Journal of Alzheimer’s Disease 101 (2024) S23–S39 S23

DOI 10.3233/JAD-230603
IOS Press

Review

Immunotherapy in Alzheimer’s Disease:

Current Status and Future Directions
Kshitij Vashistha,1 , Shivani Sharmab , Shampa Ghosha,c,1 , M. Arockia Babud , Soumya Ghosha ,
Danish Iqbale , Mehnaz Kamalf , Abdulmajeed G. Almutaryg , Saurabh Kumar Jhah , Shreesh Ojhai ,
Rakesh Bhaskarj,k,∗ , Niraj Kumar Jhal,∗ and Jitendra Kumar Sinhaa,∗
a GloNeuro, Noida, India
b Department of Pharmaceutics, R.K.S.D. College of Pharmacy, Kaithal, Haryana, India
c ICMR – National Institute of Nutrition, Tarnaka, Hyderabad, India
d Institute of Pharmaceutical Research, GLA University, Mathura, India
e Department of Health Information Management, College of Applied Medical Sciences, Buraydah Private

Colleges, Buraydah, Saudi Arabia

f Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University,

Al-Kharj, Saudi Arabia

g Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Abu Dhabi, United

Arab Emirates
h Department of Zoology, Kalindi College, University of Delhi, New Delhi, India
i Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates

University, Al Ain, United Arab Emirates

j School of Chemical Engineering, Yeungnam University, Gyeonsang, Korea
k Research Institute of Cell Culture, Yeungnam University, Gyeongsan, Korea
l Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical

Sciences, Saveetha University, Chennai, India

Accepted 22 August 2023

Abstract. Alzheimer’s disease (AD) is a progressive neurological disorder characterized by memory loss, cognitive decline,
and behavioral changes. Immunotherapy aims to harness the immune system to target the underlying pathology of AD
and has shown promise as a disease-modifying treatment for AD. By focusing on the underlying disease pathogenesis and
encouraging the removal of abnormal protein aggregates in the brain, immunotherapy shows promise as a potential treatment
for AD. The development of immunotherapy for AD began with early attempts to use antibodies to target beta-amyloid.

1 These authors contributed equally to this work.

∗ Correspondence to: Dr. Niraj Kumar Jha, Assistant Professor, GloNeuro Academy, Sector 107, Vishwakarma Road, Noida
Centre for Global Health Research, Saveetha Medical College, 201301, India. E-mails: jksinha@gloneuro.org, jitendrakumar
Saveetha Institute of Medical and Technical Sciences, Saveetha sinha@gmail.com and Dr. Rakesh Bhaskar, Assistant Professor,
University, Chennai, India. E-mail: nirajkumarjha2011@gmail. School of Chemical Engineering, Yeungnam University, Gyeon-
com; and Dr. Jitendra Kumar Sinha, Chief Scientific Officer, sang 38541, Korea. E-mail: bhaskar88@yu.ac.kr.

ISSN 1387-2877/$35.00 © 2024 – IOS Press. All rights reserved.

S24 K. Vashisth et al. / Immunotherapy in Alzheimer’s Disease: Current Status and Future Directions

The amyloid hypothesis which suggests that the accumulation of beta-amyloid in the brain triggers the pathological cascade
that leads to AD has been a driving force behind the development of immunotherapy for AD. However, recent clinical
trials of monoclonal antibodies targeting amyloid-␤ have shown mixed results, highlighting the need for further research
into alternative immunotherapy approaches. Additionally, the safety and efficacy of immunotherapy for AD remain an area
of active investigation. Some immunotherapeutic approaches have shown promise, while others have been associated with
significant side effects, including inflammation of the brain. Sleep has a significant impact on various physiological processes,
including the immune system, and has been linked to the pathogenesis of AD. Thus, improving sleep quality and duration
may benefit the immune system and potentially enhance the effectiveness of immunotherapeutic approaches for AD. In this
review, we discussed the promises of immunotherapy as a disease-modifying treatment for AD as well as possible methods
to improve the efficacy and safety of immunotherapy to achieve better therapeutic outcomes.

Keywords: Alzheimer’s disease, amyloid-␤, dementia, immunotherapy, personalized medicine, sleep-immune interactions

INTRODUCTION nance of various physiological functions, including

memory consolidation, synaptic plasticity, and neu-
Alzheimer’s disease (AD) is a major public health ronal repair [12, 13]. Sleep is a critical physiological
concern that affects millions of people globally and function that is increasingly recognized for its asso-
is characterized by a gradual loss of memory and ciation with neurodegenerative disorders, such as
cognitive decline [1]. Furthermore, accumulating evi- AD, and its role in maintaining cognitive health
dence suggests that sleep disturbances may contribute [14]. Studies have shown that disrupted sleep pat-
to AD pathology through various mechanisms, such terns, particularly in the form of sleep fragmentation
as the accumulation of amyloid-beta (A␤) and tau or deprivation, can accelerate cognitive decline and
proteins, neuroinflammation, oxidative stress, and increase the risk of developing AD [15]. This review
impaired glymphatic clearance [2, 3]. Presently, treat- aims to provide a thorough analysis of the historical
ment options for AD are limited to symptomatic context and potential applications of immunother-
management, highlighting the urgent need for inno- apy in AD, covering early attempts to treat AD with
vative, disease-modifying therapies [4]. Given the immunotherapy, the advent of the amyloid hypothe-
complex interplay between sleep and the immune sis, the state of immunotherapy in AD at the moment,
system, researchers have also explored the potential safety concerns, immunotherapy side effects, and
of immunotherapy in AD, particularly in the context novel immunotherapeutic methods. Furthermore, the
of sleep-immune interactions [5, 6]. Immunother- impact of sleep on immunotherapeutic methods will
apy approaches involve targeting the pathological be explored, as devices that improve sleep quality
processes underlying AD, such as the accumulation may have the potential to enhance the effectiveness
of A␤ and tau proteins, with antibodies or other of these treatments [16]. By shedding light on the
immune-based interventions [7]. Recent clinical tri- interplay between sleep, immunotherapy, and AD,
als have shown promising results in reducing A␤ this review seeks to discuss the prospective future
burden and improving cognitive function in patients research and contribute to the development of more
with early-stage AD [8, 9]. However, challenges effective therapeutic strategies for this debilitating
remain in optimizing the efficacy and safety of these disease.
therapies, particularly in more advanced stages of the
disease. HISTORICAL PERSPECTIVE OF
Immunotherapy has emerged as a promising IMMUNOTHERAPY IN AD
approach in AD research, with several studies demon-
strating its potential to modify the disease course Since the 1990s, when researchers first tried to uti-
[10]. Different molecules such as Sirtuin 1 (Sirt1) lize active vaccination to remove A␤ from the brains
have been identified to play an important role in of transgenic mouse models of AD, immunother-
attenuation of pathological hallmarks of AD [11]. apy has been used to treat AD [17]. A␤ peptides
Hence, they are being considered for combinatorial are administered during active vaccination to elicit
therapy with AD immunotherapy. Among physio- an immunological response and the formation of
logical processes, sleep is a complex and dynamic A␤-specific antibodies. Transgenic mice showed
process that plays an essential role in the mainte- increases in cognition and A␤ plaque reductions in
 K. Vashisth et al. / Immunotherapy in Alzheimer’s Disease: Current Status and Future Directions S25

the early outcomes of this strategy [17, 18]. Hock closely related to neurodegeneration and cognitive
and colleagues published the findings of a clini- decline [32–34].
cal experiment in which they gave A␤ vaccine to The potential for immunogenicity or the emer-
the patients representing mild to moderate AD. The gence of immunological reactions to the therapeutic
research revealed that the vaccination was secure and antibody, is thought to be another limitation of
well-tolerated, and that the brain levels of A␤ protein immunotherapy. This may result in diminished effec-
in those who received it had significantly decreased tiveness or possibly unfavorable consequences like
[19]. Based on these discoveries, scientists started infusion reactions or serum sickness [35, 36]. More-
to create passive immunotherapy methods that used over, the effectiveness of immunotherapy may be
monoclonal antibodies (mAbs) that target A␤. In hampered in certain people by pre-existing A␤ anti-
2000, A␤ mAbs 10D5 was first successfully used bodies [37, 38]. The high expense of producing
by Schenk and colleagues to lessen A␤ deposition and administering antibodies would have restricted
in the brain of a transgenic mice model of AD [20]. their accessibility and availability to patients. These
Researchers started looking into the use of mAbs difficulties highlighted the requirement for the
as an alternative kind of immunotherapy for AD creation of more efficient and reasonably priced
after the failure of A␤ vaccines. To remove amyloid immunotherapies for AD. Despite these limita-
plaques from the brain, the first-generation antibod- tions, first-generation antibodies provided important
ies, such as bapineuzumab and solanezumab were insights into the potential of immunotherapy for
developed to target A␤ protein [21]. A␤ vaccine clin- AD and paved the way for the development of
ical studies failed because some patients experienced next-generation antibodies that can overcome these
negative side effects such as meningoencephalitis and challenges.
brain inflammation [22, 23]. The limited efficacy and Early immunotherapy clinical studies for AD
potential safety issues with the use of first-generation had many difficulties and failures, including sev-
mAbs had subdued the initial excitement surround- eral promising strategies. For instance, the failures
ing these techniques. For instance, the AN1792 active demonstrated by the phase III clinical trials [39] of
immunization study is an example where the study two of the most researched mAbs, bapineuzumab and
was suspended because several participants devel- solanezumab, showed the complexity of AD patho-
oped meningoencephalitis [23]. physiology and the requirement for more efficient
The effectiveness of these antibodies in clinical therapeutic strategies where they failed to achieve
trials has been inconsistent, with some studies show- their main objectives of enhancing cognitive func-
ing a decline in A␤ levels but no improvement in tion in AD patients [25, 40]. Similar to clinical
cognitive performance and others demonstrating no studies with bapineuzumab, the first mAb, to tar-
appreciable effects on either A␤ levels or cogni- get A␤, which failed to demonstrate any discernible
tive outcomes [21, 24, 25]. The blood-brain barrier, efficacy, phase III clinical trials were conducted for
a barrier that prevents dangerous compounds from solanezumab, another A␤ targeting mAb, and that
entering the brain, proved to be a hindrance for these also failed to achieve its primary endpoints [41]. One
first-generation antibodies [26, 27]. Because of this, possible explanation for the lack of effectiveness in
to have any impact on brain A␤ levels, these anti- these trials is that the mAbs were unable to eradi-
bodies were given in high dosages or straight into the cate the brain’s aggregated and insoluble forms of
cerebrospinal fluid (CSF) [28]. Another drawback of A␤, which are known to be more closely related
these antibodies was their limited therapeutic win- to neurodegeneration and cognitive decline as stated
dow, as high doses could have adverse effects, such before [35]. Due to the possibility of immunogenic-
as vasogenic edema and micro-hemorrhages, while ity, i.e., the emergence of an immune response to the
there is no therapeutic effect at low doses [29]. The therapeutic mAb, adverse effects such as infusion
selectivity of first-generation antibodies for particular responses or serum sickness were another problem
A␤ isoforms is another of their main drawbacks. For encountered in early clinical studies [36]. The lack
instance, whereas bapineuzumab and gantenerumab of efficacy seen in some trials may have also been a
target both the soluble and insoluble forms of A␤, result of these side effects.
solanezumab preferentially targets the soluble form The administration and dose of immunotherapeu-
[30, 31]. Recent research, however, indicates that dif- tic agents were one of the main difficulties. As
ferent A␤ isoforms may play unique roles in the mentioned before, high doses of the vaccine were
pathogenesis of AD, with insoluble A␤ being more employed in the early clinical trials of AN1792 to
S26 K. Vashisth et al. / Immunotherapy in Alzheimer’s Disease: Current Status and Future Directions

induce a strong immunological response which had creation of immunotherapeutic strategies meant to
some severe side effects. These side effects pre- lower A␤ levels in the brain. Recent developments
vented the vaccine from being further developed [23, in the field, including the aforementioned devel-
42]. The process of choosing and enrolling patients opment of next-generation antibodies and the use
presented another difficulty. Early clinical studies of biomarkers to identify appropriate patients, have
frequently included individuals with moderate to renewed interest in the potential of immunotherapy as
severe AD, which may have reduced the capacity a treatment approach for AD in spite of the setbacks
of immunotherapeutic drugs to influence the course received in early clinical trials.
of the illness. Also, among patients with AD, there
was variation in the amount and distribution of amy-
loid pathology, which could have affected how well CURRENT STATUS OF
immunotherapy worked [21]. All things considered, IMMUNOTHERAPY IN AD
these difficulties and setbacks emphasize the neces-
sity of thoughtful dose and administration, patient Immunotherapy is a promising therapeutic strat-
selection and stratification, and the creation of effi- egy for AD. There are numerous immunotherapeutic
cient immunotherapy drugs for the treatment of AD. strategies, including passive and aggressive strate-
Despite these difficulties, research into immunother- gies that are currently being employed in clinical
apy for the disease has continued to be driven by the settings (Fig. 1). The delivery of premade antibod-
amyloid hypothesis, which holds that the build-up of ies that bind to particular targets is a component of
A␤ in the brain is a primary driver of AD pathology passive immunotherapy. A␤, the main component of
[43]. This idea has had a big impact on the devel- the amyloid plaques observed in the brains of AD
opment of immunotherapy for AD because many patients, is the target of the most well-known passive
of the existing immunotherapeutic methods concen- immunotherapy strategy for the treatment of AD. The
trate on reducing A␤ levels in the brain. However, first A␤-targeting monoclonal antibody created for
the amyloid hypothesis has received criticism, and AD was bapineuzumab and that due to multiple rea-
other researchers have offered replacement theories sons including but not limited to, a lack of efficacy
that emphasize the role that inflammation, tau protein, and safety issues, its clinical trials did not succeed
and other factors play in AD pathology [44, 45]. [47]. Recently, use of graphene quantum dots and
The setbacks faced in early therapeutic methods nanoparticles have shown promising results [48, 49].
that were developed following the formulation of In collaboration with immunotherapeutic paradigms,
the amyloid hypothesis led to a re-evaluation of it can prove to be a successful therapy procedure.
the immunotherapeutic approach, with researchers Several monoclonal antibodies, like solanezumab,
developing new strategies and next-generation anti- aducanumab, and gantenerumab, are presently
bodies aimed at improving efficacy and reducing undergoing clinical testing for AD (Table 1). Gan-
side effects. The amyloid hypothesis has also had an tenerumab targets both soluble and insoluble forms
impact on the design of clinical trials for immunother- of A␤, whereas solanezumab and aducanumab only
apies. Clinical studies now routinely evaluate A␤ target soluble forms of A␤. Previous clinical trials
levels in the brain using biomarkers like positron using these antibodies have had mixed results, with
emission tomography (PET) imaging, which enables some exhibiting efficacy that is encouraging and oth-
researchers to find patients with high levels of A␤ ers failing to achieve their main endpoints [25, 50].
who will likely benefit from treatment [46]. Recent In active immunotherapy, the immune system of the
clinical trials of immunotherapy for AD have yielded patient is prompted to create antibodies against par-
more encouraging outcomes despite some setbacks. ticular targets. Vaccines against A␤ are one form of
In early-stage AD, aducanumab, a mAb that targets active immunotherapy for AD. These vaccines work
A␤, has been demonstrated to lessen A␤ plaques in by stimulating the immune system to create anti-
the brain and halt cognitive deterioration [24]. Such bodies against A␤. AN1792 was shelved owing to
findings illustrate the value of continued research in security issues. CAD106 and UB-311 are two other
this field and have rekindled interest in the potential A␤ vaccines that are currently being developed in
of immunotherapy in AD management. clinical trials [51–53]. Further active immunother-
The emergence of the amyloid hypothesis has apy strategies for AD, such as the use of DNA and
significantly influenced the course of research into RNA vaccines, which can stimulate long-term anti-
immunotherapies for AD, giving the reason for the body generation, are being investigated in addition to
 K. Vashisth et al. / Immunotherapy in Alzheimer’s Disease: Current Status and Future Directions S27

Fig. 1. Molecular basis and active and passive immunization. A) Active immunization (Vaccination) stimulates the immune system to
produce antigen-specific antibodies. B) Passive immunization initiate an immune response to produce antigen-specific antibodies bypassing
the need of immune system activation. In both immunization process, anti-A␤ antibodies bind A␤, targeting the A␤ peptide for clearance.

mAbs and A␤ vaccines [24]. Immunotherapy may be the phase III trial, aducanumab significantly reduced
more effective when used in combination with other A␤ plaques and slowed cognitive deterioration in
treatments for AD, such as cholinesterase inhibitors individuals with early-stage AD [76]. But the phase
or memantine. However, more research is needed to III trial of gantenerumab, a different mAb that targets
determine the optimal combination of therapies [54, aggregated A␤, did not achieve its main objective of
55]. delaying cognitive aging [59].
The number of clinical trials examining the effec- Due to problems associated with the designs and
tiveness of immunotherapy in the treatment of AD has variable outcomes of trials between dosage groups,
increased dramatically during the past ten years. The the US Food and Drug Administration’s (FDA) deci-
majority of these studies have concentrated on A␤ sion to approve aducanumab in light of its positive
plaques, which are regarded as the disease’s defin- results has sparked controversy [77]. It received
ing characteristic. Recent clinical trial findings have accelerated approval from the FDA in June 2021;
had significant implications in this field. The knowl- however, further confirmatory trial for the medica-
edge gathered from the AN1792 experiment resulted tion is required [78]. In preclinical and early clinical
in the creation of new generation antibodies that trials, immunotherapeutic strategies other than those
are directed against A␤ plaques. As stated before, that target A␤, such as those using anti-tau anti-
clinical trials for the first generation of antibod- bodies, have also shown promise [79]. To ascertain
ies, such as bapineuzumab and solanezumab, were the efficacy and safety of these methods, further
not entirely successful [75]. However, the encourag- research is necessary as they are still in the early
ing outcomes with aducanumab and gantenerumab stages of development. The use of immunotherapy for
(second-generation antibodies) hold great promise. In AD has showed promise in recent clinical trial out-
S28 K. Vashisth et al. / Immunotherapy in Alzheimer’s Disease: Current Status and Future Directions

Table 1
Current immunotherapy treatment paradigms and their mechanism of action available for AD
Immunotherapy treatment Mechanism of action Clinical status
Monoclonal antibodies Bind to A␤ plaques and promote Aducanumab: FDA-approved (requires further
targeting A␤ clearance confirmatory trials) [56–58]
Gantenerumab: Phase III trial did not achieve
primary endpoint [59, 60]
Solanezumab: Phase III trial did not achieve primary
endpoint [61, 62]
Donanemab: Showing positive results in phase III
trials [63, 64]
Bapineuzumab: Phase III trial did not achieve
primary endpoint [21, 65]
Ponezumab: Phase II trial did not achieve primary
endpoint [66]
Active immunization with Stimulate the immune system to CAD106 and UB-311: Under clinical development
A␤ vaccines generate antibodies against A␤ [53, 67, 68]
AN1792: Discontinued due to safety issues and
development of aseptic meningitis in few patients
[42, 69, 70]
Other immunotherapy Anti-tau antibodies, DNA/RNA Preclinical and early clinical stages of development
strategies vaccines [67, 70–74]

comes, particularly when A␤ plaques are the target. response, require careful evaluation through longitu-
Recently, the use of immunotherapy in combination dinal studies [86]. To ensure the successful translation
with gene therapy has been given a focus. Gene ther- of immunotherapy into clinical practice, the devel-
apy is a promising new approach to treating AD. opment of standardized protocols, dosing regimens,
Immunotherapy could be used to enhance the effects and treatment guidelines is imperative. Collaboration
of gene therapy or to deliver genes that encode pro- between academia, pharmaceutical companies, regu-
tective proteins in the brain [80, 81]. To determine latory authorities, and healthcare providers is crucial
the long-term effectiveness and safety of these strate- to establish rigorous clinical trial designs, harmonize
gies, more research is required. The controversy outcome measures, and navigate regulatory pathways
surrounding the aducanumab approval underlines the for expedited drug approval. Furthermore, the cost-
requirement for more exacting clinical trial design effectiveness of immunotherapy and its accessibility
and outcome interpretation. to a broader population are important considerations
In the realm of clinical aspects, the implementation in the development and implementation of these ther-
of immunotherapy for AD faces several challenges apies [87]. Addressing these clinical aspects will be
[82]. One crucial aspect is patient selection and strat- vital for the successful integration of immunother-
ification. The heterogeneity of AD pathology and the apy into the existing treatment landscape for AD
varying response to immunotherapy necessitate the and ultimately improving patient outcomes. Further,
identification of suitable biomarkers and diagnostic development and testing immunotherapy approaches
tools to accurately predict treatment outcomes and for Alzheimer’s disease has been depicted in Fig. 2.
monitor disease progression [82]. Biomarkers such When assessing the possibility of this therapeutic
as A␤ and tau levels in the CSF, neuroimaging tech- method, the safety issues and side effects connected
niques including PET scans, and genetic markers to immunotherapy for AD are crucial factors to
associated with AD risk are being explored for their take into account. The emergence of amyloid-related
potential utility in patient selection and monitoring imaging abnormalities (ARIA), which has been seen
treatment response [83, 84]. Additionally, the timing in clinical studies for a number of immunothera-
of intervention is critical. Initiating immunotherapy peutic drugs including aducanumab, solanezumab,
during the early stages of the disease, when the patho- and gantenerumab, is a significant safety risk [88].
logical burden is relatively lower, may offer better Careful monitoring and changing the dose of the
chances of success compared to late-stage interven- immunotherapeutic agents as necessary can reduce
tions [85, 86]. Nevertheless, the optimal duration the incidence of ARIA. Infusion reactions and the
and frequency of immunotherapy, as well as the danger of infection are two additional possible side
long-term effects and sustainability of the treatment effects of immunotherapy for AD in addition to ARIA
 K. Vashisth et al. / Immunotherapy in Alzheimer’s Disease: Current Status and Future Directions S29

Fig. 2. Development and testing immunotherapy approaches for Alzheimer’s disease. The process begins with identifying the target antigen,
such as amyloid-␤ or tau protein, and developing a therapeutic antibody that can bind to it. Preclinical studies are then conducted to test the
safety and efficacy of the therapeutic antibody in animal models of Alzheimer’s disease. If preclinical studies are successful, clinical trials
are conducted in humans to test the safety and efficacy of the therapeutic antibody. Phase I clinical trials test the safety and dosage of the
therapeutic antibody in a small group of healthy volunteers or patients with Alzheimer’s disease. Phase II clinical trials test the efficacy and
optimal dosage of the therapeutic antibody in a larger group of patients with Alzheimer’s disease. Phase III clinical trials confirm the efficacy
and safety of the therapeutic antibody in an even larger group of patients with Alzheimer’s disease. If clinical trials are successful, regulatory
approval is sought from government agencies such as the FDA or EMA. Finally, post-marketing surveillance is conducted to monitor patient
response and side effects. This flowchart provides a visual representation of the complex process involved in developing immunotherapy
approaches for Alzheimer’s disease, highlighting key steps along the way from target identification to regulatory approval.

[89, 90]. Pre-medication or a slower infusion rate can made to target not only A␤ but also tau and alpha-
be used to treat infusion responses like fever, chills, synuclein, two pathogenic proteins involved in AD
and headache. Although the danger of infection is pathogenesis. Creating antibodies that specifically
modest, clinical studies need to be constantly watched target certain forms of A␤, such as oligomeric or
[90]. While assessing the possibility of immunother- fibrillar A␤, which are thought to be more toxic
apy for AD, it is crucial to take these safety issues and than soluble forms of A␤, is one strategy [91].
adverse effects into account. Despite these worries, Another method is to produce antibodies that target
immunotherapy has demonstrated promise in clinical A␤ protofibrils, which are believed to be an early
trials and is a viable therapeutic strategy for this life- pathogenic form of A␤ that predates the formation
threatening illness. To develop techniques to reduce of fibrillar A␤ plaques [92]. Moreover, longer half-
the risk of adverse events and to better understand lives and better pharmacokinetics are being worked
the safety profile of immunotherapy, more research on in next-generation antibodies, which may allow
is required. for less frequent dosing and higher patient compli-
ance. Lecanemab, also known as BAN2401, is one
such antibody that has a longer half-life than other
FUTURE DIRECTIONS FOR antibodies and has demonstrated good outcomes in
IMMUNOTHERAPY IN AD clinical trials [93]. Another potential approach is
to use bispecific antibodies that simultaneously tar-
The goal of new immunotherapeutic approaches get two distinct proteins. For instance, preclinical
for AD is to create antibodies of enhanced speci- investigations have demonstrated that bispecific anti-
ficity, effectiveness, and safety. These antibodies are bodies that target A␤ and tau diminish both A␤ and
S30 K. Vashisth et al. / Immunotherapy in Alzheimer’s Disease: Current Status and Future Directions

tau pathology, respectively [94, 95]. Moreover, next- ultimately result in the creation of potent therapies
generation antibodies have the potential to enhance for AD (Table 2).
the safety profile of immunotherapy by lowering There are still significant issues that need to be
the frequency of untoward effects including brain resolved despite the optimistic outcomes of recent
swelling [96, 97] which has been noted in certain clinical trials employing immunotherapy in AD. The
patients receiving immunotherapy techniques [21]. ineffectiveness of current immunotherapeutic tech-
In a mouse model of AD, for instance, a recent study niques, which target A␤ plaques in the brain, is one
found that using an antibody fragment rather than of the main obstacles. Preclinical studies are still
a complete antibody could lower the risk of brain being conducted to find additional targets and boost
swelling while still successfully lowering A␤ pathol- the efficacy of immunotherapy. Targeting tau pro-
ogy [98]. tein, another defining feature of AD pathogenesis,
Furthermore, given the intricate interactions is one strategy. Neurofibrillary tangles, which are
between A␤, tau, and other pathogenic proteins intimately related to neuronal death and cognitive
throughout the onset and course of the disease, the impairment, are formed when tau protein aggre-
development of immunotherapeutic strategies that gates. Immunotherapy that targets tau protein has
target different harmful proteins may be especially been proven in several preclinical studies to reduce
successful in treating AD [35]. Targeting differ- tau pathology and enhance cognitive performance in
ent pathogenic proteins at once may, in fact, be animal models of AD [116, 117]. For example, in
more beneficial than doing so for a single pro- a mouse model of tauopathy, Yanamandra and col-
tein in lowering pathology and enhancing cognitive leagues showed that immunization with a tau peptide
function, according to recent preclinical research vaccine reduced tau pathology and enhanced cogni-
[99, 100]. Bispecific antibodies and next-generation tive performance [90].
antibodies are just two examples of the innovative Another strategy is to create new antibodies with
immunotherapeutic strategies being researched for enhanced A␤ plaque binding affinity and speci-
the treatment of AD. The UB-311 vaccine which tar- ficity. For instance, phase Ib and phase II clinical
gets simultaneously both A␤ and tau and the CAD106 studies of aducanumab, a mAb that targets A␤,
vaccine which is intended to stimulate an immune revealed encouraging outcomes [21, 24]. The fail-
response against only A␤ are examples of innovative ure of the aducanumab in phase III trial, however,
immunotherapeutic strategies against AD [51, 53]. emphasizes the need for next-generation antibod-
Nevertheless, non-antibody-based strategies are also ies that are more efficient. Bispecific antibodies that
being researched, including the use of gene therapy target both A␤ and tau have been discovered as
to improve the immune response to A␤ [101]. This prospective candidates for next-generation antibod-
approach involves the transfer of the brain-derived ies in preclinical research [107, 108]. Preclinical
neurotrophic factor (BDNF) gene to the brain and research is also investigating the use of combina-
lower levels of A␤, which is a significant pathogenic tion therapy, which entails focusing on numerous
aspect of AD. In the transgenic mouse model, the pathways connected to the pathophysiology of AD.
researchers also showed that the nanoparticle-based In a mouse model of AD, for instance, a recent
delivery of the BDNF gene could endorse cogni- study by Chiang and co-workers [118] demonstrated
tive performance. This path shows the possibility of that combination therapy using an anti-A␤ antibody
functionalized nanoparticles as a cutting-edge gene and a gamma-secretase inhibitor improved cognitive
therapy strategy for the treatment of AD. function and decreased A␤ pathology. Combination
Last but not least, brand-new immunotherapy therapy offers the potential to improve therapeu-
approaches that do not rely on antibodies are being tic effectiveness while lowering the risk of adverse
created, like using tiny compounds to prevent the effects. Future clinical trials will be significantly
aggregation of A␤ or tau. TRx0237 is one such drug impacted by current preclinical research. First, the
that has demonstrated promise in lowering tau pathol- discovery of novel immunotherapy targets, such as
ogy in preclinical investigations [102]. Therefore, the toxic oligomeric forms of A␤ and tau protein, offers
development of new immunotherapeutic techniques chances for the creation of next-generation anti-
and next-generation antibodies holds great promise bodies with enhanced efficacy. Second, the use of
for the treatment of AD. In comparison to current combination therapy may increase the success of
immunotherapy techniques, these strategies may pro- immunotherapy while lowering the risk of negative
vide better efficacy and safety profiles, which could side effects. Finally, for patient stratification and per-
 K. Vashisth et al. / Immunotherapy in Alzheimer’s Disease: Current Status and Future Directions
Table 2
Immunotherapeutic approaches for AD. Each of the three approaches has different mechanism of action, advantages, and disadvantages
Type of immunotherapies mAbs Active immunization Passive immunization
Mechanism of Action Pre-made antibodies bind to specific antigens Stimulates patient’s own immune system to Pre-made antibodies bind to specific antigens
involved in AD. produce antibodies against AD antigens. involved in AD.
Advantages High specificity; can be engineered for optimal Can stimulate long-term immune response. [109] Immediate effect [21]
binding. [103, 104] Can stimulate a broad immune response, Can be derived from human sources [112].
Can be produced in large quantities [103] potentially targeting multiple forms of amyloid
Can be designed to target specific forms of A␤, tau, beta and other AD targets [110]
alpha-synuclein [17, 105, 106] It may be possible to develop vaccines that target
Can be engineered to have longer half-lives [93] multiple AD targets at once [111].
Can be engineered to have improved tissue
penetration [91, 107, 108]
Disadvantages Risk of immune reactions, the body may recognize Risk of immune reactions, as with monoclonal Potential for immune reactions [112]
the monoclonal antibodies as foreign [113] antibodies [115] May require frequent dosing, as with
May require frequent dosing, as the effects of May take longer to develop efficacy, as it can monoclonal antibodies [21]
monoclonal antibodies may wear off over time [114] take time for the patient’s immune system to Risk of developing resistance to passive
May not be able to penetrate the blood-brain barrier produce enough antibodies to have an effect immunotherapy over time [112]
[28] [109] Long-term use of passive immunization may
Risk of developing resistance to monoclonal May not be effective in patients who already increase the risk of infections or other adverse
antibodies over time have significant cognitive impairment or brain events [90]
May not be effective in patients who have already damage [110]
developed significant cognitive impairment or brain
damage [21]

S31
S32 K. Vashisth et al. / Immunotherapy in Alzheimer’s Disease: Current Status and Future Directions

sonalized medicine in immunotherapy research, the apy for AD works. The innate and adaptive immune
identification of biomarkers that can precisely pre- systems are both impacted by sleep which is crucial
dict treatment response and disease progression will for immune system modulation [6]. Immune mal-
be essential. function and a reduced response to immunotherapy
For the successful use of immunotherapy, the have been linked to sleep disorders such as insomnia
development of customized treatment in AD is cru- and sleep apnea [120]. There is strong evidence that
cial. To optimize therapeutic efficacy and reduce some lifestyle modifications may modify the preva-
the hazard of side effects, patient stratification, or lence of the disease. The quality of sleep may improve
the determination of those who will benefit from as a result of such a shift. There is growing evidence
a particular treatment, is essential. Age, genetic that insufficient sleep increases the amount of A␤ in
background, illness stage, and comorbidities are the brain, which in turn causes abnormal A␤ levels to
some of the variables that can affect how well an disrupt sleep and, consequently, memory consolida-
immunotherapy treatment works. For instance, the tion [121, 122]. The effectiveness of immunotherapy
apolipoprotein E (APOE) ␧4 allele is a recognized for AD may be significantly impacted by the con-
risk factor for AD, and people who carry this allele nection between sleep and the immune system (AD).
may react to immunotherapy differently than people The modulation of the immune response during
who do not. Also, the illness stage can affect how sleep is influenced by a number of factors and
well immunotherapy works, with early-stage patients may affect how well immunotherapeutic methods
having a higher chance of success than late-stage work.
patients.
The categorization and selection of patients for
immunotherapy can be aided by the use of biomark- Sleep deprivation and immune response
ers, such as concentrations of A␤, tau-beta and
tau proteins in the CSF and imaging methods Lack of sleep has been demonstrated to have a dele-
to identify A␤ and tau deposits. For instance, a terious impact on the immune system, resulting in
recent study showed that in early AD patients, decreased cytokine production, altered T-cell func-
the presence of amyloid plaques measured by tion, and decreased activation of natural killer cells
PET imaging can predict the responsiveness to [123]. Immunotherapy for AD patients may be less
the anti-amyloid antibody, aducanumab [24]. Next- successful due to these immunosuppressive effects
generation sequencing, which uses individual genetic that can hinder the body’s capacity to establish an effi-
and molecular traits to identify patients, may help cient defense against amyloid-beta and tau proteins
with patient stratification and guide the creation of [6].
specialized immunotherapies [119]. Researchers can
develop individualized therapeutic strategies that are Sleep and immune cell trafficking
optimized for individual patient by comprehending
the distinct genetic and molecular characteristics of Sleep is known to affect the movement of immune
each patient. The development of immunotherapy for cells, including T-cells and monocytes, which are cru-
AD depends critically on patient classification and cial for the removal of the proteins A␤ and tau [124].
tailored medicine. We can maximize the effective- Sleep issues may interfere with these immune cells’
ness and safety of immunotherapy for this terrible migration to the brain, impeding immunotherapy and
disease by identifying individuals who are most lowering treatment effectiveness [125].
likely to benefit from treatment and personaliz-
ing medicines to individual genetic and molecular
factors. Sleep and the glymphatic system

Sleep is when the glymphatic system is most active,

EFFECT OF SLEEP ON which is in charge of removing waste from the brain,
IMMUNOTHERAPY including A␤ [14]. Sleep deprivation may hinder
the glymphatic system’s ability to operate, causing
The field of sleep therapy is gaining momentum in harmful proteins to accumulate and perhaps lower-
today’s world. There is mounting data that suggests ing the effectiveness of immunotherapy that targets
sleep may significantly affect how well immunother- these proteins [126].
 K. Vashisth et al. / Immunotherapy in Alzheimer’s Disease: Current Status and Future Directions S33

Sleep interventions and immunotherapy and might even hold the potential to be the cure
for AD.
Drug therapies and cognitive-behavioral therapy
for insomnia have both been demonstrated to improve DISCUSSION AND CONCLUSION
the quality of sleep in AD patients [127]. The immune
system’s response and the glymphatic system’s per- AD is a well-known fatal neurological condition
formance may be strengthened by better sleep, thus with few effective treatments. Targeting the dis-
enhancing the therapeutic effects of immunotherapy ease’s underlying pathophysiology, immunotherapy
in AD patients [126]. has become a potential approach of treating AD. The
As technology developed, several instruments and creation of the amyloid hypothesis, which has had
devices were produced to aid in improving the quality a substantial impact on research into immunother-
of sleep. These devices could inadvertently con- apy, came after early attempts to use immunotherapy
tribute to an improvement in the effectiveness and/or as a treatment for AD. Early clinical trials, though,
efficiency of immunotherapeutic techniques. White encountered difficulties and failures, underscoring
noise generators create a steady sound that can be the demand for additional study. Although safety
used to conceal distracting noises in the environment issues and adverse effects must be taken into account,
and aid in relaxing and sleep. White noise has been the current situation of immunotherapy for AD is
found in studies to lengthen and increase the qual- positive, with numerous techniques in clinical devel-
ity of sleep, especially in people who have insomnia opment. Next-generation antibodies are one example
[128]. The length, stages, and quality of sleep are just of an emerging immunotherapy strategy that has the
a few of the details tracked by wearable technology potential to overcome the drawbacks of conventional
and smartphone applications that measure sleep. The methods. In addition, dietary modifications [134]
accuracy of sleep trackers varies, and even though along with personalized medicine and patient classi-
they might offer insightful data, they should only be fication are essential to the success of immunotherapy
used as supplemental tools rather than as diagnostic research for AD.
tools [129]. Sleep might have a significant impact on both
It has been demonstrated that light therapy, partic- the pathogenesis of AD and the effectiveness of
ularly blue light exposure, can improve the quality immunotherapy on AD. There has been the devel-
of sleep and regulate circadian cycles. Yet, night- opment and invention of several devices that can
time exposure to blue light in excess can interfere improve sleep quality and/or duration. These devices
with sleep. Thus, it is crucial to use light treatment can aid immunotherapeutic methods to perform bet-
devices properly and with professional supervision ter and remove of pathogenic amyloid from the brain
[130]. Sleep-inducing headbands, such as those using due to the effect of sleep on the immune system. In
electroencephalography technology, monitor brain conclusion, immunotherapy has a lot of potential as
activity and provide auditory feedback to help users a treatment for AD, and more study is needed in this
fall asleep faster. These devices have shown promise area to help those who are afflicted by this terrible ill-
in improving sleep latency and sleep quality [131]. ness. With research booming in the fields of both sleep
Modern mattresses and pillows can offer individ- study and immunotherapy, there might be significant
ualized support and comfort, which can enhance changes in the way we treat AD in the future. Overall,
the quality of your sleep. There is evidence that the growing body of evidence on the role of sleep and
certain mattress technologies, such memory foam the immune system in AD pathogenesis underscores
and adjustable air chambers, might lessen pressure the need for a multifaceted approach to disease man-
spots and encourage appropriate spinal alignment agement. Future research should aim to elucidate the
[132]. Diffusers and sleep masks infused with essen- mechanisms underlying sleep disturbances in AD and
tial oils are two examples of aromatherapy products explore the potential of immunotherapy in targeting
that can aid in creating a calm environment that these mechanisms.
promotes sleep. Some aromas, like lavender, have Furthermore, the combination of immunotherapy
been demonstrated to enhance sleep quality and with other therapeutic approaches holds promise
lessen anxiety [133]. A combination of immunother- for enhancing treatment outcomes in AD. Syn-
apeutic methods and such devices that can help ergistic effects may be achieved by combining
improve sleep might lead to a better prognosis in immunotherapy with other disease-modifying strate-
AD patients and might to better quality of life gies, such as anti-inflammatory agents, antioxidants,
S34 K. Vashisth et al. / Immunotherapy in Alzheimer’s Disease: Current Status and Future Directions

or drugs targeting tau pathology [135, 136]. Addi- CONFLICT OF INTEREST

tionally, emerging evidence suggests that lifestyle
interventions, including physical exercise, cogni- The authors have no conflict of interest to report.
tive stimulation, and a healthy diet, can influence
the efficacy of immunotherapy and potentially
delay disease progression [137, 138]. These mul- REFERENCES
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