. OR 3.2, p = 0.102
2. OR 8.4, p = 0.064

No statistical tests done

Presense of HHV-8 genome
p = 0.0017
in the blood of patients vs. controls

Herpesvirus infections vs. controls

1. Infection vs. no infection
2. Seroconversion vs. seronegative

IgG titer in patients vs. healthy
controls

HSV-2

Parkinson’s disease

Comparison

Herpesvirus

DiseaseTable 2 (continued)

6 patients, 3 controls

54 patients, 130 controls

Meta-analysis of 245 datasets

Military personel

56 patients

CohortAssociation detected, sample size 20 ALS cases, 20 controls
too small for statistical significance

HHV-7 and HHV-8 mRNAwas detected in oligodendrocytes in some individuals by FISH
but not by RT-PCR in post mortem
brain tissues

HHV-8 genome detected in 18.5%(10/54) of patients and 3% (4/130)of healthy controls

Association between herpesvirus
infections and MS

Association between EBV and MS.
No association between MS
and HSV-1, HSV-2, CMV, or VZVIncreased level of HSV-1 antibodies in’PD patients. Total IgG levelin CSF was within normal limits

Conclusion/Additional info

[138]

[137]

[136]

[135]

[134]

[133]

Refs.

Kettunen et al. Journal of Neuroinflammation(2024) 21:152
Page 9 of 30

Kettunen et al. Journal of Neuroinflammation(2024) 21:152

Page 10 of 30

Fig. 1 A variety of CNS infections are associated with AD, PD, ALS, and MS. IL2RA Interleukin-2 receptor subunit alphaHSV-1 is also the most common cause of encephalitis
worldwide.
While many members of this family of viruses havebeen implicated in neurodegenerative diseases, it isunlikely that any of these viruses would be the solecause of any neurodegenerative disease. After all,despite the extremely high prevalence of herpesvirusesin the global population, most us are not affected byneurodegeneration.
Thus, it is not surprising that studies attempting tofind correlation between neurodegenerative diseases
and herpesviruses have yielded mixed results (Table 2).

However, accounting for genetic risk factors associatedwith neurodegenerative diseases might help explain thisdiscrepancy. For example, the association between APOE
ε4 and HSV-1 in AD was first suggested by Ruth Itzhaki
et al. in the late 1990s, when they reported that the odds
of finding APOE ε4 allele in HSV-1 positive AD patientswas almost 17 times higher compared to HSV-1 negative individuals without AD (OR 16.8, 95% CI: 3.61–77.8)[141].
Linard et al. and Lopatko Lindman et al. have also
reported a 3.68–4.55-fold increase in AD risk in HSV-1
positive APOE ε4 carriers [123, 125]. Furthermore,Kettunen et al. Journal of Neuroinflammation(2024) 21:152

Lopatko Lindman et al. reported an association between
AD, HSV-1, and a risk score which was calculated fromthe presence of mutations in nine AD risk genes (ABCA7,
BIN1, CD33, CLU, CR1, EPHA1, MS4A4E, NECTIN2,
and PICALM) (OR 2.35, 95% CI: 1.21–4.56, P = 0.01)[125]. Interestingly, the combination of APOE ε4 withother pathogens, including HSV-2, did not increase AD
risk [125]. It suggests that the genotype-microbe interactions are somewhat pathogen-specific.
The mechanisms through which genetic risk factors,
such as APOE ε4 allele, increase AD risk, are still underinvestigation. However, it has been suggested that the
APOE isoform may affect for example HSV-1 latency andfrequency of reactivation [141–143] or the number oforal lesions [144].
Cell culture models also support the involvementof HSV-1 in AD. In vitro studies by Cairns et al., Qiao
et al. and D’Aiuto et al. have shown that HSV-1 can
induce AD-like pathology in human induced pluripotent stem cell (hiPSC) -derived neural cultures and
3D organoids[145–148]. The signs of AD pathology
included changes in neuronal morphology, the formation of syncytia, neuronal loss, amyloid-β and tau accumulation, expression changes in amyloid-β processing
genes (PSEN1, PSEN2, BACE1), increased expression of
pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β, IL-6,
IL-10, IL-4, CXC3R) as well as gliosis characterized bychanged astrocyte morphology, increased expression ofgenes involved in astrogliosis (e.g. glial fibrillary acidic
protein, GFAP) and microglial activation (CD11b, CD68,
HLADR) [145–148]. Fruhwürth et al. have also reported
that HSV-1 infection downregulates TREM2 pathway
in hiPSC-derived microglia which leads to impaired
interferon-β induction and impaired phagocytosis of
HSV-1 infected neurons [149]. One possible mechanism
for HSV-1-induced neuropathology is through the binding of the virus envelop glycoprotein D and the Aβ42
peptide. The amino acid residues involved in Aβ42binding are left open, which means that the Aβ42-virus
complex can act as a seed for Aβ oligomerization[150].
While this binding property may have evolved as part ofthe innate immune system (see later section), the process
has likely become harmful to the host in conditions suchas AD.
VZV is another herpesvirus, which has been researchedin terms of neurodegeneration. Some studies havereported a mild increase in the risk of dementia (1.09–
1.11-fold) [115, 117, 118] and PD (1.17–1.5-fold) [129,130] in herpes zoster patients (detectable reactivationof VZV) while others have found either no associationor an inverse association [114, 127, 151, 152]. Interestingly, Cairns et al. have reported that VZV induced gliosis and secretion of proinflammatory cytokines in hiPSC

Page 11 of 30-derived neural cultures, but not the accumulation ofamyloid-β or tau. Instead, VZV induced the reactivation of quiescent HSV-1 infection which then led to theaccumulation of Aβ and phosphorylated tau [145]. Similar reactivation could be induced by other viruses such as
SARS-CoV-2 [153–155].
Like HSV and VZV, EBV has been linked to many neurodegenerative diseases [156, 157]. The strongest linkhas been identified between EBV and MS. Up to 32-foldincrease in MS risk has been reported following EBV
infection [8, 134, 135]. Furthermore, MS is very rare inindividuals who are seronegative for EBV [158]. EBV can
infect neurons directly, disrupt BBB integrity, and cause
neuroinflammation [156]. However, the prevailing theoryis that EBV predisposes the host to MS-related autoimmunity through the infection of host B cells as well as
through molecular mimicry of host myelin-associatedproteins myelin basic protein (MBP) and glial cell adhesion molecule (GlialCAM) by the EBV nuclear antigen
1 (EBNA1) [105, 106, 159]. Since EBV is almost ubiquitously present in the population (90%), the affectedindividuals likely carry other vulnerabilities to autoimmune diseases. For example, the MS risk factor HLADRB1*15:01 can facilitate EBV entry into host B cells[160, 161]. Lifestyle factors, such as smoking, can further
modulate this interaction [162]. Furthermore, another
EBV protein, EBNA2, binds and alters the expression ofMS-associated host genes which may increase MS risk.
The effect is dependent on the presence of known protective or risk mutations for MS (listed in Table 3) [163].
Antiherpetic drugs such as valacyclovir and acyclovir
have been reported to reduce symptoms and slow disease progression in dementia patients. Linard et al. havereported that intake of at least one systemic antiherpetic
drug reduced the risk of AD (aHR 0.85, 95% CI: 0.75–
0.96, p = 0.009) in a cohort of 6642 subjects over the ageof 65. Most subjects had undergone only a single intake
of antiherpetic drugs and regular treatment was rare[124]. Antiviral therapy also reduced the risk of dementia in a Taiwanese population cohort study of 39,205
herpes zoster patients (HR 0.55, 95% CI 0.40–0.77) [118]and a South Korean cohort study of 34 505 herpes zoster
patients (aHR 0.79, 95% CI: 0.69–0.90)[117]. The typical length of antiviral drug treatment was not specified
for these studies. A study by Young-Xu et al. on 87 687
HSV-positive US veterans over the age of 50 years foundthat antiherpetic medication was associated with lower
dementia risk when compared to the untreated group(aHR 0.75, 95% CI: 0.72–0.78). The reduction in dementia
risk was associated with lower markers of neuroinflammation [167]. It is noteworthy that these therapies are notspecific to any specific herpesvirus and that the positiveeffect could also be mediated by other viral infections.

LRRK2 R1441G

SOD1 G85R

HLA-DBR1*15:01

HLA-DBR1*09:01

SNPs near genes: Tumor necrosis factor receptor-associatedfactor 3 (TRAF3); Cluster of differentiation 40 (CD40); TNF Alpha
Induced Protein 8 (TNFAIP8); TNF Receptor Superfamily Member 1A (TNFRSF1A); T-Box Transcription Factor 6 (TBX6); REST
Corepressor 1 (RCOR1)

Parkinson’s disease

ALS

Multiple sclerosis

Multiple sclerosis

Multiple sclerosis

EBV

EBV

EBV

Coxsackievirus B3

Porphyromonas gingivalis

Salmonella typhimurium, reovirus Mice carrying PD risk mutation LRRK2 p.G2019S controlled
Salmonella typhimurium infection better than wildtype mice.
However, they displayed higher mortality due to reovirus
encephalitis, which was associated with increased markers
of inflammation

LRRK2 p.G2019S

Parkison’s disease[165]

MS risk alleles and protective alleles alter the host interaction with EBV envelope protein EBNA2, which may affect EBV
latency and MS risk

HLA-DRB1*09:01 allele is associated with higher levels of bloodbiomarker for EBV reactivation (Zta-IgA) than non-carriers
in healthy individuals. The effect was higher in smokers
than non-smokers

MS risk allele HLA-DBR1*15:01 facilitates EBV entry into host B
cells

[163]

[162]

[160, 161]

Reduced lifespan and earlier start of motor dysfunction in SOD1 [166]
G85R mutation carriers compared to normal mice after coxsackievirus B3 infection

Microglial activation and loss of dopaminergic neurons
in LRRK2 R1441G mice after oral P. gingivalis administration.
Increased TNF-α, IL-1β and α-synuclein and reduced zonula
occludens-1 expression in the colon, increased serum interleukin 17 A (IL-17A), and increased IL-17 receptor A (IL-17RA)
expression in the brain

[96]

[164]

Chlamydia pneumoniae

Alzheimer’s disease APOE ε4Higher bacterial burden in AD patients who carry APOE ε4
compared to non-carriers

Expression of latency-associated transcripts was slower in APOE [142]ε4 mice compared to non-carriers

HSV-1

Alzheimer’s disease APOE ε4

[125]

[123]

[141]

References

AD risk is increased in HSV-1 positive APOE ε4 carriers compared to non-carriers. HSV-2 or CMV infection was not associated AD irrespective of APOE genotype. Genetic risk score
calculated based on nine AD risk genes increased AD risk

AD risk is increased in HSV-1 positive APOE ε4 carriers compared to non-carriers

APOE ε4 allele is more common in HSV-1 carriers than in noncarriers

ResultAlzheimer’s disease APOE ε4,
HSV-1
Risk score genes: ABCA7, BIN1, CD33, CLU, CR1, EPHA1, MS4A4E, HSV-2
NECTIN2 and PICALM
CMV

HSV-1

Alzheimer’s disease APOE ε4

Pathogen
HSV-1

Gene mutation

Alzheimer’s disease APOE ε4

DiseaseTable 3 A list of publications that studied the interactions between infections and known risk genes for AD, PD, ALS, and MS

Kettunen et al. Journal of Neuroinflammation(2024) 21:152
Page 12 of 30

Kettunen et al. Journal of Neuroinflammation(2024) 21:152

In contrast, Schnier et al. found no convincing association between antiherpetic drug use and reduction indementia risk in a study of 2.5 million individuals aged
over 65 years. They only found a small and heterogenous
negative effect in an analysis of four European databases
from Wales, Germany, Scotland and Denmark. However, the typical length of antiherpetic drug treatment
was relatively short: only 1–2 weeks [168]. In fact, it has
been suggested that the antiherpetic/antiviral treatment
lengths commonly administered in Europe are not longenough to show positive effects in these database-driven
association studies. For example, the above-mentioned
study by Young-Xu et al. reported that increasing lengthof antiviral treatment is associated with larger reductions
in dementia risk in symptomatic HSV carriers. While
any antiherpetic medication reduced the risk of dementia by 25% (HR = 0.75, 95% CI: 0.72–0.78), treatments
longer than one year reduced the risk of dementia by 43%(HR = 0.57, 95% CI, 0.53–0.61). In the subgroup receiving medication for less than 30 days, the reduction was
negligible (HR = 0.93, 95% CI: 0.87- 0.98) [167]. Thus,
more studies testing the efficacy of longer antiherpetic
drug treatments are needed. An ongoing clinical study by
Columbia University [169] is currently assessing the efficacy of 7–8-week valacyclovir treatment in HSV-1 andHSV-2-positivie patients suffering from mild AD [170].
Enteroviruses

Enteroviruses, such as poliovirus, coxsackievirus, echovirus, enterovirus-A71, and enterovirus-D68 have gainedinterest in the field of motor neuron diseases due totheir ability to infect motor neurons [171]. For example,
poliovirus, the most famous enterovirus, attacks motor
neurons of the spinal cord and brain stem causing neuroinflammation which can lead to irreversible paralysis(poliomyelitis aka. Polio). Around 28% of poliomyelitis
survivors develop motor neuron disease (post-polio syndrome) decades after acute disease suggesting a chronicor reactivated infection [172].This disorder resembles
ALS because it is characterized by gradual weakening
and atrophy of specific muscles (often the limbs affectedby poliomyelitis years earlier) due to the loss of motor
neurons in the brainstem and spinal cord. Other symptoms include muscle fasciculations, fatigue, pain, sleep
disturbance, and sometimes problems breathing or swallowing. However, post-polio syndrome can often be distinguished by the life history of poliomyelitis as well as
slower progression and more generalized fatigue [173].
The relationship between ALS and ALS-like syndromes
is still unclear, as is the involvement of enteroviruses in
ALS. Some studies have found enteroviral RNA in ALS
and motor neuron disease patients more frequently thanin controls using PCR methods [174–177]. In contrast,

Page 13 of 30

others have failed to detect enterovirus RNA in the spinal
cord of ALS patients [178–180]. The discrepancies could
be explained by geographical differences (positive resultsin France, UK, Japan vs. negative in US and Australia) orby random variation introduced by small sample sizes(< 30 samples per group for all studies except one positive study where the number of samples was ten times
higher).
Interestingly, Xue et al. have reported that sublethal
coxsackievirus B3 infection can cause an increase inproinflammatory gene expression, TDP-43 pathology,
neuronal damage, and immune cell infiltration in the
CNS of normal C57BL/6J mice. In addition, coxsackievirus B3-infected mice carrying an ALS-related mutation­SOD1G85R displayed also a reduction in their lifespan andearlier start of motor dysfunction than non-infected ALS
mice. Their results suggest that while the virus alone isable to cause neurodegenerative changes in these mice,a genetic susceptibility is needed for the onset of motor
dysfunction [166].
In contrast, MS is a disease which affects the myelin
sheaths around axons instead of the neurons themselves.
Based on the limited evidence available, enteroviruses
are not involved in the development of MS. For example,
Kuusisto et al. found no evidence of enterovirus infection in the serum or cerebrospinal fluid of 17 MS patients[181]. Similarly, Perlejewski et al. detected enterovirus
by RT-qPCR in the cerebrospinal fluid of only one MSpatient (1 out of 34) [182].
HIV

HIV/AIDS is an infectious viral disease that compromises
the host immune system due to the selective tropism of
the virus to immune cells such as CD4 positive T helper
cells, macrophages, dendritic cells, and microglia. The
replication cycle of HIV kills the host cell which results indepletion of host immune cells and generalized immune
deficiency. If left untreated, the patients succumb to secondary infections typically within 10 years [183]. In fact,
HIV patients are susceptible to other opportunistic infections such as candidiasis, toxoplasmosis and bacterial
pneumonia [184–186] as well as the reactivation of otherlatent infections such as herpesvirus infections [187,188].
Interestingly, HIV has been linked to multiple neurodegenerative diseases. Around half of HIV/AIDS
patients develop HIV-associated neurocognitive disorder(HAND) even with effective antiretroviral medication[189, 190]. Many of the symptoms resemble dementia,
such as difficulties in learning, memory, decision making,and concentration. Patients also display neuroinflammation, neuronal loss, microglia/macrophage activation,
multinucleated giant cells, and diffuse atrophy of many

Kettunen et al. Journal of Neuroinflammation(2024) 21:152

brain areas [191–193]. According to Wendelken et al.
HAND-associated brain atrophy is exacerbated by theAD risk factor APOE ε4 [194]. Furthermore, neuropathologies such as progressive brain atrophy and microglia/macrophage activation, are present even in thosewith successful antiviral therapy which suggests that thepathology is mainly driven by neuroinflammation [195–197]. However, low-level viral replication in the CNS
cannot be completely discounted even with successful
suppression of the viral load in the plasma [191]. Interestingly, the use of antiviral therapy in HIV positive individuals is associated with an increase in the CSF levelsof Aβ40 and Aβ42 compared to untreated HIV patients.
Patients suffering from HIV-associated dementia (HAD)
display reduced CSF levels of Aβ40 and Aβ42 comparedto neurocognitively unimpaired individuals. The former
is also commonly observed in AD patients [198]. These
results suggest that HIV impairs Aβ clearance to the
CSF, which may be a result of increased Aβ deposition
into mature plaques. This process may be exaggerated in
HAD patients. Increased CSF Aβ40 and Aβ42 levels following antiviral therapy would then indicate rescued Aβ
clearance, which is however not enough to rescue cognitive functions [199].
Parkinsonism is another possible, albeit rare, outcomeof HIV infection. There are multiple possible causes forparkinsonism in people living with HIV, including secondary infections, HAND, dopamine-blocking drugs
such as neuroleptics, adverse reaction to antiretroviraltherapy, and HIV encephalitis. Thus, the mechanistic
connection between HIV and parkinsonism is not clearcut. In general, the emergence of antiretroviral therapy
has reduced the occurence of HIV-associated parkinsonism. Amelioration of symptoms following antiretroviraltreatment, or the discontinuation of dopamine-blocking
drugs, has also been reported [200]. Hence, HIV testing
is worth considering in patients with otherwise unexplained parkinsonism.
Several case studies have also reported ALS-like syndrome in HIV patients, including in vivo signs of upperand lower motor neuron involvement [201–211]. However, the authors of this article are unaware whether
motor neuron loss has been documented in post mortem
or not. The patients often display earlier onset than inclassical sporadic ALS [209]. The causation between HIV
and ALS-like syndrome is yet unproven, and the putative
mechanism is still unknown. However, the mechanism
is likely indirect since HIV specifically targets immune
cells such as microglia (instead of motor neurons). Similar to HIV and parkinsonism, antiretroviral therapy has
been an effective treatment in many cases of HIV-associated ALS-like syndrome [202, 204, 208, 209] whichsuggests that the possibility of HIV infection should be

Page 14 of 30

taken into consideration in patients at high risk of exposure. In contrast, reduced risk of MS and reduced rate of
relapsing have been reported in HIV positive individuals.
It is currently not known whether the reduction in MS
risk is a result of the HIV infection itself or secondary toantiretroviral therapy. Multiple explanations have beensuggested. On the one hand, the depletion of CD4 + T
cells by HIV could inhibit the development of CD4 + T
cell-associated autoimmunity in untreated or late stage
HIV patients. On the other hand, antiretroviral therapy
could also inhibit other CNS viruses than HIV, including EBV, which could subsequently reduce MS risk. So
far, the results have been variable and clear conclusions
cannot be drawn. This and many other open questions in
the field of HIV and MS have recently been reviewed by
Stefanou et al. [212].
SARS‑CoV‑2

Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) is a respiratory virus which caused the recent
COVID-19 pandemic. Interestingly, CNS symptoms arecommon during and after SARS-CoV-2 infections, andthey can last for extended periods of time (‘long covid’).
A meta-analysis by Ceban et al. reported that twelve or
more weeks after COVID-19 diagnosis 32% of individuals suffered from fatigue (68 included studies), and 22%of cognitive impairments (43 included studies) [5]. In a
study by Xu et al. the burden of neurologic sequelae was
70 per 1000 persons after one year [213]. Changes inbrain anatomy, such as reduction in grey matter thickness and global brain volume, have also been detected
in COVID-19 patients – even milder cases [214]. Microhaemorrhages are also common [215–217].
This has triggered the questions whether SARS-CoV-2
can infect the brain, and whether the COVID-19 pandemic could increase the prevalence of neurodegenerative diseases in the future. Particularly, AD has been
implicated due to the cognitive changes seen during andafter COVID-19 disease. The diseases also share the risk
factor APOE ε4, which increases the risk of late onset AD
as well as severe COVID-19 disease [217, 218]. Furthermore, severe COVID-19 disease and mortality due to it
are more common in AD patients.
To answer the first question: Post mortem studies havedetected the presence of viral components in neurons,
glia, and brain endothelial cells in deceased COVID-19
patients (the cases were not selected based on neurological symptoms) [219–223]. Consistently, stem cell-derived
2D and 3D models have shown that SARS-CoV-2 caninfect the choroid plexus epithelium, astrocytes, subsetof neurons, and possibly even microglia [224–234]. Thus,
CNS infection by SARS-CoV-2 is possible.

Kettunen et al. Journal of Neuroinflammation(2024) 21:152

Signs of neuropathology are also present after SARSCoV-2 infection. Histopathological signs of neuroinflammation such as astrogliosis, microglial activation [219,220, 235], BBB disturbance [235, 236], and infiltration of
peripheral immune cells [219, 235] have been reported in
COVID-19 patients. Stem cell studies have also reported
microglial activation [237], cytokine production [231,232, 237, 238], astrogliosis [223, 231, 239], altered neuronal morphology [229, 238, 239], synapse elimination[230], and neuronal loss [223, 230, 232] after SARSCoV-2 infection. All of these processes are involved in
AD. Even tau accumulation has been reported [240,241], which is a hallmark of AD and other so called‘tauopathies’.
Taken together, SARS-CoV-2 does display signs ofneurodegenerative potential. However, it is possiblethat in vivo the neurodegenerative potential of SARSCoV-2 is mediated by peripheral cytokine release andbrain barrier disturbance (BBB, blood-CSF barrier) andcerebral hypoperfusion rather than by direct infection[236]. According to Matschke et. al, the severity of thehistopathological changes they observed was not correlated with the presence of viral particles in the CNS
which suggests that the peripheral inflammatory process is enough to cause CNS pathology [219]. Similarly,
Käufer et al. have reported that intranasal SARS-CoV-2
infection caused microgliosis, tau hyperphosphorylation,and α-synuclein pathology in the hamster cortex even
without CNS infection. Notably, the pathology persisted
beyond virus clearance which could have implications forlong-COVID and neurodegeneration [223].
Spirochete bacteria

Spirochetes are a group of spiral-shaped bacteria fromthe genera Spirochaeta, Treponema, Borrelia and Leptospira. Many members of this group are human pathogens
that cause diseases such as leptospirosis, Lyme disease,relapsing fever, syphilis, and periodontitis. Cases for andagainst the involvement of spirochetes in neurodegenerative diseases have been raised.
For example, Miklossy et al. have suggested the involvement of spirochetes in AD [242–244]. They have reported
that spirochetes, such as periodontal Treponema sp. andBorrelia burgdorferi, co-localize with Aβ and neurofibrillary tangles in AD brains, form plaque-like colonies,
establish latent infections, disturb cerebral blood flow,
and induce AD-related lesions and neuroinflammation[243, 244].
In vitro experiments by the same group on rat primary neurons, astrocytes, and microglia have shownthat 2–8-week exposure to Borrelia burgdorferi induces
AD-like changes, such as overexpression of the amyloid
precursor protein (APP), tau hyperphosphorylation, andPage 15 of 30

the accumulation of Aβ inclusions reminiscent of amyloid plaques. Interestingly, the presence of microglia
increased Aβ accumulation, which highlights the importance of microglia in the neurodegeneration induced byspirochetes [242].
In contrast, Gutacker et al. found no evidence of Borrelia burgdorferi in the brains of ten AD patients [245].
Similarly, Forrester et al. found no geographic correlation
between the incident rate of Lyme disease and death rateof neurodegenerative diseases in the United States [246].
However, neurodegenerative diseases are consideredhighly multifactorial, which makes such broad correlations difficult to assess. If it turns out multiple pathogengroups can trigger neurodegenerative changes in susceptible individuals, important correlations can get overlooked by studies focusing on one type of infection.
Syphilis is another pathogen that may be relevant toonly a subset of patients. Syphilis is a sexually transmitted disease caused by the spirochete Treponema pallidum, which swept through Europe in the 1500s. It has
since become rare due to effective antibiotic treatments.
CNS presentation is relatively common at the early stagesof syphilis [247]. It is characterized by sensorimotor
symptoms such as abnormal gait, tremors, and numbness of the lower limbs accompanied by cognitive andmood dysfunction such as confusion, poor concentration, depression, and irritability. Interestingly, several
cases of dementia caused by late neurosyphilis have beenreported [248–259]. Commonly the patients are around40–60-year-old at the time of diagnosis (early-onset
for dementia) and they display a variety of neurologicalsymptoms such as rapid cognitive decline, behavioral
changes, and psychosis. In some patients, the symptoms
ameliorate after treatment with antibiotics [248–259].
Thus, syphilis should be considered as a cause for dementia-like symptoms in infected individuals. Interestingly,
asymptomatic neurosyphilis patients display different levels of Aβ42 and tau in the CSF compared to AD
patients, which could be used as a biomarker to differentiate between the diseases as well as to determine thestage of neurosyphilis in a patient [260].
A few cases of suspected syphilis-induced ALS or ALSmimic syndrome have also been reported [261–263].
However, determining whether these syndromes truly fill
the criteria for ALS, and whether syphilis is causative inthese cases, is beyond the expertise of the authors of thisarticle [264]. Furthermore, anecdotal evidence suggeststhat other spirochete bacteria such as Borrelia burgdorferi can cause ALS-like pathology [265]. However, in general, Lyme disease does not seem to be associated with
ALS [266, 267].
As for MS, one study has reported spirochete bacteria in the brains of four MS patients [268], but otherKettunen et al. Journal of Neuroinflammation(2024) 21:152

evidence of spirochete involvement in MS is currently
lacking.
Bacterial pneumonia

A link has been suggested between bacterial pneumonia
and dementia. For example, a Taiwanese cohort study hasreported a positive association between bacterial pneumonia and subsequent dementia risk (HR 2.83, 95% CI:
2.53–3.18), particularly between Staphylococcus pneumonia and vascular dementia (HR 5.4) and Hemophilus
pneumonia and AD (HR 3.85, 95% CI: 1.66–8.96) [269].
Tate et al. have reported that hospitalization for pneumonia increased the risk of later developing dementia (aHR
1.9, 95% CI: 1.4–2.8, P < 0.0001) [270]. Neither study
assessed whether the infection affected the CNS directly.
Chlamydia pneumoniae is a bacterial pathogen whichcauses respiratory infections, including pneumonia. It
has been shown to sometimes enter the brain. Interestingly, Gérard et al. have reported C. pneumoniae in theneurons and glia of around 80–90% of late-onset AD
patients and only 5–10% of healthy controls. Notably, thebacteria were detected in proximity to AD-related lesions
such as amyloid plaques [164, 271, 272]. The authors
did not list the cause of death for these patients. Since
AD and dementia patients have a higher risk of hospitalization and mortality due to pneumonia than unaffected individuals [273, 274], more information would beneeded to rule out the possibility that C. pneumoniae waspresent in the brains of these patients due to an infection
secondary to AD.
However, Chacko et al. have shown that C. pneumoniae
can infect the glia in olfactory and trigeminal nerves,
olfactory bulb, and other brain areas of mice within 72 hof inoculation. They observed Aβ accumulation adjacent
to bacteria in the olfactory system, and changes in neurodegeneration-relevant pathways [275]. Lopatko Lindman et al. have studied whether the Alzheimer’s diseaserisk allele APOE ε4 mediates the risk between C. pneumoniae infection and AD. They tested the presence of C.
pneumoniae in the plasma of 360 AD and 360 matched
controls from samples that had been collected on average 9.6 years before the diagnosis. They reported noassociation between Chlamydia pneumoniae, APOE ε4
allele, and the risk of AD [125]. In contrast, Gérard et al.
have reported that C. pneumoniae burden is higher inthe brains of AD patients that carry APOE ε4 allele compared to non-carriers [164]. Others have also reported
that full length human APOE and derived peptides havedirect antimicrobial function against Gram-negative bacteria [276, 277].
C. pneumoniae has also been studied in relation to
many diseases with immunological etiology, including
MS. However, reports have been published both for andPage 16 of 30

against an association with MS, and clear conclusions
cannot be drawn yet [278].
Finally, a study by Turkel et al. assessed the presence ofChlamydia pneumoniae in the serum of 51 PD patientsand 37 matched controls. They found no statisticallysignificant correlation between C. pneumoniae and PD[279].
Fungi

Fungi have received less attention in the study of neurodegenerative diseases than viruses and bacteria due totheir lower relative abundance in the human microbiome.
However, they are relevant human pathogens, particularly in immunocompromised individuals.
Most of the exploratory work on the involvement offungi in neurodegenerative diseases has been done by asingle research group lead by Luis Carrasco. They havedetected multiple species of fungi in the brains of AD,
PD, ALS, and MS patients.
For example, they detected Candida albicans, Candida
ortholopsis, Candida tropicalis, Cladosporium, Malassezia globosa, Malassezia restricta, Neosartorya hiratsukae, Phoma, Saccharomyces cerevisae, and Sclerotinia
borealis in the brains of altogether ten AD patients but
not in the same number of controls. Not all species weredetected in all patients [280]. Similarly, they found antibodies against multiple species of fungi, as well as fungal proteins, and fungal 1,3-β-glucan in the serum of AD
patients. Such signs of fungal infection were also present
in healthy controls but at lower frequency [281]. Consistently, Yashkin et al. have reported that fungal infections
increased the risk of AD (HR 1.98, 95% CI:1.89–1.92) in adataset collected from a 5% sample of U.S. Medicare beneficiaries aged 65 + years [282] (the number of Medicare
beneficiaries was over 65 million in 2023 [283]).
The group of Luis Carrasco have also reported the presence of Botrytis, Candida, Fusarium and Malassezia species in the brains of all six PD patients using nested PCR
analysis. When they compared these results to a previously published control group (n = 12) [281], the levelof fungal infection was higher in PD patients. They also
detected chitin immunopositivity in samples from PD
patients but not from controls [284]. Interestingly, theydetected bacteria in the spinal cord, medulla, and motor
cortex of the same PD patients, which suggests the possibility of polymicrobial infection in PD. While bacteria
were also present in healthy controls (n = 9) the results
clustered separately in principal component analysis
which suggests that the infection profile was different inpatients and controls [284].
The same group has also reported fungal intracellular
structures such as yeasts and hyphae in the motor cortex, medulla, and spinal cord of all eleven assayed ALSKettunen et al. Journal of Neuroinflammation(2024) 21:152

patients. PCR and next generation sequencing revealed
fungi from multiple genera: Candida, Malassezia, Fusarium, Botrytis, Trichoderma, and Cryptococcus [285]. Bacteria were present in the spinal cord, medulla, and motor
cortex of the ALS patients but not in healthy controls,
which suggests the possibility of polymicrobial infection
also in ALS patients [286].
Similarly, polymicrobial infections of fungi and bacteria
were present in the post mortem CNS tissues of all ten
MS patients but not in controls. Particularly, the fungi
Trichosporon mucoides was found in most MS patients[287]. Furthermore, the group has detected fungal RNA,
antigens, and antibodies against multiple Candida species [288, 289] in the CSF of MS patients [288]. They also
detected fungal DNA and β-1,3 glucan in patient bloodand serum samples, respectively [289]. The same groupreported that antigens for Candida increased the risk of
MS 3.0 – 7.3-fold (depending on Candida species) in acohort of 80 MS patients and 240 matched controls [290].
As for the mechanisms of fungi-induced neurodegeneration, C. albicans has been shown to cause AD-like
pathology in cell culture models, including Aβ oligomerization and accumulation [291]. Furthermore, a study by
Wu et al. showed that intravenous infection of C. albicans in mice causes mild memory impairment which
resolves after fungal clearance. The impairment was associated with the production of proinflammatory cytokines(IL-1β, IL-6, TNF-α) as well as localized accumulation ofsoluble Aβ peptides, activated microglia, and astrocytesaround the yeast cells [291] which suggests that neuroinflammation is a key factor in the observed pathology.
Interestingly, a couple studies have shown Aβ to beprotective against Candida infections. Even though
the suggested mechanisms differed between studies(reviewed in more detail in later section), the main finding was the same: Aβ peptides can inhibit the growth of
C. albicans in vitro [291, 292]. Furthermore, full length
APOE and derived peptides may also have a direct antimicrobial function against pathogens such as Candida
yeasts [276, 277]. In fact, Vonk et al. have reported that
APOE knock-out mice display higher mortality following
C. albicans infection than their APOE wildtype controls[293]. Together this suggests a possible interplay between
fungal infections and AD risk factors.
The involvement of fungal toxins in neurodegeneration
has also been suggested. Fungal toxins such as gliotoxin
and fumonisin have been shown to destroy glia such as
astrocytes and oligodendrocytes, which could potentially lead to myelin loss in MS [294]. Gliotoxin from
Aspergillus fumigatus has been reported to induce neuroinflammation and to aggravate clinical symptoms inexperimental autoimmune encephalomyelitis mice (themost common mouse model for MS) [295]. It has also

Page 17 of 30

been reported to penetrate hiPSC model of the BBB and
to impair the barrier function as measured by transendothelial electrical resistance (TEER) and fluoresceinpermeability [296].
Together, these data show that fungal pathogens areworth considering when searching for causes for neurodegenerative diseases. However, more research on the
topic is needed in the future to better understand fungal
CNS infections in seemingly immunocompetent individuals. Furthermore, the important exploratory work done
by Carrasco et al. should be replicated by others to confirm and further elucidate the role of polymicrobial infections and different fungal species in neurodegeneration.
Toxoplasma gondii

Toxoplasma gondii is an obligate intracellular protozoan parasite, which is primarily hosted by cats andother small mammals. It infects around one third of the
global human population [65, 66]. It forms chronic, cystic
infection inside neurons, astrocytes and microglia of thebrain. Normally, the host immune response keeps theparasite in latent state, and clinical manifestations (e.g.
encephalitis) are typically seen only in immunocompromised patients.
T. gondii has been implicated in various diseases frompsychiatric and mood disorders to epilepsy and autoimmune disorders. Reports regarding its involvement inneurodegenerative diseases have been conflicting [297].
For example, a Taiwanese cohort study of 200 dementia
patients and 400 controls has reported a positive association between toxoplasmosis and dementia (HR 2.878,
95% CI = 1.71–4.97, P < 0.001). Furthermore, the treatment of toxoplasmosis by sulfadiazine or clindamycin
was associated with a reduction in dementia risk [298].
A meta-analysis of eight studies (3239 subjects) suggeststhat T. gondii may be involved in AD (OR = 1.53, 95% CI:
1.07–2.18). However, the authors were worried aboutpublication bias and called for more research on the subject [299]. In contrast, Wennberg et al. detected no association between T. gondii seropositivity and cognitive
performance in 575 adults aged 41–97 years [121].
T. gondii infection has been reported to induce production of proinflammatory cytokines (TNF-α, IL-1β,
IL-6), glial nodules, and hyperalgesia in wild type mice
[300, 301]. Interestingly, studies of T. gondii infection in
AD model mice have reported beneficial effects such as
higher levels of anti-inflammatory cytokines, reduced Aβtissue deposition, increased Aβ phagocytosis and degradation, reduced nitrite production from primary cultured
microglial cells, and better performance in memory tests[302, 303].
Multiple studies have suggested that T. gondii infections might be associated with reduced risk of MS

Kettunen et al. Journal of Neuroinflammation(2024) 21:152[304–307]. Due to the autoimmune nature of MS, the‘hygiene hypothesis’ has been suggested as an explanation for reduced disease risk in Toxoplasma carriers.
The idea is that parasites promote immunotolerance inthe host by suppressing the innate and adaptive immune
responses against themselves. The IFN-γ driven immune
response is the main host response to T. gondii infection. However, the parasite can modulate transcription
factors that regulate this pathway, e.g. signal transducer
and activator of transcription (STAT) 1, 3, and 6. It also
inhibits multiple apoptosis pathways, ROS production by
nicotinamide adenine dinucleotide phosphate (NADPH)
oxidases, as well as the nuclear factor kappa B (NF-κΒ)
pathway, which regulates the production of many proinflammatory cytokines [308]. Activation of these same
pathways have been implicated in the development ofMS, however, their roles at different stages of the diseaseremain under debate [309, 310].
The hygiene hypothesis of MS has been criticizedbecause of the link to EBV infections. [158]. However,different pathogens may have a different effect on the
immune system. In fact, protozoan parasites have been
explored as potential therapies for autoimmune diseases
and allergies [311, 312] while the data on herpesviruses
points mostly towards increased risk of autoimmunity[313]. In any case, conflicting reports on the involvementof T. gondii in MS have been published [314–317] andthus, the question remains under debate.
Extra‑CNS infections

Patients suffering from neurodegenerative diseases frequently display non-CNS infections such as gastric H.
pylori infections [318–321], periodontal disease [322,323], and changes in normal gut microbiome (dysbiosis) [324–334]. These changes have been linked to neurodegenerative diseases even in the absence of direct
CNS infection [165, 335–338], and they share common
mechanisms through which they can be detrimental to
the CNS.
One key mechanism is the ability of these microbes tomanipulate the extracellular matrix and the tight junctions of the host tissues. For example, gut microbes modulate the tight junctions of the gut epithelium by a variety
of molecules. To illustrate, beneficial short-chain fatty
acids (SCFAs), such as acetate, propionate and butyrate,
are produced by fiber-digesting bacteria and they are
utilized by host epithelial cells as an energy source. As aresult, these bacteria facilitate normal epithelial barrier
function [339, 340]. Furthermore, SCFAs are also known
to cross the BBB where they modulate microglial function via G protein-coupled receptors [339]. Patients ofneurodegenerative diseases often display reduction in
the abundance of beneficial SCFA-producing bacteria

Page 18 of 30[341, 342]. In turn, harmful gut microbes produce proinflammatory molecules such as LPS, cytokines, andprostaglandins, which disrupt the tightness of the epithelial barriers and can lead to a ‘leaky gut’. These same
molecules can transfer to blood circulation and disrupt
the BBB or cross into the CNS where they induce neuroinflammation [18–20].
Similarly, periodontal pathogens can produce molecules that disrupt BBB function [343]. For example,
the Gram-negative bacteria Porphyromonas gingivalis
and the spirochete Treponema denticola secrete molecules such as gingipains, toxic fimbriae, and dentilisin
which allows them to modulate host tight junctions andto form a suitable habitat in the periodontal pocket [74,344]. Interestingly, P. gingivalis has been associated withneurodegenerative diseases such as AD, PD and MS [165,336–338, 345–351].
P. gingivalis has been detected in the post mortem
brain tissue of AD patients. It has been reported to produce outer membrane vesicles carrying gingipains, LPS
and toxic fimbriae, which can disrupt the BBB [345, 346].
Lei et al. reported that P. gingivalis infection and secreted
gingipains increase transcytosis across the BBB by altering the expression of calveolin-1 and major facilitator
superfamily domain containing 2a (Mfsd2a). They did
not detect changes in occludin levels [344]. In contrast,
Nonaka et al. have reported that P. gingivalis/gingipain
disrupt tight junctions by direct degradation of zonula
occludens-1 and occludin [344].
Once in the brain, gingipains cause AD-related changes
such as as increase in Aβ and tau accumulation, modulate APP and tau processing, cause microglial activation and proliferation, induce IL-1β, TNF-α and IL-6
secretion, cleave APOE proteins, and induce neuronaldegeneration and synapse loss [336, 346–348, 352]. P.
gingivalis-derived LPS and inactivated bacteria also cause
the secretion of nitric oxide and prostaglandin E2 fromrat primary glial cells (95% astrocytes) [337]. Strikingly,
peripheral administration of P. gingivalis is enough tocause a variety of neurodegenerative changes, which supports the involvement of indirect mechanisms such asouter membrane vesicles [165, 336–338]. For example,
subcutaneous injection of P. gingivalis aggravated experimental autoimmune encephalomyelitis in MS model
mice [337]. Oral P. gingivalis administration also led tomicroglial activation and loss of dopaminergic neurons inmice carrying the PD risk mutation LRRK2 R1441G. The
mice displayed decreased expression of the tight junction
protein zonula occludens-1 and increased expression ofproinflammatory factors TNF-α, IL-1β, and α-synucleinin the colon. Increased serum IL-17A and increased brain
IL-17A receptor expression implicates T helper (Th)
17 lymphocytes in the observed brain pathology [353].

Kettunen et al. Journal of Neuroinflammation(2024) 21:152

Finally, P. gingivalis is not the only bacteria to produce
harmful extracellular vesicles. Similar function has been
attributed to the periodontal bacteria Aggregatibacter
actinomycetemcomitans and H. pylori [335, 354–356].
Together, these results show that non-CNS infections
can be as important for neurodegenerative diseases as
CNS infections due to their potential to induce neuroinflammation. Thus, the search for causes for these diseases
should not be limited to CNS infections, and non-CNS
infections should also be considered when designing
future treatments.
Neurodegeneration‑related aggregating proteins display
antimicrobial properties

Many neurodegenerative diseases display characteristic
protein aggregation in the nervous tissue. For example,
AD is hallmarked by the accumulation of Aβ plaques
and neurofibrillary tangles formed by hyperphosphorylated tau. Similarly, PD is hallmarked by α-synuclein
inclusions, ALS by TDP-43 and FUS aggregation, andfrontotemporal dementia with tau, TDP-43 and FUS
aggregates. TDP-43 aggregates are also reported in somecases of AD. The role of these protein aggregates is still
under debate, but traditionally they have been thought to
be toxic. However, in recent years many of these aggregating amyloid proteins have been reported to haveantimicrobial effects which suggests a role in the innate
immune response.
The role of Aβ as an antimicrobial peptide was firstsuggested by Soscia et al. in 2010 [292]. They showedthat synthetic and rodent amyloid-β peptides are effective against Gram -negative and -positive bacteria, andC. albicans. According to them, Aβ42 peptides showed
greater efficiency against microbes than the less amyloidogenic Aβ40 peptides. They also showed that Aβ is able
to bind anionic bacterial membranes, and that temporal
lobe homogenates from AD patients inhibited the growthof C. albicans more than controls. Homogenates from thecerebellum of AD patients did not have the same effect,
which makes sense considering that the cerebellum is notcommonly affected by AD. Finally, the dose-dependent
reduction on C. albicans growth by the temporal lobe
homogenates from AD patients was abolished by preincubation with antibodies against Aβ [292].
Since then, Eimer et al. have reported that the heparin-binding site on soluble Aβ oligomers bind herpesvirus glycoproteins and leads to Aβ deposition and viralentrapment [357]. Bourgade et al. have reported that
Aβ40 and Aβ42 peptides inhibit the replication of HSV-1,
an enveloped virus, but not that of non-enveloped humanadenovirus [358]. Their results suggest that Aβ may exert
its antimicrobial function through the pathogen surface

Page 19 of 30

membranes, and it may only be effective against certain
pathogens.
The effectivity of Aβ against HSV-1 has been called into
question by Bocharova et al. who reported that Aβ failed
to protect AD model mice (5xFAD) from HSV-1 infection. These mice carry mutations in APP which leads
to Aβ overexpression and early-onset AD in humans.
Bocharova et al. did not observe any colocalization of Aβ
aggregates and viral particles, or significant differences insurvival rate between infected 5xFAD and wildtype mice.
However, they did report that HSV-1 invasion was limited in areas of high Aβ burden which they attributed toincreased phagocytosis by microglia chronically activatedby Aβ [359].
This result is in line with Wu et al. who observed thatsynthetic and human Aβ40 and Aβ42 peptides inhibited the growth of C. albicans through an interaction
with immortalized murine BV-2 microglia. Mainly, theyobserved that Aβ treatment increased the phagocytosis of yeast particles by BV-2 microglia and induced thesecretion of presently unknown fungistatic compounds
from the same cells [291]. Unlike Soscia et al. they did notobserve a direct fungistatic effect of Aβ [291].
The study by Wu et al. suggests that Aβ facilitates thefast innate immune response. In short, they showed thata knockout of APP in mice impaired the clearance of
C. albicans during the early days of the infection (days
4–7). The defect was associated with hypothermia andimpaired secretion of proinflammatory cytokines. In
contrast, C. albicans clearance was enhanced 5xFAD
mice known for the overexpression of APP and Aβ. However, since all mice were able to clear the C. albicans
infection by day 10, these data suggest that Aβ is not
obligatory for fungal clearance but instead boosts the fast
immune response [291]. Interestingly, Bocharova et.al.
also observed better survival rate within the first 140 h(day 5) after HSV-1 infection in 7–10-month-old 5xFAD
mice compared to wildtype littermates. However, theresult was not statistically significant [359].
Taken together, these data support the role of Aβ as
an innate immune alarm molecule that mediates acuteresponse to microbial infection. Similar function has
been suggested to other neurodegeneration-related
aggregating proteins as we will see below.
The microtubule-associated protein Tau is involvedin cytoskeletal organization. It has been linked to manyneurodegenerative diseases termed ‘tauopathies’ due toits propensity to hyperphosphorylate and to form intracellular inclusions called ‘neurofibrillary tangles’. In AD,
the accumulation of neurofibrillary tangles is thought
to be secondary to Aβ pathology. Kobayashi et al. havereported that small synthetic peptides carrying microtubule binding sites of the tau 4R isoform display potent

Kettunen et al. Journal of Neuroinflammation(2024) 21:152

antimicrobial effects against Staphylococcus aureus andEscherichia coli. The effect was strengthened by the addition of tandem repeat sequences or sequences for nuclear
localization or laminin receptor binding site. The addition of sequences for nuclear localization or laminin
receptor binding site also made the peptides effective
against C. albicans [360]. Similarly, Kanagasingam et al.
have reported that some phosphorylated tau peptides,
but not all, reduced the viability of the periodontal bacteria P. gingivalis. The effective peptides were more prone
to form β-sheet structures than peptides that did notshow antimicrobial effects [361].
Alam et al. report that α-synuclein, which is secreted
from enteric nervous system neurons, is needed fornormal peritoneal immune response. In their study,
α-synuclein knockout mice displayed reduced immune
cell invasion of peritoneal cavity and reduced productionof proinflammatory cytokines compared to controls following injection with bacterial peptidoglycan. Furthermore, the exogenous administration of α-synuclein in
the peritoneal cavity of the knockout mice promoted leukocyte recruitment which suggests that α-synuclein can
act as an immune system alarm molecule (alarmin). In
addition, α-synuclein aggregation has been found in thegut and it has been suggested that α-synuclein pathology
could originate in the gut and travel to the brain via afferent neurons [362].
FUS and TDP-43 are RNA-binding proteins which are
known to localize in stress granules [363, 364]: intracellular assemblies formed by RNA, ribosomes and RNAbinding proteins that repress protein translation during
stress. Since viruses require the host cell machinery for
replication, the repression of host protein synthesis canprotect the system from the spread of the infection [365].
Interestingly, it has been reported that infection withthe enterovirus coxsackievirus B3 induces the cleavage
and translocation of both TDP-43 and FUS. Furthermore,
the knockout of TDP-43 or FUS induces an increase invirus titer, suggesting these proteins can repress virus
replication [366, 367].
The connection between FUS and the innate immune
system is further illustrated by the fact that poly(I:C),
stress granule-inducing respiratory syncytial virus, andtype I interferon are all able to induce FUS assembly inin vitro cell lines [368]. FUS knockout causes a reduction in the production in type 1 interferon and otherpro-inflammatory cytokines following similar infectionmimicking treatments [367].
Similarly, Dunker et al. have reported that TDP-43
is required for the regulation of the accumulation of
immunostimulatory double-stranded RNA, and for the
inhibition of interferon-mediated necrotic cell death[369]. Interestingly, a recent article by Licht-Murava

Page 20 of 30

et al. reports that aberrant TDP-43 accumulation in hippocampal astrocytes causes memory impairment by
inducing interferon-mediated antiviral response [370]. It
suggests that TDP-43 may be useful or harmful depending on the situation. Cabrera et al. have reported that
latent HSV-2 infection in mouse spinal cord was not
associated with changes in TDP-43 or FUS despite othersigns of immune activation and ALS pathology such as
leukocyte infiltration, microglial changes near motor
neurons and reduction in C9orf72 levels [371]. Thus, a lot
more research on the topic is needed.
Methodologies and future experimental avenues

In the future, population level association studies are
expected to move from associations between a single
pathogen and a neurodegenerative disease (e.g. HSV-1
and AD) to more complex models that consider a person’s lifetime infection burden and polygenic risk score[372]. Also moving the focus from severe infections
towards more prevalent milder infections will further
clarify the interaction between infections and neurodegenerative diseases. Such studies would require largescale screening of the healthy population so that elusive
patterns between asymptomatic or mild infections withneurodegeneration could be uncovered. When done consistently over long periods of time, such datasets could
also elucidate the temporal patterns of disease development. However, such projects are labor- and cost-intensive, especially when both sexes and ethnically different
human populations are represented in studies. The mostfeasible way to carry out such studies is their execution aspart of large operations such as biobanks.
Simultaneously, experimental approaches are neededto advance from mere associations towards more mechanistic insight. Progressing from broad claims such as‘infections cause neuroinflammation, which leads to neurodegeneration’ to clearer insight on why some individuals are affected while others are not, and to more detailed
processes that lead to distinct neurodegenerative diseases, requires more studies where animals or cell culture
models carrying different risk factors are infected withdifferent pathogens. Including polymicrobial infections[373] and their combinations with different genetic risk
factors into cell and animal models are likely to increase
our understanding of possible heterogeneous susceptibility to infection-associated neurodegeneration.
Both animal models and stem-cell based methods havetheir advantages. For example, hIPSC-derived 2D and 3Dmodels allow us to study infections on human brain cells,
to overcome challenges related to species differences,and to elucidate the roles of different human cells types,
e.g. neurons, astrocytes and microglia [374]. Furthermore, stem cell lines can be engineered to carry relevantKettunen et al. Journal of Neuroinflammation(2024) 21:152

genetic mutations, or they can be directly collected from
affected donors e.g. AD patients carrying APOE mutations [374]. The limitation of in vitro stem cell models isthat the peripheral immune component and the microbiome are often missing. Stem cell models also do not offer
any information on whether the cell or molecular levelchange will penetrate to the level of behavior, e.g. cognitive function or motor symptoms. Xenotransplantationof human cells into mice (chimeric models) could solve
this problem [375]. However, the xenotransplantation ofhuman cells is currently only possible in immunocompromised animals [375] which limits the relevance of
these models when studying infections. Thus, traditionalin vivo animal models are still needed. For example, animal models of latent and reactivating virus infections
have a lot to give to the field [27, 28].
Considering the importance of BBB disturbance in neurodegenerative diseases, improved models and detection
methods are needed to elucidate the role of infections inthis complex process. In humans, the measurement of
BBB integrity in vivo is still emerging. However, imaging
techniques such as positron emission tomography (PET)or magnetic resonance imaging (MRI) in combination
with small molecule contrast agents show potential [376].
In animal studies, a wider range of dyes, diffusible tagged
molecules, and in vivo and ex vivo imaging techniques
are available [377]. In cell culture, trans-epithelial electrical resistance (TEER) and immunocytochemistry oftight junction proteins are common ways to study barrier
integrity [378]. Stem cell-derived BBB-on-a-chip models
are also under development [379].
Finally, the addition of pharmacological interventions
into animal and cell culture-based models can be very
powerful. Combined use of antimicrobials and antiinflammatory drugs, such as resveratrol [380–382], curcumin [383], or omega-3 fatty acids [384], should tell us
more about the role of each component in neurodegeneration. However, some compounds, such as resveratrol[382] and some antifungals [385], display both antiviral
and anti-inflammatory properties. Thus, any experimental procedures need to be carefully planned.

Conclusions
The current literature shows that a broad range ofpathogenic CNS and extra-CNS infections are linked
to AD, PD, ALS, and MS. While some pathogens seemto be more strongly associated with certain diseases
than others (e.g. EBV and MS), no direct causality can
yet be assigned. Instead, the current data suggests thatthe neurodegenerative potential of CNS pathogenic
infections is tied to the neuroinflammation which follows. The current understanding of the antimicrobial
effects of neurodegeneration-associated aggregating

Page 21 of 30

proteins supports this view. Furthermore, many of us
carry CNS infections without ever developing neurodegenerative disease, which suggests that a combination of genetic susceptibility factors and environmental
triggers, such as infections, are needed for the development of neurodegenerative pathologies. Going forward,
more research on the interplay between genetic risk
factors and CNS infections is needed, as well as on the
cumulative effect of multiple simultaneous or subsequent infections. While it is impossible to stop people
from ever getting infections again, antimicrobial andanti-inflammatory drugs and dietary supplements haveshown some promise in the treatment of neurodegenerative diseases. Thus, better understanding of the roleof CNS infections in neurodegenerative diseases could
help us detect vulnerable individuals and to target a
combination of antimicrobial and anti-inflammatory
therapies to those that could most benefit from them.
Abbreviations
AD	Alzheimer’s diseaseAβ	Amyloid-beta(a)HR	(Adjusted) hazard ratio
ALS	Amyotrophic lateral sclerosis
APP	Amyloid precursor protein
APOE	Apolipoprotein E
BBB	Blood–brain barrier
95% CI	95% Confidence interval
CMV	Cytomegalovirus
CNS	Central nervous system
EBV	Epstein-Barr virus
FUS	Fused in sarcoma
HHV	Human herpesvirus
HAND	Hiv-associated neurocognitive disorder
HIV/AIDS	Human immunodeficiency virus/acquired immune deficiency
syndrome
HPV	Human papillomavirus
HSV	Herpes simplex virus
iPSC	Induced pluripotent stem cell
LPS	Lipopolysaccharide
MBP	Myelin basic protein
MS	Multiple sclerosis(a)OR	(Adjusted) odds ratioPD	Parkinson’s disease
ROS	Reactive oxygen species
RT-qPCR	Real time quantitative polymerase chain reaction
SARS-CoV-2	Severe acute respiratory syndrome coronavirus 2
SCFA	Short-chain fatty acid
SOD-1	Superoxide dismutase 1
TDP-43	Transitive response DNA-binding protein 43
TREM2	Triggering receptor expressed on myeloid cells 2
VZV	Varicella zoster virus
Acknowledgements
Not applicable.
Author contributions
PK performed the literature search and a majority of the writing. JK & TR provided comments on the text at multiple stages of the writing. All authors readand approved the final manuscript.
Funding
Open Access funding provided by University of Helsinki (including Helsinki
University Central Hospital). The work was supported by Research Council of
Finland grant # 334525, and Sigrid Juselius Foundation.

Kettunen et al. Journal of Neuroinflammation(2024) 21:152

Page 22 of 30

Availability of data and materials
Not applicable.
18.

Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Received: 17 March 2024 Accepted: 23 May 2024

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20.
21.

22.
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