REVIEW

published: 12 April 2022

doi: 10.3389/fnagi.2022.870517

Impact of Anti-amyloid-β Monoclonal

Antibodies on the Pathology and
Clinical Profile of Alzheimer’s
Disease: A Focus on Aducanumab
and Lecanemab
Mingchao Shi 1 , Fengna Chu 1 , Feiqi Zhu 2* and Jie Zhu 1,3*
1
Department of Neurology, Neuroscience Center, The First Hospital of Jilin University, Changchun, China, 2 Cognitive
Impairment Ward of Neurology Department, The Third Affiliated Hospital of Shenzhen University Medical College, Shenzhen,
China, 3 Division of Neurogeriatrcs, Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Karolinska
University Hospital Solna, Stockholm, Sweden

Edited by:
Rajesh Tampi, Alzheimer’s disease (AD) is the most prevalent form of age-related dementia in the
Creighton University, United States
world, and its main pathological features consist of amyloid-β (Aβ) plaque deposits and
Reviewed by:
Ganesh Gopalakrishna,
neurofibrillary tangles formed by hyperphosphorylated tau protein. So far, only a few AD
Banner Alzheimer’s Institute, treatments approved have been applied in the clinic, but the effects of these drugs are
United States
limited only for partial symptomatic relief to patients with AD and are unable to alter AD
Aarti Gupta,
Yale University, United States progression. Later, all efforts for AD treatments with targeting the pathogenic factors
*Correspondence: were unsuccessful over the past decades, which suggested that the pathogenesis
Feiqi Zhu of AD is complex. Recently, disease-modifying therapies (DMTs) that can change the
[email protected]
Jie Zhu
underlying pathophysiology of AD, with anti-Aβ monoclonal antibodies (mabs) (e.g.,
[email protected]; aducanumab, bapineuzumab, gantenerumab, solanezumab, and lecanemab) have
[email protected];
been developed successively and conducted in clinical trials based on the theory that
[email protected]
a systemic failure of cell-mediated Aβ clearance contributes to AD occurrence and
Specialty section: progression. In the review, we summarized recent studies on the therapeutic effects
This article was submitted to
and clinical trial results of these mabs in patients with AD. Specifically, we focused on
Alzheimer’s Disease and Related
Dementias, the discussion of the impact of aducanumab and lecanemab on AD pathology and
a section of the journal clinical profiles. The review provides a possible evidence for applying immunotherapy
Frontiers in Aging Neuroscience
with anti-Aβ mabs in AD and analyzes lessons learned from these clinical trials in order
Received: 06 February 2022
Accepted: 11 March 2022 to further study the therapeutic and adverse effects of these anti-Aβ mabs on AD.
Published: 12 April 2022
Keywords: Alzheimer’s disease, amyloid-β, monoclonal antibodies, lecanemab, aducanumab, treatment
Citation:
Shi M, Chu F, Zhu F and Zhu J
(2022) Impact of Anti-amyloid-β
Monoclonal Antibodies on
INTRODUCTION
the Pathology and Clinical Profile
of Alzheimer’s Disease: A Focus on
Alzheimer’s disease (AD) as a chronic neurodegenerative disorder is the most common age-
Aducanumab and Lecanemab. associated dementia accompanied by progressive loss of memory and cognitive functions as well
Front. Aging Neurosci. 14:870517. as synaptic dysfunction (Alexiou et al., 2020). By 2050, there will be 115 million people, of which
doi: 10.3389/fnagi.2022.870517 10–30% of population aged 65 years or above are affected by AD. It becomes a public health

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Shi et al. Anti-amyloid-β Monoclonal Antibodies on Alzheimer’s Disease

predicament in the world, and there is a significant impact on the of AD also indicated the adaptive immune response contributing
direct cost of AD to the society (Povova et al., 2012; Masters et al., to the deposition of Aβ in the brain and misfolded tau
2015; Angelucci et al., 2019). proteins (Ashraf et al., 2018; Uddin et al., 2020b), which
The two main neuropathological hallmarks of AD are might open new perspectives in the treatments for AD with
amyloid-β (Aβ) plaques and neurofibrillary tangles formed by active and passive anti-Aβ immunotherapies clearing brain Aβ
intracellular accumulation of hyperphosphorylated tau protein deposits (Ciccocioppo et al., 2020). Recently, anti-Aβ monoclonal
(Serrano-Pozo et al., 2011; Bloom, 2014; Uddin et al., 2020a). antibodies (mabs) as the immune therapeutic approaches have
One of them, the amyloidogenic pathway, may be involved in been investigated as a treatment for AD, including aducanumab,
the pathogenesis of AD. Aβ peptides, such as Aβ40 , Aβ42 , and bapineuzumab, gantenerumab, solanezumab, and lecanemab.
Aβ43 , are the products of the successive cleavage of amyloid These mabs are distinct in selectivity for polymorphic variants
precursor protein (APP) by β- and γ-secretases, and they can and recognize epitopes based on the specific portion and
assemble into insoluble beta-sheet fibrillar aggregates that deposit conformations of Aβ (Arndt et al., 2018). Among these mabs,
extracellularly in the brain parenchyma and cerebral vasculature, aducanumab and gantenerumab partially target oligomers, while
causing the damage of synaptic structure and function, and most mabs clear insoluble Aβ plaques (Tolar et al., 2020a).
neuronal atrophy in the hippocampus area and then spreading to Thus, these mabs target Aβ via the distinct metabolic pathways
cortical regions, resulting in cognitive impairment and dementia to remove Aβ and soluble misfolded oligomeric antecedents
(Lu et al., 2013; Khan et al., 2014). In addition, inflammation or to prevent the adoption of misfolded conformations of Aβ,
can also contribute to the development of AD (Guillot-Sestier declining the levels and toxicity of Aβ in the brain (Olzscha et al.,
and Town, 2013; Goetzl et al., 2018; Webers et al., 2020). So far, 2011; Guo and Lee, 2014). All these mabs can reduce the levels
only a few drugs approved have been applied in the clinic for of Aβ peptides, 1–40 and 1–42 in cerebrospinal fluid (CSF), or
treatment in AD, such as the acetylcholinesterase inhibitors and plasma at various degrees with different doses, but the effects of
the non-competitive N-methyl-D-aspartate receptor antagonist. the mabs on p181-tau level differed, which have been discussed in
However, these drugs are unable to alter AD progression, only the below sections.
for partial symptomatic relief (Olivares et al., 2012). Based on the In the review, we discussed the effects of mabs, including
amyloid cascade hypothesis, it is believed that the clearance of aducanumab, bapineuzumab, gantenerumab, solanezumab, and
brain Aβ plaques may treat AD and cease disease progression, lecanemab on AD, especially the concentration on the impacts
which promoted the development of innovative anti-Aβ drugs of aducanumab and lecanemab on AD pathology and clinical
to prevent Aβ aggregation in the brain in the past 30 years. manifestations. These mabs have been tested in participants with
Unfortunately, all efforts in the treatment of AD targeting the early AD, preclinical stage of familial AD, and asymptomatic
pathogenic Aβ or tau have failed in the past, which proposed that participants with a high risk of developing AD. To date,
the pathogenesis of AD is more complex and multifactorial (Zhu the outcomes of clinical trials seem to stand by the amyloid
et al., 2020). At present, anti-Aβ therapies are still under debate. hypothesis in the pathogenesis of AD. However, there were a
There is a growing evidence that innate immune plays an series of clinical trial failures with applying these mabs, which is
important role in AD’s etiology, although the central nervous still a question on further development of Aβ-targeting drugs. To
system (CNS) has long been considered an immune-privileged provide further evidence applying immunotherapy for disease-
site (Guillot-Sestier and Town, 2013; Webers et al., 2020). modifying therapies (DMTs) in AD and analyze lessons learned
Furthermore, the new insights on the pathogenesis and therapy from previous and current clinical trials, we summarized the
updated studies on these mabs in clinical trials in patients with
Abbreviations: AD, Alzheimer’s disease; Aβ, amyloid β; CNS, central nervous AD and further evaluated the possibility and effectiveness of the
system; mabs, monoclonal antibodies; DMTs, disease-modifying therapies; immunotherapies with mabs in AD.
IV, intravenous; BBB, blood–brain barrier; IgG1, immunoglobulin 1; mab,
monoclonal antibody; ABO, Aβ oligomers; FDA, Food and Drug Administration;
MCI, mild cognitive impairment; CDRS, Clinical Dementia Rating-Sum; MMSE,
Mini-Mental State Examination; ARIAs, amyloid-related imaging abnormalities; IMMUNOTHERAPIES WITH MABS IN
APOE4, ε4 allele of apolipoprotein E gene; QALYs, quality-adjusted life-years; PATIENTS WITH AD AND ITS ANIMAL
SOC, standard of care; CSF, cerebrospinal fluid; ARIA-E, Alzheimer’s related
imaging abnormality-cerebral edema; ARIA-H, Alzheimer’s related imaging MODELS
abnormality microhemorrhages; tg, transgenic; PET, positron emission computed
tomography; scFvs, single-chain variable fragments; Fcγ6Rs, Fc-gamma receptors; The immunotherapeutic approaches are promoting Aβ clearance
ADAS-Cog, Alzheimer’s Disease assessment scale–cognitive subscale score; CDR-
SB, clinical dementia rating –sum of boxes; ADAD, autosomal dominant AD;
from the brain of AD via injection of Aβ antigens (active
DIAD, dominantly inherited AD; NfL, neurofilament light; DS, Down syndrome; immunization) or anti-Aβ antibodies (passive immunization;
NDC, non-demented controls; MRI, magnetic resonance imaging; ADCS-ADL, Panza et al., 2012). Passive immunization with anti-Aβ antibodies
Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory; can enhance Aβ clearance from plasma and the CNS, leading to
CDRSB, Clinical Dementia Rating Sum of Boxes; CDR-SOB, Clinical Dementia
Rating–Sum of Boxes; DAD, Disability Assessment for Dementia; FAQ, Functional a decline in Aβ burden through the peripheral sink mechanism
Activities Questionnaire; FCSRT, Free and Cued Selective Reminding Test; NPI- of action (Zhang and Lee, 2011; Imbimbo et al., 2012). After
Q, Neuropsychiatric Inventory Questionnaire; NTB, Neuropsychological Test intravenous (IV) administration by these anti-Aβ mabs, they
Battery; PiB PET, Pittsburgh compound B positron emission tomography; p-tau,
bind to soluble Aβ peptides in the periphery and sequester
Phosphorylated-tau 181; SUVr, Standardized uptake value ratio; t-tau, Total
tau; 18F-FDG PET, Positron emission tomography with 2-deoxy-2-[fluorine- them into an immune complex that can be removed from the
18]fluoro-D-glucose. circulation, thereby reducing plasma Aβ levels. To keep the

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Shi et al. Anti-amyloid-β Monoclonal Antibodies on Alzheimer’s Disease

balance between Aβ oligomers (ABOs), aggregates, and plaques stage of disease, and successful development of aducanumab is
in the CNS, amyloid can transform to produce soluble monomers considered a milestone in the treatment of AD (Dhillon, 2021).
and can pass through the blood–brain barrier (BBB) to restore the Aducanumab binds to Aβ plaques and ABO and stimulates
decreased plasma Aβ levels. Finally, the low CNS Aβ level reduced microglia to clear Aβ by reducing brain Aβ in a dose- and time-
Aβ-related cellular toxicity and pathology (Zhang and Lee, 2011). dependent manner by slowing down cognitive impairment in
Recently, treatment with the second generation of anti-Aβ prodromal or mild AD measured by Clinical Dementia Rating-
mabs in AD has made a great progress in clinical trials. A crucial Sum of Boxes (CDR-SB) and Mini-Mental State Examination
feature shared by these mabs is their ability to engage neurotoxic (MMSE) scores (Sevigny et al., 2016; Linse et al., 2020). In
soluble ABOs, albeit to various degrees. Until now, the results a double-blind randomized and placebo-controlled conditions,
from phase III clinical trials with most mabs were unsuccessful. phase Ib study, treatment with aducanumab, was obtained
However, aducanumab in its phase III study obtained relative successful outcomes and showed to be a benefit to AD-associated
positive outcomes, despite the controversy (Panza et al., 2019), MCI or mild AD dementia. Thus, aducanumab was advanced
which supports to continue the testing of the anti-Aβ mabs in the to phase III clinical trials in September 2015 (ClinicalTrials.gov,
treatment of AD. Currently, in this study, some of the mentioned 2020a,b).
mabs to decline brain Aβ levels are still probing in clinical trials A study that recruited 196 patients with AD treated with
(Decourt et al., 2021). The therapeutic and side effects of the mabs aducanumab showed a similar result that aducanumab reduced
in AD and its animal models are presented in Table 1. Aβ plaques and slowly declined in clinical measures in patients
with prodromal or mild AD (Budd Haeberlein et al., 2017).
In addition, aducanumab revealed a significant efficacy on
Aducanumab both clinical and biomarker outcomes (Haeberlein et al., 2020)
Aducanumab, a human immunoglobulin 1 (IgG1) mab, can and an acceptable safety and tolerability profile, as well as
selectively target aggregated Aβ, including neuritic Aβ plaques linear pharmacokinetics at a dose of ≤30 mg/kg in a single-
and high molecular weight ABOs but excludes Aβ monomers dose study (Ferrero et al., 2016). Amyloid-related imaging
(Sevigny et al., 2016; Linse et al., 2020). In the CNS, abnormalities (ARIAs), the side effect associated with the removal
aducanumab displays a preference for parenchymal over vascular of Aβ, were dose-dependent in the aducanumab-treated group.
Aβ (Sevigny et al., 2016). ARIAs occurred more often in ε4 allele of apolipoprotein E
Treatments with anti-Aβ mabs in AD animal models have gene (APOE4) carriers, the strongest genetic risk factor for
been very successful, which can improve cognitive functions the late-onset AD, than non-carriers (Cummings et al., 2018;
and decrease brain pathology via microglial stimulation and Lin et al., 2018), which was a main safety finding and could
prevention of Aβ aggregation (Novakovic et al., 2013; Vander justify further application of aducanumab for the treatment
Zanden and Chi, 2020). Aducanumab has been shown to have of AD (Sevigny et al., 2016). Recently, the significant results
a clear therapeutic effect and effectively remove Aβ from the demonstrated the modest but greatest efficacy in a phase III
brain of mice. Aducanumab can enter the brain of transgenic (tg) trial by aducanumab, supplying important Aβ validation as
mice and bind parenchymal Aβ and decline soluble and insoluble a therapeutic target (Schneider, 2020). Aducanumab has been
Aβ (Sevigny et al., 2016). Ten-month-old tgAPPPS1-21 mice demonstrated as a worthwhile application probably in dose−
(AD animal model) were treated chronically with aducanumab and treatment duration−related lowering of Aβ plaques across
for 4 months of weekly dosing (10 mg/kg), which showed the phase Ib (PRIME trial), IV, and III studies (Schneider,
that aducanumab was obviously suppressed Aβ toxicity and 2020). The trial results were not always consistent and were
enhanced phagocytosis and cell viability (Bastrup et al., 2021). accompanied by differences in the studies of 945 patients
To increase the brain levels of aducanumab, treatment with (Engage) and 803 patients (Emerge) in 2018, which displayed that
aducanumab combination together with ultrasound in APP23 aducanumab treatments were trending positive in the Emerge
mice, an AD model, can restore cognition in APP23 mice due to group and trending negative in the Engage group (Lin et al.,
ultrasound scan with intravenously injected microbubbles, which 2018). The inconsistent results may be attributed to aducanumab
temporarily opens the BBB, facilitating aducanumab entry into entering the brain at low concentrations or lack of selectivity
the brain (Leinenga et al., 2021). In Tg2576 mice, as an AD for the soluble ABOs (Knopman et al., 2021). Fortunately,
model, aducanumab lowered Aβ plaque in a dose-dependent several additional trials conducted in the Engage and Emerge
manner in 9-month-old mice but not in 22-month old mice groups later showed that patients in the Engage group treated
(Kastanenka et al., 2016; Sevigny et al., 2016), indicating that with aducanumab experienced a slow decline similar to the
aducanumab was more effective in preventing Aβ aggregation Emerge group change in CDR-SB relative to the placebo group
than in clearing the existing amyloid plaques (Kastanenka et al., (ClinicalTrials.gov, 2020a,b). The trials showed excellent dose-
2016). However, the cognitive or behavioral improvement did dependent amyloid clearance in both groups, while inconsistency
not occur after treatment with aducanumab in such mice was observed in cognitive outcomes in these studies. Thus,
(Kastanenka et al., 2016). the correct application of aducanumab dosage was essential for
Aducanumab was approved as the first DMT for AD by the reducing clinical decline, brain Aβ, and CSF phosphorylated-tau
United States Food and Drug Administration (FDA) in June of levels in AD (Wang et al., 2016).
2021 (Dhillon, 2021). Aducanumab treatment was initiated in Herring et al. (2021) predicted the long-term clinical benefits
patients with mild cognitive impairment (MCI) or mild dementia of patients with early AD treated by aducanumab evaluated

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Shi et al. Anti-amyloid-β Monoclonal Antibodies on Alzheimer’s Disease

TABLE 1 | Treatments of patients with AD and animal models with anti-Aβ monoclonal antibodies.

Pre-clinical and Anti-Aβ monoclonal Immune response and Clinical profiles changes Side effects References
clinical studies antibodies pathological changes after therapies
after therapies

Tg2576 transgenic Aducanumab Binding parenchymal Aβ, Slowing clinical progression ARIA-E and Sevigny et al., 2016;
mice and soluble and insoluble via detections by MMSE superficial siderosis Swanson et al., 2021
Prodromal or mild AD Aβ ↓(mice) and CDR-SB; (patients) (Sevigny
patients Amyloid plaque at week 54 No changes on NTB or et al., 2016)
↓by PET scan (patients) FCSRT (patients) ARIA-E 35.2%,
ARIA-E was highest
in ApoE4 + subjects
(Swanson et al.,
2021)
Mild to moderate AD Bapineuzumab No significant changes in No significant improvement ARIA-E and cerebral Vandenberghe et al.,
whole-brain volume. in clinical symptoms microhemorrhage ↑ 2016
(ADAS-Cog/11, DAD, NTB,
Z-score, CDR-SOB and
Dependence Scale)
Prodromal AD patients Gantenerumab (105 or Biomarkers of neural and No significant improvement ARIA-E 6.6% (105 Ostrowitzki et al., 2017
225 mg/4 weeks) synaptic degeneration↓; in clinical symptoms in 105 mg), 3.5% (225 mg).
PET SUVr↓ in 225 mg dose or 225 mg (CDR-SB, ARIA-H 22.9% (105
group; MRI volumetry: No ADAS-Cog 13, MMSE, and mg), 16.2% (225 mg)
difference; CSF: t-tau and FAQ, FCSRT with
p-tau↓ immediate recall total recall,
CANTAB, and NPI-Q)
Prodromal to moderate Gantenerumab (1200 PET: resulted in robust Aβ Slowed clinical decline with Klein et al., 2019
AD mg/4 weeks) plaque removal at 2 years higher Aβ removal in 1,200
mg group (CDR-SB,
ADAS-Cog 11, and MMSE)
DIAD mutation Gantenerumab (1200 PiB-PET: brain Aβ No difference in cognitive ARIA-E 19.2% Salloway et al., 2021
dominantly inherited mg/4 weeks) (Salloway deposition ↓; CSF: Aβ42↑, decline between the
Alzheimer’s disease et al., 2021) t-tau and p-tau 181 ↓, NfL↑ gantenerumab and control
(Salloway et al., 2021) slowed at year 4.
18F-FDG-PET and
volumetric MRI: no
difference in brain cortical
metabolism or atrophy
Early Alzheimer’s Lecanemab (10 mg/kg CSF: Aβ42↑, p-tau ↓ Improvement in clinical ARIA-E 10% ARIA-H: Swanson et al., 2021
disease biweekly) PET SUVr:brain Aβ ↓at symptoms (ADCOMS, 10.7%
18 months ADAS-Cog14, CDR-SB) ARIA-E and ARIA-H
Greater reductions of was higher in
cognitive decline in ApoE4 + subjects
ApoE4 + subjects Infusion reactions
19.9%
Mild AD (Farlow et al., Solanezumab Total Aβ40 and Aβ42 in No significant improvement Farlow et al., 2012;
2012; Honig et al., CSF↑ (ADAS-cog14, MMSE, Honig et al., 2018
2018) Unbound Aβ40 in CSF↓ ADCS-iADL, FAQ, CDR-SB
Unbound Aβ42 in CSF↑ score) (Farlow et al., 2012;
(Farlow et al., 2012; Honig Honig et al., 2018)
et al., 2018)
DIAD mutation CSF NfL ↑, Aβ PET, t-tau or Faster cognitive decline in ARIA-E was lower in Salloway et al., 2021
dominantly inherited p-tau181: No difference the solanezumab group vs. solanezumab group
Alzheimer’s disease Brain cortical metabolism the control groups
18F-FDG-PET or atrophy:
No difference

by a Markov modeling approach. The results were that effect of aducanumab compared with other mabs on AD is
aducanumab treatment caused 0.65 increased patient quality- described in the “Bapineuzumab, crenezumab, gantenerumab,
adjusted life-years (QALYs) and 0.09 fewer nursing staff QALYs and solanezumab” section.
lost compared with patients treated with standard of care From June 2021, aducanumab was approved to treat mild AD
(SOC) (Herring et al., 2021). Therefore, the clinical trials with until today, which has been caused considerable medical and
aducanumab are now still undergoing in the two large-scale scientific controversy (Tampi et al., 2021). Although aducanumab
phase III trials and will obtain the final results in 2023. The does reduce Aβ, there is a lack of reliable evidence that it has

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Shi et al. Anti-amyloid-β Monoclonal Antibodies on Alzheimer’s Disease

significant benefits to patients with AD (Fleck, 2021). In phase outcomes. Bapineuzumab and gantenerumab reduced CSF p181-
III, among patients treated with high-dose aducanumab, ∼35% tau by small and large effect sizes, respectively. Aducanumab,
of patients occurred ARIA-related cerebral edema (ARIA-E), bapineuzumab, crenezumab, and gantenerumab increased ARIAs
and ∼18–22.7% of patients had ARIA-related microhemorrhages risk. The outcomes of all mabs pooled together showed that
(ARIA-H) or other side effects, such as headache, dizziness, and these mabs alleviated clinical symptoms by small effect sizes,
nausea. Most ARIA-E events occurred in the early stages of caused biomarker improvements by large effect sizes, and
aducanumab treatment. These results were consistent with other enhanced ARIAs by a large effect size. In short, aducanumab
clinical studies of anti-Aβ antibodies, and the risk of ARIA-E was exerts the most beneficial effects, followed by solanezumab
reduced during subsequent treatment. These findings caused the (Avgerinos et al., 2021).
scientists to confuse by the FDA’s decision, which was based on In addition, several clinical trials in patients with AD
the reduction of a surrogate marker (Aβ) rather than on data have also been conducted with aducanumab, bapineuzumab,
showing clinical efficacy (Nisticò and Borg, 2021). Therefore, gantenerumab, and solanezumab previously. In the randomized-
FDA calls for further evaluation of the effect of aducanumab controlled trials, the majority of the outcomes from 13
on AD in 2021 (Kuller and Lopez, 2021). In February 2022, an phase III trials using aducanumab, bapineuzumab, crenezumab,
article published in Neurology summarized all trials conducted gantenerumab, and solanezumab were positive, and from 3
and indicated that aducanumab significantly reduced Aβ plaques phase II trials using crenezumab and aducanumab were largely
in the brain. However, it has not yet been proved whether it negative. As a significant adverse effect in the treatment groups,
has an effect on AD-related symptoms. It is reported that about ARIAs were ranged between 0.2 and 22% (Loureiro et al., 2020). It
40% of patients treated with aducanumab experienced brain was also observed that the therapeutic effect of bapineuzumab on
swelling and bleeding as their side effects, but most side effects AD showed a vague result in improving cognition accompanied
disappeared when aducanumab was stopped. So far, aducanumab by obvious side effects, such as vasogenic edema and rarely brain
is only approved for MCI and early AD but not for patients microhemorrhages (Panza et al., 2012). Gantenerumab displayed
with moderate to severe AD. FDA recommends close monitoring significant biomarker effects without clinical efficacy (Klein et al.,
with magnetic resonance imaging (MRI) in patients treated with 2019). Solanezumab, a humanized anti-Aβ mab directed against
aducanumab, and more in-depth studies are needed on many Aβ peptide neutralizing soluble Aβ, was reported to have a good
aspects of aducanumab treatment (Day et al., 2022). safety profile during the phase II trial (Farlow et al., 2012).
Overall, aducanumab is the first approved mab for DMTs in However, Honig et al. (2018) found that the treatment of mild
mild AD, and the therapeutic effects obtained in clinical trials AD with solanezumab at a dose of 400 mg for 1 month did not
were inconclusive so far, which is required to conduct more clinic significantly affect cognitive decline.
trials, especially in asymptomatic and Aβ-positive individuals. Furthermore, quantifying the effects of aducanumab,
A phase IIIb open-label trial including 2,400 participants treated bapineuzumab, gantenerumab, and solanezumab on oligomer
with aducanumab at 10 mg/kg/month injections for 2 years has production and aggregation kinetics, and correlating these effects
been conducted, and safety and tolerability parameters are the with the affinity and stoichiometry of each mab for monomeric
primary endpoints, hoping to get definite results by the end of and fibrous Aβ showed that only aducanumab dramatically
2023 (Chiao et al., 2019; Knopman et al., 2021). reduced the flux of ABOs (Linse et al., 2020). To prevent
bapineuzumab treatment from microhemorrhages and vasogenic
Bapineuzumab, Crenezumab, edemas in patients with AD, the single-chain variable fragments
Gantenerumab, and Solanezumab (scFvs) derived from bapineuzumab, which targets N-terminal of
The therapeutic effects of these exogenous mabs on AD are the Aβ peptide and recognizes monomers, oligomers, and fibrils,
through targeting and removing brain Aβ, such as aducanumab were used to treat 3xTg-AD mice, an animal model for AD.
targeting both ABOs and plaques, crenezumab targeting ABOs, The results showed that 3xTg-AD mice partially recovered the
gantenerumab targeting Aβ fibrils, and solanezumab targeting values in brain volume, compared with the controls (Güell-Bosch
Aβ monomers. When compared with other mabs, bapineuzumab et al., 2020). The therapeutic effect of scFvs was manifested as
showed stronger immunoreactivity on fixed tissue samples than clearance of intracellular Aβ, reduction of neuronal loss, and
with sodium dodecyl sulfate-denatured samples on Western improvement of cognitive impairment, and the treatment was
blots, indicating conformational preferences of this antibody safe (Esquerda-Canals et al., 2019b). In addition, scFvs more
(Zampar et al., 2020). easily passed BBB and were co-localized with Aβ peptide in glia
In a total of 17 clinical studies, 12,585 patients with AD at the late phase post-injection, resulting in declining Aβ peptide
were divided into several subgroups treated with aducanumab, levels in the brain (Esquerda-Canals et al., 2019a).
bapineuzumab, crenezumab, gantenerumab, and solanezumab, Crenezumab, as a humanized IgG4 mab, can bind to multiple
respectively. The results revealed that aducanumab improved forms of aggregated Aβ, including oligomers, fibrils, and plaques,
cognitive function by small effect sizes and declined Aβ to clear excess Aβ (Salloway et al., 2018), particularly it has
detected by positron emission tomography (PET) and CSF a 10-fold higher affinity toward soluble oligomers that are
p181-tau by large effect sizes. Solanezumab improved cognitive primary drivers of Aβ-related neurotoxicity (Cummings et al.,
function by small effect sizes and enhanced CSF Aβ1-40 levels 2018). Thus, crenezumab can strongly inhibit oligomer-induced
by a moderate effect size. Bapineuzumab, crenezumab, and neurotoxicity (Lin et al., 2018) and block Aβ aggregation and
gantenerumab had no effect on the improvement of clinical promote Aβ disaggregation of oligomers (Ultsch et al., 2016).

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Shi et al. Anti-amyloid-β Monoclonal Antibodies on Alzheimer’s Disease

Unlike IgG1, crenezumab declines the activation of Fc- stages of recruited patients in order to evaluate the efficacy and
gamma receptors (Fcγ6Rs) on CNS macrophages preventing safety of gantenerumab. Unfortunately, the results were also
neuroinflammation caused by inflammatory cytokines and other failed (Salloway et al., 2021). However, the trials that enrolled
inflammatory mediators that trigger Aβ neurotoxicity (Ultsch 81 patients treated with gantenerumab at 225 mg dose showed
et al., 2016). Crenezumab can prevent from vascular side effects that Aβ levels in one-third of the participants declined below
caused by IgG1 mab, such as ARIA-E, ARIA-H, and complement- the threshold for Aβ positivity at the end of the treatment
dependent cytotoxicity. The safety of crenezumab treatment is (Klein et al., 2018). In patients with prodromal to moderate
obviously enhanced due to a lower risk of inducing ARIAs AD, gantenerumab treatment up to 1,200 mg once every month
(Crehan and Lemere, 2016; Graham et al., 2017). showed obvious Aβ removal (Klein et al., 2019) and continued
In two phase I studies including healthy participants, it to decline Aβ plaque at 3 years after the start of the treatment
was proved that crenezumab was well-tolerated in healthy (Klein et al., 2021).
participants with an acceptable safety profile (Dolton et al., In addition, a phase II study was performed to assess the
2021). However, phase 3 clinical trials recruited 750 patients safety, tolerability, and biomarker efficacy of gantenerumab vs.
with prodromal to mild AD, and the outcomes were completely solanezumab in patients with a risk of the rare autosomal
negative, since there was no difference between crenezumab dominant AD (ADAD) gene mutation in 2012. The results from
and placebo subgroups or within the prodromal vs. mild AD the study were negative. Gantenerumab and solanezumab at low
subgroups assessed by several parameters, such as Alzheimer’s doses could not significantly slow cognitive decline and were
Disease Assessment Scale–Cognitive Subscale score (ADAS-Cog) not better than placebo after treatment for 48 months (Farlow
and MMSE (Salloway et al., 2018), suggesting that crenezumab et al., 2020). Although gantenerumab was proved ineffective in
had no therapeutic effect on AD symptoms. Although there were another study, dose-dependent effects observed in clinical and
about 94% of participants with at least one adverse event, most biomarker endpoints suggested that testing with higher dosing
adverse events were mild or moderate in a completed phase Ib for long term may be necessary to achieve clinical efficacy
study with crenezumab. Moreover, participants showed a very (Ostrowitzki et al., 2017).
low percentage of new ARIA-E and ARIA-H, and the safety of Gantenerumab and other two mabs, solanezumab and
crenezumab treatment was acceptable (Guthrie et al., 2020). In crenezumab, were tested in 144 carriers of ADAD for the
addition, the experience gained from two unfinished phase II evaluation of their efficacy in two long-term preventive studies
clinical trials in patients with very mild AD was to test high- (Dominantly Inherited Alzheimer Network Trials Unit Adaptive
dose crenezumab in such patients in the future (Cummings et al., Prevention Trial [DIAN-TU-APT] and Alzheimer Preventive
2018), and the view has also been supported by a phase Ib Initiative-ADAD) for 4 years. The outcomes of both studies were
study (Yoshida et al., 2020). Recently, a phase II clinical trial also negative, indicating that these mabs could not be prevented
for crenezumab that recruited patients in the preclinical phase from cognitive decline in ADAD that may not be triggered by
of AD, who carried the presenilin 1 E280A autosomal dominant Aβ (Imbimbo et al., 2021). A similar result was obtained in
mutation, was conducted and completed in February 2022. another study with dominantly inherited AD (DIAD) received
In the AD animal models, intracerebral injection by by gantenerumab, solanezumab, and placebo, respectively, for 4–
crenezumab in Tg2576 mice did not show any inflammatory 7 years. Finally, the result demonstrated that both gantenerumab
response, indicating that crenezumab can significantly inhibit and solanezumab had no beneficial effect on cognitive measures
inflammation in the brain (Ultsch et al., 2016), which is compared with controls. The asymptomatic subjects did not
beneficial to AD. display cognitive decline; symptomatic participants had declined
Gantenerumab, as a fully human anti-Aβ IgG1 mab, targets before reaching the target doses (Salloway et al., 2021). Although
Aβ fibrils with subnanomolar affinity (Klein et al., 2021) gantenerumab significantly lowed Aβ plaques, CSF total tau, and
and binds at a conformational epitope with N-terminal and p181-tau, as well as weakened the enhancement of neurofilament
central amino acids in a configuration that cannot be achieved light (NfL), it had no effect on the improvement of cognition.
with the structure of Aβ monomers (Bohrmann et al., 2012). Furthermore, ARIAs-E was found by 19.2, 2.5, and 0% in
Particularly, gantenerumab is suitable for long-term DMT for gantenerumab, placebo, and solanezumab groups, respectively
patients with AD. (Salloway et al., 2021). Currently, an investigation of potential
The part 1 of phase II/III study for the evaluation of the efficacy clinical benefits related to gantenerumab-induced Aβ-lowering in
and safety of gantenerumab at different doses in 799 patients patients with prodromal-to-mild AD is ongoing as GRADUATE
with prodromal AD was conducted through measuring changes phase III trials (Klein et al., 2021), and it will be completed
in the CDR-SB score, brain Aβ levels, cognition, and behavior, as in November 2023.
well as through other tests for a total of 26 months. Since it is In brief, gantenerumab is able to remove cerebral Aβ plaques
impossible to receive the efficacy on the primary and secondary and normalize Aβ42, tau, and p181-tau levels in CSF and inhibit
endpoints in the clinic trial after a 26-month period, it had to NfL; therefore, it is necessary to further continue investigating
early terminate in 2017 (Ostrowitzki et al., 2017). The post hoc gantenerumab at higher dosage in prodromal AD or AD by
analysis of gantenerumab’s data showed a little bit positive result determining the effects of gantenerumab on the prevention and
in patients with faster progressors. Therefore, the clinical trial treatment of AD.
regimes have been altered according to several factors, such Solanezumab, as a humanized version of a murine
as injecting doses, observed periods, and the amount/different antibody, is similar in its binding to crenezumab

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Shi et al. Anti-amyloid-β Monoclonal Antibodies on Alzheimer’s Disease

(Tian Hui Kwan et al., 2020). Solanezumab can reduce brain Aβ for edema, H for hemorrhage) assessed by MRI was comparable
burden by altering CNS and plasma Aβ clearance in both tg mice with that of placebo, and lecanemab was well-tolerated across
of AD and patients through target engagement of solanezumab all doses (Logovinsky et al., 2016). Modest efficacy has been
with soluble CNS Aβ peptides, which may lead to Aβ efflux observed in the highest doses of lecanemab and the risk of
into the periphery or disturbance of the fibrillar-soluble Aβ vasogenic edema limited higher dosing of lecanemab application,
equilibrium that ultimately reduced soluble brain Aβ (DeMattos particularly in APOE4 carriers (Abushakra et al., 2016, 2017). In
et al., 2001; Legleiter et al., 2004; Doody et al., 2014). a randomized double-blind clinical trial, 609 subjects with early
Previously, two clinical tri0061ls investigating solanezumab AD, MCI, and mild AD dementia were treated by lecanemab,
have been completed, which provided sufficient evidence that and 245 subjects were treated by placebo. The results showed
solanezumab is benefit to prodromal AD (Honig et al., 2018). that lecanemab (10 mg/kg biweekly) significantly decreased
In addition, solanezumab led to insignificant therapeutic benefits brain Aβ, which was different when compared with the placebo
at the earlier stages of AD. Salloway et al. (2021) reported that a group at 72 weeks, indicating in favor of active treatment with
greater cognitive drop was observed in the solanezumab-treated lecanemab (Swanson et al., 2020, 2021). The therapeutic effect
group and did not show benefits to downstream biomarkers. of lecanemab was supported by changes in CSF biomarkers, and
Unimaginably, solanezumab obviously accelerated cognitive lecanemab was well-tolerated with 9.9% incidence of ARIAs-E
drop in both asymptomatic and symptomatic participants, and at 10 mg/kg biweekly (Swanson et al., 2021). Lecanemab also
the failure further challenges the Aβ pathogenicity hypothesis showed a significant efficacy on both clinical and biomarker
in AD (Imbimbo et al., 2021). The reason for the failure outcomes (Logovinsky et al., 2016). In the phases I and II
of solanezumab treatment may be that its biological effect (2b) trials, the outcomes suggested that lecanemab completely
of removing brain Aβ plaques was not enough to cause the removed Aβ plaques from brain, alleviated cognitive decline,
improvement of patients’ cognition. However, the incidence and had a low incidence ARIA-E in early AD (Wang et al.,
of ARIAs was 0.9 and 0.4% for solanezumab and placebo, 2016; Swanson et al., 2021). As such, lecanemab may have a
respectively, indicating that solanezumab did not induce ARIAs potential effect on AD pathology to slow down the progression of
displaying its great tolerability and safety (Doody et al., 2014). AD. Based on favorable preclinical findings and multiple clinical
Currently, to evaluate whether IV infusion of solanezumab trial results, lecanemab is a potential viable mab’s drug for the
can slow the rate of progression of cognitive decline and improves treatment of AD.
disease-related biomarkers in DIAD, a phase II/III randomized, For the evaluation of the efficacy of lecanemab on cognition
double-blind, placebo-controlled study that recruited 490 in early AD compared with placebo, the phase III randomized,
participants is ongoing (DIAN-TU trial), which may determine placebo-controlled, double-blind, parallel-group trial has been
the tolerability, toxicity, and adequate dose of solanezumab in conducted. In the trials, lecanemab at 10 mg/kg has been
the AD population and is planned to be completed in July 2022 administered intravenously once every 2 weeks, which results
(Decourt et al., 2021). have not yet been published (Tian Hui Kwan et al., 2020;
In conclusion, solanezumab therapy did not decrease Swanson et al., 2021). Another study aims to investigate the
cognition decline, but showed to reduce brain Aβ level. efficacy and safety of lecanemab in preclinical AD, including
These findings provide moderate support for the continuous the participants with either a first-degree relative diagnosed
investigation of its effectiveness and safety. with dementia onset before age 75 with at least one APOE4
allele or high Aβ levels in brain or CSF, by a designed
Lecanemab therapeutic protocol (5 mg/kg every 2 weeks for 2 months,
Lecanemab is a humanized IgG1 of the mouse mab158 and can then 10 mg/kg every 2 weeks for 2 years, and 10 mg/kg every
selectively bind to large, soluble Aβ protofibrils that are the most 4 weeks for 4.5 years), which may provide clinical evidence
neurotoxic and contribute to the pathogenesis of AD (Logovinsky to determine its efficacy and safety for applying lecanemab in
et al., 2016). It has been evidenced that lecanemab can reduce such patients (Swanson et al., 2018; Tian Hui Kwan et al.,
the pathogenic Aβ, prevent Aβ deposition, and selectively reduce 2020).
Aβ protofibrils in the brain and CSF of AD animal models Lecanemab seems to be the most promising treatment for
(Söllvander et al., 2015; Tucker et al., 2015). AD among these mabs due to the decline of brain Aβ levels,
Brain samples from Down syndrome (DS) that caused by the alleviation of cognitive decline, and a low incidence ARIA-
trisomy of chromosome 21 leading to develop Aβ brain pathology E. It has a moderate therapeutic effect and better safety. However,
followed by cognitive and behavioral deterioration, AD, and non- the results from several clinical trials were largely negative and
demented controls (NDCs) were analyzed different Aβ species by failed to show clinically relevant effects in patients with clinically
immunohistochemical staining with anti-Aβ antibodies. It was manifest or prodromal dementia. It is necessary to conduct
observed higher immunohistochemical staining of Aβ deposits further investigations on the efficacy and safety of lecanemab.
with lecanemab in DS and AD compared with NDC, suggesting
that lecanemab may be possible to retain DS’s cognitive abilities
(Johannesson et al., 2021). DISCUSSION
Previously, the safety and tolerability were investigated in
patients with mild to moderate AD in the first clinical study with Amyloid hypothesis is considered to be related to the etiology
lecanemab. The results found that incidence of ARIA-E/H (E of AD, but nearly all pharmaceutical therapies targeting Aβ

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Shi et al. Anti-amyloid-β Monoclonal Antibodies on Alzheimer’s Disease

have failed in the clinic during the past about 20 years, with aducanumab and lecanemab. It is noteworthy to choose
indicating that the pathogenesis of AD is quite complex and the appropriate subjects with biomarker evidence and optimal
should be multifactorial. Despite many problems regarding dosage of mabs in the future clinical trials. It is necessary to
immunotherapy for AD and these knowledge gaps in the choose DIAD as the appropriate subjects, since they can be
pathogenesis of AD, the studies have still progressed in observed for AD-related biological changes decades before the
developing more anti-Aβ mabs for the treatment of AD. onset of AD. Early intervention with mabs in the asymptomatic
Currently, several anti-Aβ mabs, such as aducanumab, and symptomatic stages can delay or slow the progression of
bapineuzumab, gantenerumab, solanezumab, and lecanemab, AD, because the pathologic process of AD begins decades prior
have developed and conducted in clinical trials. However, to functional decline and diagnosis, which have confirmed by
the results of most clinical trials with these mabs were neuroimaging, biomarker, and clinical data studies (Bateman
largely negative, which raised many questions about the et al., 2012; Fleisher et al., 2012; Mielke et al., 2012). However,
future development of AD drugs and has proven challenging. the timing of this previous intervention had been too late to
The main problems of treatments with these mabs are impact on neurodegenerative process of AD (Callaway, 2012;
failing to show clinically relevant effects in patients with Miller, 2012). Although aducanumab (Sevigny et al., 2016; Linse
clinically manifest or prodromal dementia, and the high et al., 2020), crenezumab (Salloway et al., 2018), gantenerumab
incidence of ARIAs caused by some mabs, indicating that (Ostrowitzki et al., 2017), and solanezumab (Salloway et al.,
the risk of adverse events outweighs the benefits of the 2021) have been conducted in several clinical trials with the
treatments. Thereby, majority of clinic trials with these anti- asymptomatic stages of the subjects, the outcomes were negative
Aβ mabs therapies did not meet primary endpoints and or vague, which may be due to short observation time and use
stopped the clinical trials. To conduct further studies and of inappropriate doses. There is still a lack of reliable evidence
analyze lessons learned from these trials, several questions and trials for the use of these mabs to prevent AD. It is crucial
should be addressed before these trials can be used as to conduct an early intervention with mabs, and the current
evidence to support the Aβ cascade hypothesis of AD and to ongoing phase III trials will hopefully give light to this critical
treat such patients. issue. The optimal mab dosage is key to the success of clinical
First, it is crucial to further explore the role of amyloid trials, because increasing dosage in the later period of AD might
hypothesis in the pathogenesis of AD. Although it has been have a negative impact on the trial results (Salloway et al.,
believed that Aβ42 is the major Aβ toxic species linked 2021).
with AD pathogenesis, recent studies proposed that Aβ40 is Third, it should be considered that ideal therapeutic drugs,
also involved in the AD development and progression via a such as mabs, should cross BBB efficiently and sustain the
more complex mechanism (Strozyk et al., 2003; Fagan et al., brain levels to prevent oligomer formation and inhibit their
2006; Blennow et al., 2010; Michno et al., 2019). Hence, toxicity continuously (Tolar et al., 2020b) or alter the route
future directions merit in exploring the role of Aβ40 in the of administration so that the drugs (mabs) can directly
pathogenesis of AD. Simultaneously, it is a key point to enter the brain via nasal route or intracerebral injection.
study the relationship between cerebral Aβ levels and cognitive AD process starts with amyloid buildup, while cognitive
decline. Later, it is warranted to develop the agents, such impairment is the last event during the pathological process
as immunotherapies with mabs effectively inhibiting ABO (Jack and Holtzman, 2013); hence, DMTs with mabs must
formation and their toxic effect, as well as to conduct their be performed early. Otherwise, treatment will be ineffective
clinical trials. In addition, the synergistic benefits regarding due to late treatment just like the current treatment situation
the combinations of anti-inflammation, anti-Aβ, and anti-tau (van Dyck, 2018).
drugs merit further study due to multifactor participation in
the etiology of AD.
Second, the benefits of treatment with mabs in preclinical CONCLUSION
AD, MCI due to AD, and mild AD must be further provided
sufficient evidence and confirmed by the continuation of Recently, the novel highly specific mabs targeting Aβ as DMTs
randomized, placebo-controlled, double-blind clinical trials to for AD have been developed and conducted in several clinical
determine the effect of anti-Aβ mabs therapy in asymptomatic trials. Although most results from the clinical trials were
carriers of autosomal-dominant mutations related to early- unsuccessful, the mabs as the new generation of DMTs may
onset AD (Loureiro et al., 2020). Previously, the late-stage offer an additional possibility of therapeutic options. These mabs
trials in AD treated with the mabs targeting distinct species have been proven to be relatively safe in humans and some
of Aβ had provided relatively favorable evidence that inhibited of them were proved to have mild to moderate effects on
soluble ABOs only, not Aβ plaque by aducanumab, lecanemab, declining brain Aβ levels and improving cognitive impairment.
gantenerumab, and donanemab, which may be an effective Among them, aducanumab and lecanemab have relatively good
approach to improve the clinic, slow, or stop AD progression. effects. However, the efficacy of these mabs in patients was
Another powerful evidence was due to higher levels of ABOs uncertain, and there are still many questions to be solved.
in APOE4 carriers’ brains, and the efficacy of anti-Aβ mabs was Future DMTs for AD should focus on preventing cognitive
greater, which strongly supports for continuing clinical trials decline in cognitively unimpaired individuals with evidence of
with these mabs, especially, further conducting clinical trials cerebral amyloidosis.

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Shi et al. Anti-amyloid-β Monoclonal Antibodies on Alzheimer’s Disease

AUTHOR CONTRIBUTIONS FUNDING

MS, FC, and FZ prepared the manuscript. FC and JZ helped to This study was supported by the project of the First
conceived and reviewed the manuscript. JZ conceived, wrote, and Hospital of Jilin University, in Changchun City, Jilin Province
finalized the manuscript. All authors read and approved the final and the Sanming Project of Medicine in Shenzhen City
manuscript. (SZSM201801014), Guangdong Province of China.

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Tian Hui Kwan, A., Arfaie, S., Therriault, J., Rosa-Neto, P., and Gauthier, S. Publisher’s Note: All claims expressed in this article are solely those of the authors
(2020). Lessons learnt from the second generation of anti-amyloid monoclonal and do not necessarily represent those of their affiliated organizations, or those of
antibodies clinical trials. Dement. Geriatr. Cogn. Disord. 49, 334–348. doi: 10. the publisher, the editors and the reviewers. Any product that may be evaluated in
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Tolar, M., Abushakra, S., Hey, J. A., Porsteinsson, A., and Sabbagh, M. endorsed by the publisher.
(2020a). Aducanumab, gantenerumab, BAN2401, and ALZ-801-the first
wave of amyloid-targeting drugs for Alzheimer’s disease with potential for Copyright © 2022 Shi, Chu, Zhu and Zhu. This is an open-access article distributed
near term approval. Alzheimers Res. Ther. 12:95. doi: 10.1186/s13195-020-0 under the terms of the Creative Commons Attribution License (CC BY). The use,
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Tolar, M., Abushakra, S., and Sabbagh, M. (2020b). The path forward in Alzheimer’s author(s) and the copyright owner(s) are credited and that the original publication
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