Recent advances in Alzheimer’s disease pathogenesis and therapeutics from an immune perspective

Abstract

The prevalence of Alzheimer’s disease, the most common type of dementia, is continuously increasing. Many recent reports have indicated that immune-related mechanisms play a vital role in Alzheimer’s disease pathogenesis, such that the imbalance between the immune response and central nervous system leads to neuroinflammation.
The inflammatory response in Alzheimer’s disease is a “double-edged sword”. Neuroinflammation protects neuronal cells in the initial stages of Alzheimer’s disease, while sustained inflammation promotes neurodegeneration. Alterations in the peripheral immune system, such as increased inflammation, lead to the activation of the central immune response, which in turn causes neuroinflammation and neuronal damage. Additionally, an imbalance between pro- and anti-inflammatory cytokines, which are secreted by the central and peripheral immune systems, induces complex immune responses and contributes to Alzheimer’s disease pathogenesis. In this review, we aimed to summarize our current knowledge of the role of the immune system in Alzheimer’s disease pathology. We performed an in-depth investigation on the contribution of each immune system component to Alzheimer’s disease progression at different disease stages. More importantly, we discuss novel immune-related therapeutic strategies for Alzheimer’s disease treatment currently being investigated via clinical trials.
The scrutinized observations of immune responses in different brain regions at various stages of Alzheimer’s disease might help identify potential treatment strategies for Alzheimer’s disease. The modulation of immune components in the brain by targeting cytokines and other factors, which compromise immune response and neuroinflammation, is recommended as a promising alternative for Alzheimer’s disease treatment. Clinical trials are currently investigating the efficacies of numerous vaccines and monoclonal antibodies targeting amyloid beta peptide and tau protein for Alzheimer’s disease treatment. Moreover, aducanumab and lecanemab were approved by the Food and Drug Administration as monoclonal antibody-based drugs for Alzheimer’s disease treatment in 2021 and 2023, respectively. However, these drugs are effective only against mild symptoms due to the irreversible neuronal damage found in patients with Alzheimer’s disease progression. In addition, side effects including amyloid-related imaging abnormalities (such as vasogenic edema, microhemorrhages, and hemosiderosis) were reported in patients undergoing Alzheimer’s disease treatment using monoclonal antibodies. Thus, the future development of therapeutic agents for Alzheimer’s disease requires more sophisticated and multi-plunged approaches considering various biomarkers and immune landscapes characterizing the different stages of Alzheimer’s disease.

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Vol.:(0123456789)
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Journal of Pharmaceutical Investigation (2023) 53:667–684
https://doi.org/10.1007/s40005-023-00631-0
REVIEW
Recent advances inAlzheimer’s disease pathogenesis andtherapeutics
fromanimmune perspective
Thai‑DuongNguyen1· LoiNguyenDang1· Jung‑HeeJang2· SoyeunPark1
Received: 19 May 2023 / Accepted: 18 August 2023 / Published online: 7 September 2023
© The Author(s) under exclusive licence to The Korean Society of Pharmaceutical Sciences and Technology 2023
Abstract
Background The prevalence of Alzheimer’s disease, the most common type of dementia, is continuously increasing. Many
recent reports have indicated that immune-related mechanisms play a vital role in Alzheimer’s disease pathogenesis, such
that the imbalance between the immune response and central nervous system leads to neuroinflammation.
Area covered The inflammatory response in Alzheimer’s disease is a “double-edged sword”. Neuroinflammation protects
neuronal cells in the initial stages of Alzheimer’s disease, while sustained inflammation promotes neurodegeneration. Altera-
tions in the peripheral immune system, such as increased inflammation, lead to the activation of the central immune response,
which in turn causes neuroinflammation and neuronal damage. Additionally, an imbalance between pro- and anti-inflamma-
tory cytokines, which are secreted by the central and peripheral immune systems, induces complex immune responses and
contributes to Alzheimer’s disease pathogenesis. In this review, we aimed to summarize our current knowledge of the role
of the immune system in Alzheimer’s disease pathology. We performed an in-depth investigation on the contribution of each
immune system component to Alzheimer’s disease progression at different disease stages. More importantly, we discuss
novel immune-related therapeutic strategies for Alzheimer’s disease treatment currently being investigated via clinical trials.
Expert opinion The scrutinized observations of immune responses in different brain regions at various stages of Alzheimer’s
disease might help identify potential treatment strategies for Alzheimer’s disease. The modulation of immune components in
the brain by targeting cytokines and other factors, which compromise immune response and neuroinflammation, is recom-
mended as a promising alternative for Alzheimer’s disease treatment. Clinical trials are currently investigating the efficacies
of numerous vaccines and monoclonal antibodies targeting amyloid beta peptide and tau protein for Alzheimer’s disease
treatment. Moreover, aducanumab and lecanemab were approved by the Food and Drug Administration as monoclonal
antibody-based drugs for Alzheimer’s disease treatment in 2021 and 2023, respectively. However, these drugs are effective
only against mild symptoms due to the irreversible neuronal damage found in patients with Alzheimer’s disease progression.
In addition, side effects including amyloid-related imaging abnormalities (such as vasogenic edema, microhemorrhages, and
hemosiderosis) were reported in patients undergoing Alzheimer’s disease treatment using monoclonal antibodies. Thus, the
future development of therapeutic agents for Alzheimer’s disease requires more sophisticated and multi-plunged approaches
considering various biomarkers and immune landscapes characterizing the different stages of Alzheimer’s disease.
Keywords Alzheimer’s disease· Immunotherapy· Neuroinflammation· Amyloid beta· Tau protein· Microglia
Introduction
Alzheimer’s disease (AD) is a neurodegenerative disorder
affecting cognition, memory, thinking, and social ability,
thereby impacting the quality of daily life among elderly
persons (Guan etal. 2019). Age-related diseases, includ-
ing AD, are emerging as important medical problems due
to the rapid growth of the elderly population, especially
in developed countries. Thus, understanding the molecu-
lar mechanisms related to AD development is important.
Thai-Duong Nguyen and Loi Nguyen Dang have contributed
equally to this work.
* Soyeun Park
sypark20@kmu.ac.kr
1 College ofPharmacy, Keimyung University, Daegu42601,
RepublicofKorea
2 School ofMedicine, Keimyung University, Daegu42601,
RepublicofKorea

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It has two pathological hallmarks: extraneuronal amyloid
beta peptide (Aβ) plaque deposits trigger a chemical cascade
that causes AD development, while a deviated tau structure
leads to an abnormal aggregation in the neurons of patients
with AD (Busche etal. 2020). AD has phenotypical varia-
tions, and the AD phenotype diversity is attributed to the
age of onset, symptom presentation, disease progression,
and genetic mutations. Hence, the availability of phenotyp-
ing evaluation methods facilitates diagnosis and decision
on disease-modifying treatments for AD. In the case of Aβ
and tau protein-caused AD, the concentration of Aβ produc-
tion and tau protein accumulation in neurons is measured
through cerebrospinal fluid (CSF) testing. Positron emis-
sion tomography is used to visualize the abovementioned
proteins. Magnetic resonance imaging and computed tomog-
raphy allow for a detailed observation of cerebral damage
level caused by Aβ and tau protein, which may indicate AD
progression (Tan etal. 2014). Atomic force microscopy has
been recently employed to characterize and quantify Aβ and
tau aggregation (Watanabe-Nakayama etal. 2020). Amy-
loid precursor protein (APP) mutation, presenilin 1 muta-
tion, presenilin 2 mutation, and apolipoprotein E expression
associated with the AD phenotype are evaluated via genome-
wide association studies or imaging genetics (Saykin etal.
2010). For clinical symptoms of AD, standardized cognitive
tests are used to assess memory impairment (one of the ear-
liest and most prominent symptoms of AD), attention, and
executive functions. Moreover, clinicians can perform neu-
ropsychological evaluation, mini-mental state examination,
and behavioral and psychiatric assessments for a detailed
diagnosis.
Various recent studies have indicated that Aβs, tau pro-
teins, and the immune system play critical roles in AD
pathogenesis (Janelidze etal. 2022; Zieneldien etal. 2022).
In addition, numerous investigations have demonstrated the
immune-related mechanisms in AD pathogenesis, such that
the overexpression of pro-inflammatory biomarkers during
early AD leads to neurological dysfunction in the central
nervous system (CNS) (Janelidze etal. 2018). The inflam-
matory response in AD is a “double-edged sword.” Neu-
roinflammation is a self-protective mechanism during the
initial stages of AD; however, sustained inflammation can
promote neurodegeneration. Neuroinflammation can protect
the brain by supporting neuronal tissue repair and cellular
debris removal. During the initial stages of AD, resident
brain immune cells, such as microglia and astrocytes, pro-
mote Aβ clearance (Fan etal. 2017). Activated microglia
engulf Aβ plaques through phagocytosis, leading to endo-
lysosomal degradation. In addition, proteases, such as nepri-
lysin and the insulin-degrading enzymes in microglia, play
vital roles in Aβ clearance (Fu etal. 2020). Nevertheless,
during the later stages of AD, activated microglia secrete
pro-inflammatory cytokines, including interleukin (IL)-1β,
IL-6, and tumor necrosis factor-α (TNF-α), which results in
neurodegeneration (Fan etal. 2017). Consequently, micro-
glial Aβ clearance is attenuated during AD progression,
thereby exacerbating the neuroinflammatory responses.
This review outlines our current knowledge on the char-
acter of the immune system in AD pathogenesis. We exten-
sively investigated the contribution of each immune system
component to AD progression at different stages; moreover,
we discussed novel immune-related therapeutic strategies
for AD treatment.
Innate immunity inAD
Although innate immunity is the first line of non-targeted
defense against pathogen invasion, unnecessary immune
response activation in patients with AD contributes to neu-
roinflammation and brain damage. Herein, we discuss the
correlation of innate immunity with AD pathogenesis to
clarify the pathogenesis and enhance the development of
therapeutic approaches for AD treatment.
Central immunity
Reactive astrocytes and activated microglia perform various
neurotoxic and neuroprotective functions depending on their
phenotypes at different stages of disease progression. The
detailed functions of central immune cells that are associated
with AD are presented in the following sections.
Microglia
Microglia are resident immune cells that act as principal
inflammatory factors (Bouvier etal. 2016). They are con-
verted into an active phagocytic phenotype in response to
acute neuronal injury and contribute to the repair of dam-
aged tissues and restoration of homeostasis. There are two
main active phenotypes: pro-inflammatory M1 and neuro-
protective M2 microglia (Zhang etal. 2017). Classical M1
microglia fight foreign pathogens through the release of vari-
ous inflammatory mediators, such as IL-1, IL-6, interferon
(IFN)-γ, TNF-α, and free radicals (Chauhan etal. 2021),
thereby inducing an adaptive immune response. However,
they can be chronically activated under pathological condi-
tions, thereby harming healthy neurons and inducing neu-
roinflammation. Moreover, M2 microglia, which constitute
an alternative phenotype, are activated via anti-inflamma-
tory cytokines such as IL-4, IL-10, IL-13, and transforming
growth factor beta (TGF-β), thereby enhancing angiogen-
esis, immunoregulation, and tissue repair (Chauhan etal.
2021).
Microglia play a biphasic role in neurodegenerative dis-
orders as neurotoxic M1 or neuroprotective M2 phenotypes.

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Microglial differentiation varies depending on the nature
of the inflammatory responses and stages of AD develop-
ment. In the early asymptomatic phase of AD, the M2 phe-
notype enhances Aβ phagocytosis and clearance, thereby
contributing to the mitigation of pathologic AD progression
(Yang etal. 2011). Neurotoxic microglia are less effective
in clearing Aβs and tau proteins as well as releasing pro-
inflammatory cytokines, thereby decreasing Aβ uptake and
degradation. Furthermore, they trigger tau hyperphospho-
rylation, which exacerbates tau neurotoxicity (Wang etal.
2022). During AD pathogenesis, prolonged inflammation
might attenuate microglial housekeeping and sensing func-
tions as well as interfere with defense mechanisms, leading
to the complication of neuroinflammation. A specific micro-
glial phenotype may be expressed at different stages of AD
pathogenesis (Mathys etal. 2017). Careful observations of
microglial responses in different brain regions at various
stages of AD might help in the identification of potential
treatment strategies for AD.
Astrocytes
Astrocytes, also known as astroglia, account for the highest
percentage of glial cells in the human brain (von Bartheld
etal. 2016). In normal brain tissues, they play a role in vari-
ous neurophysiological functions to promote the develop-
ment and maturation of neuronal cells (Verkhratsky etal.
2018). Similar to microglia, reactive astrocytes have two
phenotypes: pro-inflammatory (neurotoxic) and immu-
noregulatory (neuroprotective) phenotypes, which have
been termed as “A1” and “A2,” respectively. Their distribu-
tion may vary based on disease progression. The A1 phe-
notype upregulates various complement cascade genes that
are destructive for synapses, suggesting its harmful nature
(Chun etal. 2018). In contrast, the A2 phenotype is a pro-
tective astrocyte that upregulates the expression of various
neurotrophic factors (Chun etal. 2018).
In terms of AD pathology, these cells also promote
the accumulation and degradation of Aβ deposits through
phagocytosis and the expression of Aβ-degrading proteases,
such as neprilysin, endothelin-converting enzymes, and
matrix metalloproteinases (Ries etal. 2016). Additionally,
astrocytes participate in the clearance of soluble Aβ from the
parenchyma via paravenous drainage (Xu etal. 2015). Fur-
thermore, the interference of astrocytes in the calcineurin/
nuclear factor of activated T cells signaling pathway reduces
Aβ levels and astrogliosis, resulting in improved cognition
(Sompol etal. 2017). In AD, Aβ deposits may produce
chemotactic mediators to assemble and activate astrocytes
(Aβ-activated astrocytes), which exacerbate cytokine-medi-
ated neuroinflammatory responses, leading to an exces-
sive secretion of various pro-inflammatory cytokines and
chemokines, such as IL-1β, IL-6, TNF-α, IFN-γ, and TGF-β
(Singh etal. 2020; LaRocca etal. 2021).
Peripheral immunity
Various studies have revealed that peripheral immune cells
contribute to Aβ metabolism and inflammatory response
control in AD (Munawara etal. 2021). More importantly, the
presence of peripheral inflammatory biomarkers in asymp-
tomatic individuals is related to various clinical character-
istics, such as cognition, brain structure, functional brain
connectivity, and amyloidosis (Pérez-González etal. 2021).
The following sections discuss the characteristics and role
of peripheral immune cells in AD pathogenesis.
Monocytes
Monocytes, the corresponding microglial cells in the periph-
ery, play a positive role in AD pathogenesis by degrading Aβ
plaques (Yan etal. 2022). Peripheral monocytes can take up
Aβ in the blood. However, this phagocytic capacity is nega-
tively influenced by aging and AD pathogenesis. Further-
more, there is a positive correlation between a decline in the
Aβ capture capacity of peripheral monocytes and Aβ levels.
The expression of toll-like receptor 2 (TLR2), an Aβ uptake-
related receptor in monocytes, was found to be downregu-
lated in patients with AD (Chen etal. 2020). The importance
of monocytes in AD pathogenesis can be explained by the
considerable expression of monocyte receptors, such as trig-
gering receptor expressed in myeloid cells 2 (TREM2) and
CD33, to Aβ phagocytosis, which is modulated in patients
with AD (Bradshaw etal. 2013; Zhao etal. 2018). These
findings demonstrate that monocytes provide substantial
reduction in serum Aβ levels, and hence, monocyte-induced
Aβ phagocytosis can promote AD (Chen etal. 2020).
The function of blood monocytes in Aβ plaque clearance
in the CNS is controversial. Studies conducted on AD mouse
models have reported that circulating blood monocytes can
penetrate the brain and differentiate into macrophages before
accumulating in Aβ-rich areas and clearing Aβ plaques in
the peripheral blood (Malm etal. 2005). Moreover, mono-
cytes can differentiate into activated macrophages, which
clear Aβ plaques more effectively than microglia (Simard
etal. 2006). Although circulating monocytes can cross the
blood-brain barrier (BBB) and phagocytize Aβs in neuronal
cells of patients with AD, many recent reports have revealed
that their capacity for Aβ clearance is defective compared
with that of cells from age-matched healthy control partici-
pants (Fiala etal. 2007). The transportation of Aβ plaques
into endosomes and lysosomes is interrupted; therefore, Aβ
phagocytosis is reduced in AD. In summary, these findings
indicate the vital function of monocyte-mediated Aβ clear-
ance in AD pathogenesis.

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Neutrophils
In AD, neutrophil activity is altered during different stages
of pathogenesis. Specifically, more neutrophils were found
in patients with AD than in age-matched controls, whereas
neutrophil function was reduced in the later stages of AD
(Vida etal. 2017; Rossi etal. 2021). Neutrophil-related brain
damage occurs when these cells migrate to Aβs, releasing
inflammatory mediators, including myeloperoxidase and
reactive oxygen species (ROS), and secreting neutrophil
extracellular traps (NETs), which are entangled structures
that comprise proteases and chromatin (Manda-Handzlik
etal. 2019). ROS-mediated oxidative products were found
to be increased in the brain and CSF samples of patients
with AD (Gamba etal. 2019). NETs are formed by a sign-
aling pathway in neutrophils initiated by chemokines or
ROS, resulting in the decomposition of nuclear and cellular
membranes. In AD animal models and patients, NETs are
deposited near Aβ plaques in the cerebrovascular and intra-
parenchymal regions. Several studies have suggested that
pro-inflammatory cytokines associate with Aβ and ROS to
induce intraparenchymal NETosis, a type of NET-regulated
cell death, leading to neuronal damage (Zenaro etal. 2015).
Moreover, neutrophil reduction or blockade of lymphocyte
function-associated antigen 1, an integrin found on lympho-
cytes, mitigates disease severity in animal models of sterile
inflammation, which proves the vital role of neutrophils in
AD pathogenesis and the potential of neutrophil-directed
therapy as a treatment for AD (Zenaro etal. 2015).
In addition, the neutrophil-to-lymphocyte ratio (NLR) is
a simple, non-invasive biomarker of systemic inflammatory
response that correlates with cognitive impairment (Rossi
etal. 2021). Recent clinical studies have reported correla-
tions between NLR and cognitive impairment; increased
neutrophil counts or higher NLRs were correlated with AD
occurrence, suggesting that neutrophil count alteration may
be used as a marker for early AD diagnosis and treatment
prediction (Huang etal. 2022).
Cytokines
Peripheral immune biomarkers, such as TNF-α, IL-6, and
IL-1β, are associated with AD development (Ou etal.
2021). This association has been proven by numerous sys-
tematic reviews and meta-analytical studies, which have
reported increased peripheral levels of pro-inflammatory
cytokines, such as IL-1β, IL-6, TNF-α, and monocyte
chemoattractant protein-1 in patients with AD (Ng etal.
2018; Shen etal. 2019). Table1 shows cytokine altera-
tions in AD pathogenesis. Several reports have indicated
that abnormal cytokine levels are associated with cognitive
impairment in patients with Silva etal. (2021) analyzed
brain and plasma IL-6 levels using magnetic resonance
imaging and immunofluorescence assay, whereas cognitive
assessment tools (such as the frontal assessment battery,
brief cognitive battery, and mini-mental state examina-
tion) were used to evaluate cognition. The results showed a
negative correlation between brain and plasma IL-6 levels
and the performance of the cognitive tests. Hennessy etal.
(2017) used a T-maze task to evaluate the effect of TNF-α
on working memory in a mouse model. An acute elevation
of TNF-α levels triggered acute cognitive deficits in mice
with prior neurodegeneration.
IL‑1 IL-1 exacerbates chronic neuroinflammation in AD
through adaptive innate immune responses. IL-1 overex-
pression is positively correlated with the development of
AD plaques (Ghosh etal. 2013). Normally, IL-1 levels are
low or undetectable in human blood. Therefore, although
patients with AD demonstrated a small increase in IL-1
levels, they show a statistically meaningful increase on
examination.
IL-1α and IL-1β levels are considered high-risk fac-
tors for AD pathogenesis. The peripheral levels of these
isoforms were found to be elevated in patients with AD
compared with those of control participants (Italiani etal.
2018). Increased serum IL-1α levels have been observed
in patients with AD. IL-1β drives APP synthesis, result-
ing in Aβ plaque production and deposition. It is also
involved in tau phosphorylation, a key pathogenic process
in AD (Ng etal. 2018). In a meta-analysis, Shen etal.
(2019) compared IL-1β levels between the AD and con-
trol groups and demonstrated that the AD/control ratio
was 2.463 (p < 0.001). In another meta-analysis, Ng etal.
(2018) reported that the aging population with AD had
significantly higher IL-1β levels in peripheral circulation
than controls (p = 0.047). The increased IL-1β levels in
biological fluids might be a stage marker of neurodegen-
eration between patients with AD and the normal aging
population.
IL‑6 IL-6, secreted by immune cells, is a cytokine with pro-
and anti-inflammatory roles, resulting in neuroprotective
and neurodegenerative roles in the CNS. Thus, the deregu-
lation of IL-6 plays an essential pathogenic role in chronic
inflammatory diseases and multifactorial autoimmune dis-
orders such as AD (Rothaug etal. 2016). The enrichment
of Aβ deposits and tau tangles can stimulate glial cells to
release IL-6 in AD; conversely, IL-6 levels enhance the Aβ
formation and tau phosphorylation (Xie etal. 2020). How-
ever, alterations in IL-6 expression in AD are heterogeneous
throughout the brain parenchyma. IL-6 levels are markedly
higher in the parietal cortex and lower in the temporal cor-
tex, occipital cortex, and cerebellum in patients with AD
compared with those of age-matched controls (Hampel etal.
2005).

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Table 1 Inflammatory biomarkers associated with AD pathogenesis
Immune system Immune biomarker Models Findings References
Innate immunity IL-1β ↑APP/PS1 mice AD patients Microglia produced IL-1β sufficient to trigger excessive
levels of IL-6 in APP/PS1 mice.
Patients with AD had elevated cerebral IL-1β and IL-6
levels.
Lopez-Rodriguez etal. (2021)
Patients with mild to moderate AD and MCI as well as
healthy controls
Patients with AD and MCI had elevated serum IL-1β
levels compared with healthy controls.
Forlenza etal. (2009)
APPswe/PS1dE9 double transgenic mice treated with
inhibited IL-1β
IL-1β was upregulated in the hippocampi of AD mice.
Inhibition of IL-1β reduced amyloid plaques and oxida-
tive stress in the hippocampus, leading to diminished
neuronal damage.
Zhang etal. (2021)
3xTg-AD mice treated with chronic dosing of an IL-1
receptor-blocking antibody
There were significant alterations in brain inflammatory
responses, thereby alleviating cognitive impairment,
significantly attenuating tau tangles, and partly reduc-
ing Aβ deposits.
Inhibited IL-1 levels reduce the activity of tau kinases
and phospho-tau levels in the brain.
Kitazawa etal. (2011)
IL-1α ↑Peripheral venous blood of patients with EOAD and
LOAD as well as age-matched healthy participants
Serum IL-1α levels were markedly reduced in patients
with EOAD and LOAD compared with those in
controls.
Dursun etal. (2015)
IL-6 ↑Patients with AD, post-mortem AD brain, APP/PS1, and
WT male mice
The hyperintensities on T2-weighted MRI correlated
positively with plasma levels of IL-6 and inversely
with cognitive ability in patients with AD.
Post-mortem AD brains showed increased IL-6 levels.
In AD mice, IL-6 neutralization diminished memory
loss and regulated peripheral IL-6 levels.
Lyra e Silva etal. (2021)
TgCRND8 and Tg2576 mice overexpressed with murine
IL-6 (mIL-6).
Expression levels of mIL-6 increased in gliosis, and Aβ
deposition decreased.
There was no effect on APP processing or Aβ levels due
to mIL-6-induced neuroinflammation.
Although mIL-6 exacerbated Aβ pathology, mIL-6-me-
diated microglial phagocytic events may be helpful
in the early stages of AD pathology by boosting the
clearance of Aβ deposits.
Chakrabarty etal. (2010)
Patients with AD and healthy controls IL-6 levels were markedly higher in patients with AD
than in controls.
A negative correlation was observed between cognitive
functions and IL-6 levels in AD patients with depres-
sion.
Khemka etal. (2014)
TNF-α ↑Caucasian patients with AD and MCI TNF-α levels were markedly increased in patients with
AD than in patients with MCI.
Culjak etal. (2020)

672 Journal of Pharmaceutical Investigation (2023) 53:667–684
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A meta-analysis reported higher peripheral IL-6 lev-
els in patients with AD than in the controls (Shen etal.
2019). Nevertheless, peripheral IL-6 levels were not nota-
bly higher in elderly patients with AD than in the age-
matched controls. This is supported by previous studies
that reported increased peripheral IL-6 levels at AD onset
but not during AD progression (Ng etal. 2018).
TNF‑α TNF-α acts as a coordinator of the pro-inflamma-
tory cytokine cascade in acute conditions such as injury or
infection. Moreover, chronic TNF-α production has been
recorded in neuroinflammatory disorders, such as AD,
Parkinson’s disease, and multiple sclerosis. In the brains
of patients with AD, TNF-α promotes the accumulation
of Aβ plaques and hyperphosphorylated tau (Ou et al.
2021). Some meta-analyses have indicated no statistically
significant differences in TNF-α levels between patients
with AD and cognitively normal controls; however, most
studies have reported elevated TNF-α levels in the CSF
of patients with AD compared with those in cognitively
normal controls (Janelsins etal. 2008).
Interestingly, peripheral TNF-α levels vary based on the
stage and severity of AD pathogenesis. Peripheral TNF-α
levels are markedly lower in mild to moderate AD than
in severe AD (Zota etal. 2009). Moreover, another study
observed lower peripheral TNF-α levels in patients with
early- and late-onset AD compared with healthy controls
(Alvarez etal. 1996). The inconsistency in data on TNF-α
levels might be explained by the difference in sample col-
lection procedures and the considerably low TNF-α levels
in biological fluids, which reduce the reproducibility of the
measurements used in these studies.
Monitoring the levels of suitable biomarkers at different
stages of AD is important for research on AD pathogenesis
and treatment. However, individual biomarkers might be
insufficient to fully describe AD pathophysiology. Evaluat-
ing a combination of multiple biomarkers characterizing
the different AD stages is a more suitable approach for
providing a comprehensive AD pathophysiology.
Adaptive immunity inAD
The adaptive immune system, including T and B cells,
positively contributes to Aβ phagocytosis. Specific anti-
bodies produced by B cells against Aβ have been observed
at different levels in the peripheral blood of patients with
AD (Gaskin etal. 1993; Du etal. 2001). In the following
sections, we discuss the functions of AD-related adaptive
immunity and the reasons to consider immunotherapies as
potential treatments for AD.
ILinterleukin, AD Alzheimer’s disease, APP/PS1amyloid precursor protein/presenilin 1, MCImild cognitive impairment, APPswe/PS1dE9 mice overexpress the Swedish mutation of APP
together with PS1 deleted in exon 9, Aβamyloid-β peptide, EOADearly-onset Alzheimer’s disease, LOADlate-onset Alzheimer’s disease, MRImagnetic resonance imaging, WTwild-type,
TgCRND8 micetransgene contains human APP695 with the Swedish and Indiana mutation under the control of the hamster prion gene promoter, Tg2576 mice transgenic mice express the
human APP gene carrying the Swedish mutation, mIL-6murine IL-6, C57BL/6mice are resistant to audiogenic seizures, have a relatively low bone density, and develop age related hearing loss,
CD1 micean outbred mouse line derived from the original colony of Swiss mice, Aβ1–42Aβs contain 42 amino acids, Absantibodies, LPSlipopolysaccharide, 3xTg-AD micetriple-transgenic
AD mice, iNOSinducible nitric oxide synthase
Table 1 (continued)
Immune system Immune biomarker Models Findings References
Patients with AD Serum TNF-α levels were markedly increased in
patients with AD compared with controls.
An inverse correlation was observed between cognitive
function and TNF-α levels in patients with AD and
depression.
Khemka etal. (2014)
C57BL/6 mice with existing neurodegeneration Acute elevation and sustained increase in TNF-α levels
significantly affected cognitive function degeneration.
Hennessy etal. (2017)
Adaptive immunity Modified IL-17A Abs Male Sprague–Dawley rats injected with LPS IL-17 A Abs improved LPS-induced memory damage
and prevented LPS-induced secretion of pro-inflam-
matory cytokines, iNOS, and cyclooxygenase-2.
Yang etal. (2018)
Female 3xTg-AD mice Neutralization of IL-17 reduced short-term memory loss
at the early stages of AD.
Brigas etal. (2021)

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T cells
Various reports have indicated that T cells play essential
roles in AD pathogenesis, which is related to neuroinflam-
mation. CD4 + T cells secrete pro-inflammatory cytokines
to activate microglia, contributing to neuroinflammatory
responses (Dionisio-Santos etal. 2019). Aβ plaques increase
the number of T cells in mice and patients with AD, thereby
enhancing the release of cytokines, which are primary
modulators of glial cell activity (Miscia etal. 2009). Many
pro-inflammatory cytokines, including IL-10, TNF-α, IL-6,
IL-1β, and monocyte chemoattractant protein-1, are secreted
by activated T cells in patients with AD (Lombardi etal.
1999), thereby activating microglia and astrocytes (Ramesh
etal. 2013). Moreover, pro-inflammatory cytokines contrib-
ute to the proliferation of Th1 and Th17 cells in patients with
AD (Oberstein etal. 2018).
Studies on APP/PS1 mice have reported that Th1 cells
are involved in IFN-γ secretion, which activates microglia
and astrocytes. This process exacerbates the disruption of
cell homeostasis, which subsequently promotes Aβ accu-
mulation, damages synaptic plasticity, and accelerates cog-
nitive deficit onset (Browne etal. 2013). A recent study
using familiar AD mice bearing five AD-linked mutations
(5xfAD mice) reported that the Aβ plaque clearance capac-
ity increased after the injection of Aβ-specific Th1 cells.
This phenomenon enhances the differentiation of major his-
tocompatibility complex class II microglia through T cell
activation, thereby expanding microglial phagocytic activity
(Mittal etal. 2019). Thus, the “double-edged sword” effect
of Th1 cells in AD could be related to the disease stage, sug-
gesting that an appropriate control of these cells at different
stages of AD pathogenesis might be a potential strategy for
AD treatment. Nevertheless, Th17 cells produce IL-17A,
a signature cytokine that exacerbates neuropathological
changes in patients with AD (Oberstein etal. 2018). Stud-
ies have indicated that CSF and plasma IL-17A levels are
elevated in patients with neurodegenerative diseases, dem-
onstrating the important role of this cytokine in the onset of
neurodegenerative disorders. IL-17A levels are correlated
with disease onset and severity (Gu etal. 2013). Studies have
revealed significant elevations in CSF and serum IL-17A
levels in patients with AD (Chen etal. 2014). Moreover,
IL-17A levels were significantly elevated in various mouse
models compared with those in wild-type controls (St-
Amour etal. 2019). However, its role in CNS neurodegener-
ative disorders, especially AD, is not completely understood.
CD8 + T cells are located near the neuronal processes
and microglia. Patients with AD show a significant increase
in the number of activated CD8 + T cells in the CSF com-
pared with age-matched healthy controls. This enhancement
is related to cognition and neuroanatomical consequences
(Gate etal. 2020). Moreover, studies have reported a strong
correlation between CD8 + T cell infiltration and tau pathol-
ogy in patients and animal models (Laurent etal. 2017).
B cells
Evidence from clinical and animal studies has demonstrated
that B cells play a regulatory function in the onset and devel-
opment of AD. Xiong etal. (2021) demonstrated that B cell
depletion causes cognitive disorder and enhances cerebral
Aβ deposition in AD mice. Furthermore, Späni etal. (2015)
showed that B cells play a critical role in Aβ clearance in
knockout mice lacking functional B and T cells and in APP/
PS1 transgenic mice. They also reported an interaction
between adaptive immunity and microglial activity in Aβ
phagocytosis.
Anti-Aβ1−42 antibodies derived from B cells seldom infil-
trate the BBB and diffuse into the healthy brain parenchyma
(Banks etal. 2002). However, various studies using animal
models have indicated that high doses of anti-Aβ antibod-
ies reduce cerebral Aβ levels (Rinne etal. 2010) and cause
cerebral microhemorrhage, leading to BBB disruption; thus,
anti-Aβ antibodies can penetrate the BBB (Wilcock etal.
2004). Moreover, serum and CSF anti-Aβ1−42 antibody lev-
els markedly decreased in patients with AD compared with
healthy controls (Qu etal. 2014). In a Rag-5xfAD mouse
model, predominant levels of non-Aβ-specific antibodies
produced by B cells increased Aβ phagocytosis (Marsh etal.
2016). Moreover, a phase 3 trial (NCT03887455) involv-
ing patients aged 50–90 years with early AD was conducted
using a humanized IgG1 (lecanemab) monoclonal antibody
(mAb) that binds with high affinity to soluble Aβ. Some
adverse events were observed; however, the results indicated
that lecanemab use decreased Aβ levels and showed less
cognitive impairment in patients with early AD compared
with the control group at 18 months (van Dyck etal. 2022).
Regulatory B cells (Bregs) secrete anti-inflammatory
factors and have a vital immunosuppressive function. Most
Breg immunosuppressive abilities are enhanced by TLR
activation. Furthermore, the soluble oligomer Aβ aggre-
gates bind to and activate TLR4 (Kasus-Jacobi etal. 2022).
In addition, Bregs secrete TGF-β, which forms monomers
or complexes with immunoglobulins to suppress immunity
(Honke etal. 2022). They induce the production of myeloid-
derived suppressive cells via the TGF-β signaling pathway.
Moreover, they inhibit Th1 and Th17 cells through IL-35
activity (Yu etal. 2018). Additionally, IL-35 acts on regula-
tory cells to promote IL-10 secretion with anti-inflammatory
functions (Zhang etal. 2022).
In addition to Aβ, the formation of neurofibrillary tangles
triggered by the hyperphosphorylation of tau proteins is a
hallmark of AD pathogenesis. Thus, reducing phosphoryl-
ated tau levels might be a promising AD therapeutic strategy.
A report has found that anti-tau mAb-based therapies are

674 Journal of Pharmaceutical Investigation (2023) 53:667–684
1 3
potential treatment strategies for AD (Umeda etal. 2015).
These mAbs target specific regions of the tau protein and
prevent the formation and spread of tau fibrils, which are
toxic to nerve cells. Although these mAb-based therapeutic
strategies show promising results, they are in the early stages
of development, and thus, more research is needed to deter-
mine their safety and efficacy for AD treatment.
Crosstalk betweentheperipheral
andcentral immune systems
The CNS has an immune-privileged environment owing
to the BBB. Many recent reports have revealed that the
peripheral immune system is essential in regulating CNS
homeostasis. Numerous studies have demonstrated that the
crosstalk between the peripheral and central immune sys-
tems is involved in AD onset and development. Cytokines
secreted in the periphery cross the BBB, activate glial cells,
and exacerbate neuroinflammation in the brain (Ramesh
etal. 2013). Circulating immune cells can penetrate the
brain, and hence contribute to neuroinflammatory responses
and neurodegenerative disease progression. Interestingly,
peripheral and central immune system dysregulations were
found to be associated with cognitive function and clini-
cal status. However, the degrees of peripheral and central
immune system dysregulations were not correlated with
AD progression (Bettcher etal. 2021). Moreover, innate
and adaptive immune functions change depending on AD
progression. Figure1 illustrates the factors that contribute
to the innate and adaptive immunity mechanisms.
Many studies using animal models of AD-like pathol-
ogy have shown that resident central and peripheral immune
components that penetrate the CNS are involved in neuro-
inflammatory responses and the development of neurode-
generative disorders (Wendeln etal. 2018). Villeda etal.
demonstrated a correlation among blood-borne factors,
neurogenesis, and cognitive function in an animal model
(Villeda etal. 2011). In terms of peripheral innate immune
cells, elevated levels of monocyte-derived macrophages
infiltrate the CNS under neuroinflammatory conditions (Ju
etal. 2022). Additionally, neutrophils have been found in
mouse models of Aβ pathology and in brains of patients with
AD (Zenaro etal. 2015).
Immunotherapy
Immunotherapy in AD involves two approaches: active and
passive immunization. The active pathway or vaccination
depends on the immune system to stimulate anti-antigen
antibodies. An active drug usually consists of disease-
related antigens and immune-boosting adjuvants. The spe-
cific epitope (antigen) activates helper T cells, enhancing the
Fig. 1 Interaction between central and peripheral immunity as well
as innate and adaptive immunity A Innate immune cells play vital
functions in the peripheral and central nervous systems. Microglia
and astrocytes are major components of the central immune system,
whereas monocytes and neutrophils are the basic elements of the
peripheral immune system. B Adaptive immunity, including T and
B cells, positively contributes to Aβ phagocytosis. Specific anti-Aβ
antibodies produced by B cells have been found in the peripheral
blood of patients with Alzheimer’s disease. T cells enter the brain of
patients with and influence pathology and disease progression

675Journal of Pharmaceutical Investigation (2023) 53:667–684
1 3
production of specific antibodies by B cells through class II
molecules. Self T-helper included epitope directly targets
B cells to secret antibodies. A single administration of the
AD vaccine offers a long-term immune response; thus, it
is cost-effective and time-saving for the patient. However,
the activation of vaccine relies on immunity, and therefore
this therapy does not show much clinical benefit in elderly,
immunodeficient patients with AD. Thus, passive immuno-
therapy is an alternative strategy to overcome immunodefi-
ciency. Pre-designed antibodies are injected into the periph-
eral blood and act directly without mediating the immune
system. However, passive therapy requires repeated antibody
administration, and the antibodies do not easily penetrate the
BBB (Lemere 2013). In addition, amyloid-related imaging
abnormalities (ARIA) caused by antibody administration
remain a serious concern (Filippi etal. 2022).
The immunotherapeutic drugs for AD treatment were
developed to reduce or remove toxic Aβ and tau protein.
Current studies have proposed three mechanisms of action
of antibodies against Aβs and tau proteins. First, the “periph-
eral sink hypothesis” refers to the reduced sequestration of
Aβ in the blood by peripheral antibodies. Second, the anti-
body crosses the BBB and binds to pathological Aβ and
tau conformers to prevent aggregation. Third, the antibody
activates resident microglia to phagocytize Aβ deposits or
inhibit the spread of tau proteins (Nisbet etal. 2015) (Figs.2
and 3)
Immunotherapeutic agents targeting Aβ
Active immunotherapy
Aβ-mediated AD originates from APP mutation, a trans-
membrane protein found in cerebral cells. APP is catabo-
lized by α-, β-, and γ-secretases; subsequently, it under-
goes amyloidogenic or non-amyloidogenic cleavage. Aβ, a
type of amyloidogenic fragment (Fig.2), is a 38–43 amino
acid peptide (Chen etal. 2017). Aβ1−40/Aβ1−42 is more
abundant than other amyloidogenic variants (Bitan etal.
2003). Most studies that develop new AD therapeutics have
focused on Aβ1−42 variants because they are more neuro-
toxic and prone to overproduction and deposition (Musiek
and Holtzman 2015; Bitan etal. 2003), creating various
abnormal conformations, such as misfolded monomers,
oligomers, protofibrils, and insoluble fibrils in plaques
(Bharadwaj etal. 2009). Toxic amyloid accumulation
Fig. 2 IAmyloid pathology in Alzheimer’s disease (AD); IIStructure of amyloid-β peptide (Aβ); Active IIIand passive IVimmunotherapeutic
drugs against Aβ; (1–3) Proposed mechanisms of action of AD immunotherapy

676 Journal of Pharmaceutical Investigation (2023) 53:667–684
1 3
leads to cerebral cell loss and dementia (Reiss etal. 2018),
which are characteristics of AD pathology. Thus, Aβ42/40 is
an important biomarker for AD therapeutics. In an active
approach, a vaccine containing a full-length Aβ or an Aβ
fragment was administered to activate the immune system
to produce antibodies, while passive immunotherapeutic
drugs deliver anti-Aβ antibodies and directly disassemble
Aβ by targeting Aβ deposits in the AD brain (Fig.2). In
Table2, we summarize the representative active immu-
notherapeutic agents that target Aβ, and their details are
discussed in the following sections.
ABvac40 ABvac40 is the first AD vaccine that was devel-
oped to target the C terminus of Aβ1−40. Its multiple frag-
ments are decorated around an outstanding carrier protein,
the keyhole limpet cyanine that merges with the adjuvant
alum hydroxide. This vaccine could greatly eliminate N-ter-
minal modified Aβs and does not recognize other APPs in
the cell membrane. This advantage might improve the safety
and efficiency of Lacosta etal. (2018) released clinical data
to prove the safety and tolerability of ABvac40 in detect-
ing specific anti-Aβ antibodies in plasma samples of 92% of
their study participants. Moreover, ARIA was not detected
throughout a phase 1 trial (Lacosta etal. 2018).
ACI‑24 ACI-24 is a liposomal anti-Aβ vaccine contain-
ing an Aβ1−15 sequence anchored between palmitoylated
lysine tandems. This design can differently induce a
conformation-specific immune response (Hickman etal.
2011), which further confirms that AD is a conformational
disease. Muhs etal. (2007) developed two ACI vaccines of
Aβ1−15 with tetrapalmitoylated preparations (PalmAβ1–15
or ACI-24) and Aβ1−16 linked to a polyethylenegly-
col spacer (PEG-Aβ1–16). In an animal study using APP
transgenic mice, PalmAβ1−15 use induced IgG activity
and improved memory impairment, whereas PEG-Aβ1−16
administration elicited IgM activity with no improvement
in memory deficits. Thus, only ACI-24 has been tested via
a clinical trial. Additionally, ACI-24-treated mice showed
significant reductions in the levels of insoluble amyloid
deposits and soluble Aβ1–42 (Muhs etal. 2007). Moreo-
ver, optimized ACI-24 greatly suppressed the expression
of pyroglutamate Aβ3−42, which is highly toxic to cerebral
cells (Vukicevic et al. 2022). Rudan Njavro etal. (2022)
Fig. 3 ITau pathology in Alzheimer’s disease (AD); IIStructure of tau protein; Active IIIand passive IVimmunotherapeutic drugs against tau
protein; (1–3) Proposed mechanism of action of AD immunotherapy. Active (III) and (IV) passive immunotherapeutic drugs against tau protein

677Journal of Pharmaceutical Investigation (2023) 53:667–684
1 3
discovered that APP/PS1 mice vaccinated with ACI-
24 displayed reductions in the levels of Aβ plaques and
microglia related to AD pathology (Rudan Njavro etal.
2022).
ALZ‑101 ALZ-101 will enter a Phase 1b trial by the end
of 2023 without any preclinical studies published. ALZ-
101 comprises modified non-neurotoxic Aβ1−42 oligomers
designed using AβCC peptide technology to prevent Aβ
misfolding. AβCC utilizes a disulfide bond to cross-link
Aβs, which enables the peptides to remain consistently
stable and in a non-neurotoxic oligomeric form (Sand-
berg etal. 2010). Patients with early-stage AD have been
employed to assess the safety and tolerability of the vac-
cine.
UB‑311 UB-311 contains two synthetic Aβ1–14 sequences
delivered by a Th2-based system designed using the
UBITh® platform to boost immunogenicity and minimize
inflammation. A clinical study showed that UB-311 admin-
istration activates anti-Aβ antibody production, and UB-311
enters the brain parenchyma via the “amyloid sink hypoth-
esis” (Fig.2). Subsequently, the anti-Aβ antibodies bind to
monomeric, oligomeric, and fibrillar Aβ to clear them from
the brain (Wang etal. 2017). Additionally, an animal study
demonstrated that antibodies generated by UB-311 admin-
istration specifically bind to N-terminal Aβ and neutralize
toxic Aβ (Wang et al. 2007). UB-311 is the first Aβ-based
vaccine in phase 3 clinical trial (NCT03531710); in 2020,
it showed promising results in terms of safety, tolerability,
immunogenicity, cognitive improvement in patients with
mild AD, and no report of ARIA.
Passive immunotherapy
Aducanumab Aducanumab (Aduhelm®, Biogen) was
approved by the Food and Drug Administration (FDA)
in 2022 as an anti-Aβ agent that binds with Aβ plaques
in AD treatment. In 2023, the FDA also approved the use
of lecanemab (Leqembi®, Eisai) through the accelerated
approval pathway, based on a reasonable likelihood of
clinical benefit in phase 2 trials. Lecanemab (BAN2401),
a humanized IgG1 mAb, purposely targets Aβ protofibrils.
mAb158, a murine version of lecanemab, was found to clear
large protofibrils in mouse brains during 13 weeks of treat-
ment (Tucker et al. 2015). Subsequently, its mechanism of
action was discovered to be related to astrocytes. Moreo-
ver, mAb158 is initially needed to bind to Aβ42 protofibrils,
forming a complex that is engulfed by astrocytes (Söllvan-
der etal. 2018). Lecanemab use was also proven safe and
tolerable in a phase 1 clinical trial (Logovinsky etal. 2016).
The outcomes of a phase 2 trial confirmed that lecanemab
use can slow the development of mild, moderate, and severe
AD (Tahami Monfared et al. 2022). However, lecanemab
use is still under scrutiny because of the risk of ARIA inci-
dence. Furthermore, a phase 3 trial has been conducted to
further observe its efficacy.
ACU‑193 A humanized IgG2m4 mAb, strongly binds to Aβ
oligomers with > 500-fold selectivity and nanomolar affin-
ity compared with other Aβ conformations, such as mono-
mers and fibrils (Krafft etal. 2013). The high selectivity and
affinity offer outstanding safety and efficacy compared with
other therapeutic antibodies. In addition, the administration
of gantenerumab, donanemab, and aducanumab may cause
Table 2 Immunotherapeutic agents targeting Aβ under clinical trial
KLHkeyhole limpet hemocyanin, IgGimmunoglobulin G, Aβamyloid beta, AβpE3Aβ at position 3
Type Drug name Main component/drug
carrier
Company Mechanism of action Status ClinicalTrials.
gov Identifier
Active ABvac40 C-terminal fragments of
Aβ /KLH
Araclon Biotech Vaccination Phase 2 NCT03461276
ACI-24 Aβ1−15 peptide/liposome AC Immune SA Vaccination Phase 2 NCT05462106
ALZ-101 Non-toxic oligomers Alzinova AB Vaccination Phase 1 NCT05328115
UB-311 Synthetic Aβ1−14 peptides United Neuroscience Vaccination Phase 3 NCT03531710
Passive ACU-193 Humanized IgG2m4 Acumen Pharmaceuticals,
Inc.
Binding to soluble Aβ
oligomers
Phase 1 NCT04931459
Donanemab Humanized IgG1 Eli Lilly & Co. Binding to the N-truncated
pyroglutamate AβpE3
Phase 3 NCT04437511
Trontinemab Humanized IgG1 Hoffmann-La Roche Binding to Aβ fibrils and
plaques
Phase 1 NCT04023994
PRX012 Humanized IgG1 Prothena Binding to Aβ fibrils Ongoing Phase 1 –
DNL919 TREM2 agonist Denali Therapeutics Inc. Activating TREM2
protein and stimulating
microglia
Phase 1 NCT05450549

678 Journal of Pharmaceutical Investigation (2023) 53:667–684
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ARIA, a serious adverse effect of immunotherapy, because
these agents bind to plaques (Filippi etal. 2022). A clinical
trial conducted using preclinical data has proven the safety
and tolerability of ACU-193 use with a significant clearance
of Aβ oligomers (Siemers etal. 2023), which are considered
toxic compared with others Aβ species.
Donanemab Donanemab (LY3002813), a humanized IgG1
mAb produced based on mouse mE8-IgG2a, binds to the
pyroglutamate form of Aβ (Aβp3–42). Lowe etal. evaluated
the safety, tolerability, and immunogenicity of donanemab
use and reported that it can dramatically clear Aβ plaques
in mild to moderate AD. However, ARIA occurrence was
recorded in 37% of patients (Lowe etal. 2021). In 2022, a
clinical trial investigated the clinical outcomes of partici-
pants with early symptomatic AD and reported that plaques
were not reaccumulated after treatment discontinuation. In
addition, tau protein levels decreased in association with
plaque reduction (Shcherbinin etal. 2022). This result also
supported the hypothesis of amyloid-induced tau pathology.
Trontinemab Trontinemab was modified from gan-
tenerumab to enhance BBB permeability by decorating its
Fab region to bind to the transferrin receptor. Trontinemab
levels in the brains of AD mice were shown to be 55 times
higher than gantenerumab levels (Niewoehner et al. 2014).
The use of this new mAb demonstrated its safety, toler-
ability, immunogenicity, and pharmacokinetics in a phase
1 clinical trial (NCT04023994). Thus, trontinemab is a
new mAb-based AD therapeutic agent that can be used to
improve BBB permeability.
PRX012 A humanized IgG1 mAb that binds to fibrils at the
N-terminus, can clear AβpE3-42-included amyloid plaques
through microglial activity. The use of this antibody is
promising as the next generation of immunotherapeutic AD
treatments, and it is currently ongoing a clinical trial since
2022 (Tam etal. 2021).
DNL919 A TREM2 agonist antibody, contains a transfer-
rin-receptor with which it penetrates the BBB. It indirectly
binds to any Aβ conformation but abundantly clears amy-
loids via TREM2 receptor signaling-mediated microglial
survival and Aβ phagocytosis (van Lengerich etal. 2023).
In 2022, a phase 1 clinical trial confirmed its safety, tolera-
bility, pharmacodynamics, and pharmacokinetics in healthy
individuals.
Immunotherapeutic agents targeting tau protein
Tau protein, a microtubule-associated protein, is dominant
in neurons (LoPresti etal. 1995). The human tau gene is
located at chromosome 17q21. Tau protein promotes the
formation and stability of microtubules, as well as the sus-
tenance of the integrity of axonal cytoskeletal structure and
signal transmission (Black etal. 1996). Similar to other pro-
teins, tau protein undergoes typical post-translational modi-
fications, such as proteolysis, phosphorylation, and acetyla-
tion, to achieve its function and cellular localization (Avila
etal. 2004). Because of its interactions with functional
proteins (Lloret etal. 2011) and Aβ-induced tau pathology
(Stancu etal. 2014), tau undergoes hyperphosphorylation.
Three mechanisms regarding tau-mediated AD have been
studies (Fig.3). First, increased phosphorylation leads to
low binding affinity between tau protein and microtubules,
producing an unstable neuronal cytoskeleton (Fig.3) (Kada-
vath etal. 2015). Second, hyperphosphorylated tau highly
self-aggregates to generate oligomers and paired helical fila-
ments, which are assembled into neurofibrillary tangles that
are abundant in the brains of patients with AD (Virginia
M-Y Lee, Michel Goedert, and Trojanowski 2001). These
aggregations correlate with neurodegeneration (Gendron and
Petrucelli 2009). Third, free-phosphorylated tau spreads via
“transneuronal propagation” from neuron to neuron and is
assembled into neurofibrillary tangles in neighboring neu-
rons. Additionally, tau aggregation can cumulatively damage
almost all cerebral areas in the long term (Bell etal. 2020;
Hou etal. 2021). Therefore, except for Aβ-based therapy,
tau-directed therapy is reportedly effective in patients with
AD (Table3).
Active immunotherapy
AADvac1 AADvac1 is a first-in-man tau vaccine generated
from the peptide sequence 294KDNIKHVPGGGS305 and
coupled to keyhole limpet hemocyanin that targets tau pro-
tein at the microtubule-binding region (MTBR). A phase 1
clinical trial showed the safety, tolerability, and high immu-
nogenicity of AADvac1 (NCT02579252). However, there
were no significant improvements in cognitive and func-
tional tests in a phase 2 trial (Novak etal. 2019).
ACI‑35 ACI-35 is a liposomal-based 16-amino acid pep-
tide including phosphorylated S396 and S404. In an animal
experiment, this vaccine was found to stimulate the immune
system to produce high titers of polyclonal IgG antibodies
against tauopathies (Theunis etal. 2013). A phase 2 trial is
underway to assess the efficacy of ACI-35.
Passive immunotherapy
APNmAb005 A humanized IgG mAb that targets tau oli-
gomers accumulating around synapses, is delivered via
artificial lipid vesicles to elicit tau oligomer binding and
clearance from synapses. In mice, APNmAb005 is highly
specific against the oligomeric form of tau protein at the

679Journal of Pharmaceutical Investigation (2023) 53:667–684
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early stage of AD, in which neurofibrillary tangles are not
yet abundant. Consequently, it can promote synaptic stabi-
lization and neuronal survival. Moreover, it was observed
to be immunoreactive in human cerebral nerves and glial
cells (Tai etal. 2022). A phase 1 clinical trial was initiated
in April 2022, and the primary safety and efficacy outcome
results are expected by 2023 (NCT05344989).
E2814 A humanized IgG1 mAb, targets an HVPGG epitope
in the MTBR of tau protein, which is a crucial point involv-
ing tau seeds and aggregates (Albert et al. 2019). E2814
prevents the deposition of phosphorylated tau in vitro.
Moreover, it can bind to extracellular tau and associate
with activated microglial cells to accelerate their clearance,
thereby inhibiting tau propagation (Roberts et al. 2020).
A clinical trial has evaluated E2814 use as a single treat-
ment or in combination with other disease-modifying agents
(NCT04971733).
JNJ‑63733657 A humanized IgG1 mAb, targets phospho-
rylated tau at residue 217, which belongs to the MTBR.
Similar to E2814, this antibody can prevent the transneu-
ronal propagation of free tau protein. In a phase 1 clinical
trial (NCT03375697), the use of JNJ-63733657 demon-
strated safety, tolerability, and dose-dependent reductions
in free p217 tau fragments. During phase 2, which started
in January 2021, JNJ-63733657 use was proven to be safe
and effective in slowing cognitive and functional decline in
patients with early-stage AD.
Bepranemab Bepranemab (UCB0107), a humanized
IgG4 mAb, binds to the MTBR of tau around amino acids
235–250. This binding can also result in the inhibition of
the cell-to-cell spread of tau protein(Albert et al. 2019;
Falcon etal. 2015). Phase 1 clinical trials (NCT03375697,
NCT03605082) have reported that the use of bepranemab is
safe and tolerable. The phase 2 trials have aimed to test its
efficacy in patients with mild cognitive impairment or mild
AD.
Lu AF87908 A humanized IgG1 mAb, targets tau proteins
at the S396-phosphorylated site. Its mouse variant, C10.2,
highly targets pS396/pS404-tau peptide. In rTg4510 brain
mice, C10.2 use was found to reduce tau seeding. Moreover,
Andersson etal. proved that C10.2 use can clear tau protein
via its Fcγ receptor. Specifically, the Fcγ receptor binds to
microglia and interacts with functional lysosomes to boost
clearance (Rosenqvist etal. 2018; Andersson et al. 2019).
The safety and efficacy of Lu AF87908 in healthy partici-
pants and patients with AD have been assessed in a phase 1
clinical trial (NCT04149860).
Ongoing discussion onthePD‑1/PD‑L1
pathway inAD
The programmed death-1 (PD-1)/programmed death-ligand
1 (PD-L1) pathway has been investigated for immune-related
cancer treatment. PD-1 receptor is inhibited during auto-
immune diseases and regulates T cell activation. PD-L1,
its ligand, is a type I transmembrane protein. The PD-1/
PD-L1 complex triggers the upregulation of IL-10 secre-
tion and inhibition of T cell activation. The PD-1/PD-L1
Table 3 Immunotherapeutic agents targeting tau protein under clinical trials
KLHkeyhole limpet hemocyanin, IgGimmunoglobulin G, MTBRmicrotubule-binding region
Type Drug name Main component/drug car-
rier
Company Mechanism of action Phase ClinicalTrials.
gov Identifier
Active AADvac1 294–305 Synthetic peptide/
KLH
Axon Neuroscience SE Vaccination Phase 2 NCT02579252
ACI-35 393–408 Synthetic peptides/
liposome
AC Immune SA, Janssen Vaccination Phase 2 NCT04445831
Passive APNmAb005 Humanized IgG Aprinoia Therapeutics Recognizing synaptic tau
oligomers
Phase 1 NCT05344989
Bepranemab Humanized IgG4 Hoffmann-La Roche, UCB
S.A.
Recognizing amino acids
235–250 near the MTBR
of tau
Phase 2 NCT04867616
E2814 Humanized IgG1 Eisai Co., Ltd. Recognizing an HVPGG
epitope in the MTBR of
tau
Phase 1/2 NCT04971733
JNJ-6373657 Humanized IgG1 Janssen Recognizing the MTBR of
tau
Phase 2 NCT05407818
Lu AF87908 Humanized mouse IgG1 Lundbeck Recognizing phospho-Ser
396 of tau
Phase 1 NCT04149860

680 Journal of Pharmaceutical Investigation (2023) 53:667–684
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pathway has recently been found to be a potential target for
AD immunotherapy.
A study showed that PD-1/PD-L1 pathway suppression
results in the amelioration of cognitive impairment in tau-
mediated AD mice (Rosenzweig etal. 2019). Moreover,
5xfAD mice administered with anti-PD-1 antibody dis-
played cognitive recovery, learning ability, and reduction
in neuronal loss. This antibody treatment also enhanced the
activation of monocyte-derived macrophages, resulting in an
increased secretion of IL-10, an anti-inflammatory modula-
tor. Wu etal. (2022) recently investigated the role of the
PD-1/PD-L1 pathway in healthy volunteers and patients
with AD; they reported that a decrease in peripheral CD8+
T cell count was correlated with PD-L1 overactivation, lead-
ing to neuronal damage (Wu etal. 2022). Importantly, they
observed that variations occurred during the different stages
of AD progression; the PD-1-negative CD8 + T cell count
decreased in patients with moderate AD.
In contrast, Kummer etal. (2021) proved that the pres-
ence of PD-L1 in astrocytes increased the level of Aβ, which
mediates AD pathology (Kummer etal. 2021). Similarly,
microglial PD-1 was overexpressed in 9-month-old APP/PS1
mice. In microglia, PD-1 knockdown triggered the secre-
tion of more pro-inflammatory cytokines than in wild-type
cells in the presence of Aβ deposits. Cognitive impairment
was found to be correlated with inflammatory response in
APP/PS1 mice that underwent PD-1 knockdown. Moreo-
ver, invivo experiments showed decreased Aβ clearance in
microglia that underwent PD-1 knockdown. These findings
confirm that the activation of the PD-1/PD-L1 pathway can
reduce Aβ-mediated AD progression. Overall, the altered
PD-1/PD-L1 signal in AD pathology may serve as an impor-
tant biomarker in detecting AD progression and a new AD
treatment target.
Conclusion
Many AD-related preclinical and clinical studies have been
rigorously conducted over the past decade; however, the pro-
gress of AD treatment is not significant. Immune-related bio-
markers have recently emerged as essential factors in AD onset
and progression. Specifically, the IL family and TNF-α have
been found to have remarkable neuroinflammatory effects in
AD. Alterations in the immune system have been researched
in both patients with AD and animal models, and biomarkers
to the diagnosis of early- and late-onset AD have been pro-
vided. The determination of the exact AD stage is critical in
selecting a precise treatment regimen. Additionally, immune
factors have been suggested as potential targets for AD treat-
ment, and various approaches targeting ILs to prevent neurode-
generation are being investigated in animal studies. However,
compared with cancerous inflammation, examining AD from
an immunological standpoint is hindered by research barri-
ers, such as the limited number of AD animal models. Thus,
future research on immune system-mediated AD may require
more effort in clarifying AD pathogenesis and discovering new
targets for individual therapeutic interventions.
Neurodegeneration-correlated inflammation has received
special attention regarding immune system response-based
therapy. Currently, 11 vaccines and 33 mAbs targeting either
Aβ or tau protein are under clinical trial for AD treatment. The
applications of aducanumab (which targets Aβ) and lecanemab
(which slows down the progression of cognitive decline) were
approved by the FDA in 2021 and 2023, respectively. They
all focus on the clearance and prevention of Aβ and tau pro-
tein deposits, which have been proven as major players in the
destruction of cerebral cells. Nevertheless, since the existing
damage on neuronal function cannot be recovered through
immunotherapy, improvement in cognitive function has not
been achieved, especially for severe AD. Nonetheless, all
immunotherapeutic drugs are effective against mild AD symp-
toms. Strategies for recovering neuronal damage after rebal-
ancing the homeostasis of Aβ and tau proteins remain unclear.
In addition, novel strategies are required to overcome ARIA
in immunotherapeutically treated patients. Moreover, deliver-
ing sufficient amounts of mAbs through the BBB to achieve
the desired efficacy has been challenging. Big pharmaceutical
companies have recently made numerous attempts to enhance
the penetration of vaccines or antibodies via the BBB. The
next generation of mAbs in the market are those with modified
Fab regions using transferrin-receptor binding moieties, such
as trontinemab and DNL919. Nevertheless, the immunothera-
peutic treatment of patients with AD currently relies on Aβ and
tau protein clearance. The modulation of microglial and T cell
activation in the brain by targeting cytokines and other factors,
which compromise immune response and neuroinflammation,
can be a promising alternative for AD treatment.
Acknowledgements This work was supported by the Keimyung Uni-
versity Research Grant of 2020.
Declarations
Conflict of interest All authors (T.D. Nguyen, L.N. Dang, J.H. Jang,
and S.Y. Park) declare that they have no conflict of interest.
Research involving human and animal rights This article does not
contain any studies with human and animal participants conducted by
any of the authors.
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