Comparative efficacy and safety of monoclonal antibodies for cognitive decline in patients with alzheimers disease a systematic review and network meta analysis

CNS Drugs (2024) 38:169–192
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SYSTEMATIC REVIEW

Comparative Efficacy and Safety of Monoclonal Antibodies
for Cognitive Decline in Patients with Alzheimer’s Disease:
A Systematic Review and Network Meta‑Analysis

Yue Qiao1 · Jian Gu1 · Miao Yu1 · Yuewei Chi1 · Ying Ma1

Accepted: 6 February 2024 / Published online: 1 March 2024
© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2024

Abstract
Background  Recent clinical trials of anti-Aβ monoclonal antibodies (mAbs) in the treatment of early Alzheimer’s disease
(AD) have produced encouraging cognitive and clinical results. The purpose of this network meta-analysis (NMA) was to
compare and rank mAb drugs according to their efficacy and safety.
Methods  PubMed, Embase, Web of Science, and the Cochrane Library were searched for randomized controlled trials
testing various mAbs for the treatment of cognitive decline in patients with AD, up to March 31, 2023. R software (version
4.2.3) along with JAGS and STATA software (version 15.0) were used for statistical analysis. Odds ratio (OR) for binary
variables, mean difference (MD) for continuous variables, and their 95% confidence intervals (CI) were utilized to estimate
treatment effects and rank probabilities for each mAb in terms of safety and efficacy outcomes. We calculated the surface
under the cumulative ranking area (SUCRA) to evaluate each mAb, with higher SUCRA values indicating better efficacy
or lower likelihood of adverse events.
Results  Thirty-three randomized controlled trials with a total of 21,087 patients were included in the current NMA, involving
eight different mAbs. SUCRA values showed that aducanumab (87.01% and 99.37%, respectively) was the most likely to
achieve the best therapeutic effect based on the changes of Mini-Mental State Examination (MMSE) and Clinical Dementia
Rating scale Sum of Boxes (CDR-SB) scores. Donanemab (88.50% and 99.00%, respectively) performed better than other
therapies for Alzheimer's Disease Assessment Scale–cognitive subscale (ADAS-cog) and Positron Emission Tomography-
Standardized Uptake Value ratio (PET-SUVr). Lecanemab (87.24%) may be the most promising way to slow down the
decrease of Alzheimer's Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) score. In the analysis of the

incidence of adverse events (subjects with any treatment-emergent adverse event), gantenerumab (89.12%) had the least
potential for adverse events, while lecanemab (0.79%) may cause more adverse events. Solanezumab (95.75% and 80.38%,
respectively) had the lowest incidence of amyloid-related imaging abnormalities characterized by edema and effusion (ARIA-
E) and by cerebral microhemorrhages (ARIA-H) of the included immunotherapies. While SUCRA values provided a com-
prehensive measure of treatment efficacy, the inherent statistical uncertainty required careful analysis in clinical application.
Conclusion  Despite immunotherapies significantly increasing the risks of adverse events and ARIA, the data suggest that
mAbs can effectively improve the cognitive function of patients with mild and moderate AD. According to the NMA, adu-
canumab was the most likely to achieve significant improvements in different cognitive and clinical assessments (statistically
improved MMSE and CDR-SB), followed by donanemab (statistically improved ADAS-Cog, and PET-SUVr) and lecanemab
(statistically improved ADCS-ADL).

* Ying Ma 1 Introduction

Alzheimer's disease (AD) is characterized by relentlessly
1 Department of Neurology, Shengjing Hospital of China progressive neurodegeneration resulting in symptoms that
Medical University, Shenyang 110000, Liaoning, China affect language and motivation, and cause behavioral and
cognitive disorders that gradually lead to patient mortality
[1, 2]. It is the most common type of dementia, accounting
for 60–70% of cases [3]. It is estimated that the number of

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170 Y. Qiao et al.

Key Points  evidence that different therapeutic strategies for clearing
brain Aβ may be effective for altering disease course, and
Among individual drugs, aducanumab was the most monoclonal antibodies (mAbs) against Aβ have attracted
likely to achieve significant improvements in different more and more attention.
cognitive and clinical assessments (statistically improved
MMSE and CDR-SB) followed by donanemab (sta- Mounting evidence suggests that mAbs demonstrate

tistically improved ADAS-Cog, and PET-SUVr) and potential in improving outcomes for the treatment of patients
lecanemab (statistically improved ADCS-ADL). at early stages of AD. For example, bapineuzumab was the
first N-terminus-directed anti-Aβ antibody tested in humans,
These treatments also increase the risk of adverse events, reducing Aβ level, but demonstrating little improvement
such as amyloid-related imaging abnormalities. Thus, in cognition for AD patients [14]. Subsequently, several
their use requires careful consideration and further anti-Aβ mAb drugs were tested in clinical trials. With the
research. recent approval of lecanemab, the first mAb for Alzheimer’s
disease, via the accelerated approval pathway in the US,
patients diagnosed with AD will increase to 65.7 million by attention now moves to understanding the efficacy and safety
2030 and 115.4 million by 2050, which has attracted world- profile of this and the other mAbs. Previous paired meta-
wide attention [4, 5]. analysis had evaluated efficacy and safety of all types of
immunotherapy drugs against Aβ within a narrow obser-
New diagnostic methods, including advanced neuroim- vation range [15]. Therefore, the objective of this network
aging technology and biochemical biomarkers, are steadily meta-analysis (NMA) was to compare and rank mAbs
becoming available as accurate methods for detecting AD. according to their efficacy and safety in patients with pos-
However, there is no effective treatment, and prevention is sible or probable AD, in order to provide additional evidence
still the priority [6]. Therefore, it is essential to understand for clinical decision makers to choose the most appropriate
the underlying pathology of AD and develop disease-mod- treatment.
ifying therapies that not only improve symptoms but also
alter the disease course. 2 Methods

AD is characterized by three neuropathological features The study protocol was prospectively registered with the
including extracellular amyloid beta-peptide (Aβ) plaques, International Prospective Register for Systematic Reviews
intraneuronal neurofibrillary tangles (NFT) composed of (CRD42023416047). This NMA was performed following
hyper-phosphorylated tau protein, and loss of synapses as the Preferred Reporting Items for Systematic Reviews and
well as neurons, but the exact mechanisms by which they Meta-Analyses (PRISMA) [16] and Cochrane guidelines
ultimately cause cognitive deficits are still unclear [1, 7]. [17].

The treatment scheme for AD remains limited. The estab- 2.1 Literature Search
lished US Food and Drug Administration (FDA) approved

pharmacological interventions, such as donepezil, galan- In this NMA, randomized controlled trials investigating the
tamine, rivastigmine, and memantine, have only modest treatment of AD with anti-Aβ mAbs were identified through
and transient effects, and do not stop the progression of PubMed, Embase, Cochrane Library, and Web of Science
dementia [8]. The amyloid cascade hypothesis is the most with a search deadline of March 31, 2023. The reference lists
widely accepted hypothesis so far, which proposes that the of pertinent meta-analyses, reviews, pooled analyses, and
imbalance between the deposition of neurotoxic Aβ protein included trials were carefully reviewed manually in order
and the production and elimination of Aβ triggers a series to identify any additional studies using all relevant combi-
of pathological changes, including amyloid plaques, neu- nations of the following search terms: ‘aducanumab’, ‘bap-
rofibrillary tangles, neuronal dysfunction, and dementia [9, ineuzumab’, ‘crenezumab’, ‘donanemab’, ‘gantenerumab’,
10]. In the past two decades, strategies targeted at the amy- ‘lecanemab’, ‘ponezumab’ ‘solanezumab’, and ‘Alzheimer
loid cascade hypothesis have included drugs that focus on Disease’, see Supplementary Material S1 in the electronic
reducing amyloid-β production (β-secretase 1 inhibitor or supplementary material (ESM) for the specific search strategy.
α-secretase modulator) or increasing amyloid-β clearance
(anti-amyloid-β antibodies or active immunotherapy) [11]. 2.2 Selection Criteria
However, unfortunately, due to adverse effects and a lack of
therapeutic effect, most compounds have been unsuccessful Upon initial screening, we included published randomized
in phase II/III trials [12, 13]. Recent studies have provided controlled trials (RCTs) that recruited patients diagnosed

Comparative Efficacy and Safety of Monoclonal Antibodies for Alzheimer’s Disease 171

with mild cognitive impairment (MCI) or AD at any disease 2.5 Data Analysis
stage, in order to compare the efficacy and safety of all mAbs
(aducanumab, bapineuzumab, crenezumab, donanemab, The Bayesian network meta-data analysis was performed
gantenerumab, lecanemab, ponezumab, and solanezumab) using R software (version 4.2.3) along with JAGS software
in this target population. and STATA software (version 15.0). We used mean differ-
ences (MD) from baseline with 95% confidence intervals
Reported outcomes included at least one of the follow- (CI) to calculate the continuous data, such as the change
ing outcome indicators: Mini-Mental State Examination from baseline of MMSE, as reported. As for the binary
(MMSE), Clinical Dementia Rating scale–Sum of Boxes data, including AE, ARIA-E and ARIA-H, the odds ratio
(CDR-SB), Alzheimer's Disease Assessment Scale–cogni- (OR) analysis of 95% CI is calculated. If there was no raw

tive subscale (ADAS-cog), Alzheimer's Disease Cooperative data (e.g., without standard deviations [SDs], only p values
Study–Activities of Daily Living (ADCS-ADL), standard- or ranges are reported), SDs and 95% CIs provided in the
ized uptake value ratio of amyloid positron emission tomog- publication were calculated using established methods for
raphy (PET-SUVr), adverse events (AEs; subjects with any estimation [18]. The use of a random effects model or fixed
treatment-emergent AE [TEAE]); and amyloid-related effects model depended on the statistical value of each result
imaging abnormalities characterized by edema and effusion heterogeneity. If there was significant heterogeneity, I2 > 50,
(ARIA-E) or cerebral microhemorrhages (ARIA-H). a random effects model was carried out, if I2 ≤ 50, a fixed
effects model was carried out.
The exclusion criteria are (i) non-RCT research, such as
meeting abstracts, agreements, letters, case reports, system- In order to verify the consistency between direct compari-
atic reviews, and animal experiments; (ii) unavailability of sons and indirect comparisons, we used the node splitting
full text or unavailability of usable data; and (iii) studies not method through the design-by-treatment interaction model
including patients with AD. In the case of multiple publi- in the closed loop in the evidence network [19]. A p value
cations based on the same RCT, we only included articles higher than 0.05 (p > 0.05) indicates that there is no signifi-
with the richest information and the largest sample source. cant inconsistency between direct and indirect comparisons,
Articles were included for review only after a consensus was on the contrary, the difference is statistically significant [20].
reached among all three investigators.
We calculated the surface under the cumulative ranking
2.3 Data Extraction area (SUCRA) to rank the charts and the priority of the dif-
ferent interventions, in which the larger the SUCRA value,
To ensure accuracy of the data collected, two evaluators the better the efficacy or safety [21]. For the results of each
independently extracted the relevant data from the retrieved trial, the potential retrieval bias was assessed using funnel
literature, and any conflict was resolved through discussion plots to represent individual studies against some measure
between the first two evaluators or adjudication by a third of each study's size or precision.
author. The following data were extracted from each study:
the author, publication year, clinical trial number, country, 3 Results
sample size, sex, age, severity of AD, MMSE baseline,
ApoE allele carrying status, follow-up, and results. At the 3.1 Literature Search Results
same time, we recorded the incidence of adverse events
such as ARIA-E and ARIA-H, so as to evaluate the safety We found 1058 articles from PubMed, Embase, Cochrane

of anti-Aβ mAbs. Library and Web of Science, of which 400 studies were dis-
carded because of duplication. We excluded a further 609
2.4 Risk of Bias articles after reviewing the titles and abstracts. Finally, after
reviewing the full text of 51 papers, 33 studies were found to
Literature quality assessment of the included studies was fulfil the inclusion criteria. A PRISMA flowchart illustrating
performed by two independent reviewers through the risk- the specific screening process is shown in Fig. 1.
of-bias analysis assessment tool provided by the Cochrane
Handbook for Systematic Reviews of Interventions 5.4.0 3.2 Eligible Studies and Patient Characteristics
[17], and any discrepancies were resolved by consensus. The
evaluation included random sequence generation (selective A total of 33 randomized controlled trials [14, 22–53] were
bias), distribution concealment (selective bias), method of included, including 17,686 patients who received eight dif-
blinding implementers and participants (implementation ferent mAbs (aducanumab, bapineuzumab, crenezumab,
bias), method of blinding result evaluation (detection bias), donanemab, gantenerumab, lecanemab, ponezumab,
data result integrity (loss bias), selective report of research and solanezumab), and placebo was the most common
results (reporting bias) and other biases.

172 Y. Qiao et al.

Fig. 1  PRISMA flow diagram
of current network meta-analy-
sis. PRISMA Preferred Report-
ing Items for Systematic review
and Meta-analysis

comparison. Of the 33 included trials, 32 were two-group The network diagram of qualified comparisons of all
trials and one was a three-group clinical trial. See Table 1 result measurements is shown in Figs. 3 and 4, which
for the baseline characteristics and design features of trials includes nine interventions. RCTs are connected by a net-
included in this NMA. work diagram composed of points and lines. The dots rep-
resent different interventions, and their sizes represent the
3.3 Risk of Bias number of participants in each intervention. The straight

lines indicate that there is direct comparison evidence
The overall risk included in the bias assessment of the between two interventions, and the thickness of the lines
studies is low to moderate. All the RCTs used the random indicates the number of studies directly compared between
number acquisition method, but only 19 papers provided the two interventions. In this study, there was a closed loop
a detailed description. Consideration should be given to of indirect evidence and the node-split model was used to
the lack of information on the randomization process and test the inconsistency. When using the node splitting method
allocation procedure, which were judged to have ambiguous to evaluate MMSE and CDR-SB analysis, there is no obvi-
risk of bias. One study was considered to have a high risk ous inconsistencies between direct evidence and indirect
of bias in terms of "incomplete result data" [28]. Almost all evidence (see Table 2 and Supplementary table S10 in the
studies are funded by large pharmaceutical companies. The ESM).
risk-of-bias assessment of the included literature is shown
in Fig. 2.

Table 1  Trial features and baseline characteristics of participants for 33 trials included in the network meta-analysis Comparative Efficacy and Safety of Monoclonal Antibodies for Alzheimer’s Disease

Study Country Phase Sample size Gender (M/F) Mean age (years) Severity MMSE (baseline) ApoE e4 carriers Follow- Outcome
of AD (%) up

EG CG EG CG EG CG EG CG EG CG

Treatment: Aducanumab

Ferrero et al. United I 0.3 mg/kg: 6 14 12/27 5/9 72.0 ± 66.9 ± Mild to 23.0 ± 22.1 ± 2 (33) 4 (29) 6 mo F1,F5
8.4 8.7 mod- 1.9 2.4 2 (33)
2016 [33] States erate 1 (17) F1,F2,F3,F4,F8
72.8 ± prob- 22.0 ± 24.7 ± 4 (67) F1,F2,F3,F4,F5,F6,F7
NCT01397539 1 mg/kg: 6 67.0 ± 7.2 able 3.4 3.6 2 (33)
8.8 AD 3 (50)
70.8 ± 18.3 ± 26.4 ± 1 (33)
3 mg/kg: 6 63.0 ± 7.4 Prodro- 2.7 1.8 19 (61) 26 (65) 54 wk

5.0 mal or 21 (66)
69.8 ± mild 18.3 ± 26.4 ± 21 (70)
10 mg/kg: 6 72.7 ± 7.7 AD 4.9 1.7 20 (63)
4.5 362 (67) 368 (67) 78 wk
Mild/ 23.0 ±
20 mg/kg: 6 66.8 ± MCI 3.1
8.9
19.8 ±
30 mg/kg: 6 63.3 ± 4.6
9.0
24.7 ±
60 mg/kg: 3 73.7 ± 1.5
9.5
23.6 ±
Sevigny et al. United I 1 mg/kg: 31 40 65/60 17/23 72.6 ± 3.3
7.8
2016 [24] States 23.2 ±
4.2
NCT01677572 3 mg/kg: 32 70.5 ±
8.2 24.4 ±
2.9
6 mg/kg: 30 73.3 ±
9.3 24.8 ±
3.1
10 mg/kg: 32 73.7 ±
8.3 26.3 ±
1.7
Haeberlein et al. United III 3 mg/kg or 548 510/553 258/290 70.6 ±

2022 [53] States 6 mg/kg 7.4

NCT02484547 (low dose):

543

10 mg/kg 70.6 ± 26.3 ± 365 (67)
(high dose): 7.5 1.7 391 (71) 176 (69)
547
26.4 ±
Haeberlein et al. III 3 mg/kg or 545 526/576 258/287 70.4 ± Mild/ 1.8
MCI
2022 [53] 6 mg/kg 7.0

NCT02477800 (low dose):

547

10 mg/kg 70.0 ± 26.4 ± 378 (68)
(high dose): 7.7 1.8
555

173

Table 1  (continued) 174

Study Country Phase Sample size Gender (M/F) Mean age (years) Severity MMSE (baseline) ApoE e4 carriers Follow- Outcome
of AD (%) up

EG CG EG CG EG CG EG CG EG CG

Treatment: Bapineuzumab

Lu and Brashear United I 5 mg/kg: 6 10 15/15 6/4 65.8 ± 71.0 ± Mild to 19.0 ± 19.9 6 mo F1
10 mg/kg: 6 11.63 10.16 mod- 4.10 (5.24)
2019 [37] States erate F1,F4
74.2 ± 68.8 ± AD 19.7 ± F1
NCT02484547 10.70 8.9 4.32 F1,F4,F8
Mild to F2,F3,F5,F7
20 m/kg: 6 69.0 ± 69.88 ± mod- 20.3 ±
9.49 10.71 erate 4.27
40 mg/kg: 6 AD
79.3 ± 73.3 ± 17.3 ±
80 mg/kg: 6 4.03 8.79 Mild to 3.88
mod-
Arai et al. Japan I 0.15 mg/kg: 6 8 14/11 4/4 66.8 ± 70.0 ± erate 19.5 ± 20.6 ± 52 wk
15/7 1/7 9.47 8·81 AD 2.59 3.0
2016 [44] 49/61 13/23
11/8 3/4 60.7 ± Mild to 16.8 ±
NCT00397891 0.5 mg/kg: 6 5.2 mod- 2.9
erate
1 mg/kg: 6 72.2 ± AD 21.0 ±
8.4 3.6
2 mg/kg: 6 Mild to
72.2 ± mod- 21.0 ±
Black et al. 2010 United I 0.5 mg/kg: 6 8 10.9 erate 4.6 20.8 2 y
AD
[49] States 64.8 ± 20.2 ±
5.2 2.8
1.5 mg/kg: 6
74.67 ± 21.8

5 mg/kg: 10 5.65
21.3
Brody et al. United II 2 mg/kg: 37 36 72.33 ± 22.3 ± 22 22 13 mo
9.85 22.3 2.84 (59.5) (61.1) 78 wk
2016 [39] States
74.70 ± 22.3 ± 22.29 ± 22 5 (71)
NCT01254773 7 mg/kg: 36 7.44 2.78 2.69 (61.1)

20 mg/kg: 37 73.5 ± 21.5 ± 22
8.34 2.47 (59.5)
Rinne et al. 2010 Finland II (0.5, 1, or 7
[27] 74.1 ± 21.9 ± 12 (63)
9.26 2.99
2 mg/kg): 19
70.5 ± 21 ±
8.68 2.33

67.26 ±
8.60

Y. Qiao et al.

Table 1  (continued) Comparative Efficacy and Safety of Monoclonal Antibodies for Alzheimer’s Disease

Study Country Phase Sample size Gender (M/F) Mean age (years) Severity MMSE (baseline) ApoE e4 carriers Follow- Outcome
of AD (%) up F6

EG CG EG CG EG CG Mild to EG CG EG CG 78 wk
61/61 43/64 67.9 ± mod-
Salloway et al. United II 0.15 mg/kg: 25 70.1 ± erate 20.9 ± 20.7 ± 72 74

31 0.82 0.85 AD 0.29 0.30
2009 [14] States (60.5) (69.8)
0.5 mg/kg: 33 28 72.3 ±
NCT00112073 8.4
1.0 mg/kg: 29 26
Salloway et al. United III 300/358 190/242 72.0 ± 71.9 ± Mild 20.8 ± 20.7 ± 658 658 78 wk F2,F4,F5,F6
2.0 mg/kg: 29 27 8.0 10.1 3.1 3.2 (100) (100) F2,F4,F5,F6
2014 [52] States 0.5 mg/kg: 432
70.2 21.2 ± F2,F6
658 3.2

NCT00575055 21.0 ±
3.0
Salloway et al. III 0.5 mg/kg: 493 289/344 245/248 73.1 ± Mild 21.2 ± 0 0 78 wk
314 9.3 3.4 20.8 ±
2014 [52] Mild to 3.1
1.0 mg/kg: 73.5 ± mod- 21.2 ±
NCT00574132 307 9.1 erate 3.3 21.3 ± 0 0
AD 3.21
0.5 mg/kg: 6 72.2 ± 21.0 ± 0 0
8.4 Mild to 3.6
1.0 mg/kg: 6 mod- 0 0
72.2 ± erate 21.0 ±
Vandenberghe Belgium III 0.5 mg/kg: 10.9 AD 4.6 100 100 78 wk
et al. 2016 [26] 650
NCT00667810 431 231/419 168/263 70.9 Mild to 20.9 ±
mod- 3.1
Vandenberghe III 0.5 mg/kg: 328 221/287 138/190 71.1 69.7 erate 0 0 78 wk F2,F6
AD 20.8 ±
et al. 2016 [26] 255 3.2

NCT00676143 20.8 ±
3.1
1 mg/kg: 253 70.7 0
21.2 ±
Brashear et al. United III 0.5 mg/kg: 524 368/439 258/266 73.0 ± 71.8 ± 3.36 0 0 83 wk F1,F2
337 9.47 10.10
2018 [28] States 21.2 ±
3.27
NCT00575055 1 mg/kg: 329 73.2 ± 0
9.30 21.0 ±
3.09
2 mg/kg: 141 73.7 ± 0
9.53

175

Table 1  (continued) 176

Study Country Phase Sample size Gender (M/F) Mean age (years) Severity MMSE (baseline) ApoE e4 carriers Follow- Outcome
of AD (%) up

EG CG EG CG EG CG EG CG EG CG

Treatment: Crenezumab

Guthrie et al. United Ib 30 mg/kg: 10 14 33/28 6/8 73.4 ± 71.4 ± Mild to 23.3 ± 20.9 ± 6 (60) 10 133 wk F1,F3
45 mg/kg: 11 6.75 6.75 mod- 3.8 2.8 (71.4)
2020 [48] States erate 10
73.3 ± 7 AD 22.2 ± 21.5 ± (90.9)

NCT02353598 2.7 2.6
Mild to 17 (81)
60 mg/kg: 21 72.9 ± mod- 23.2 ± 21.6 ±
6.25 erate 3.3 2.5
120 mg/kg: 19 AD 12
69.4 ± 22.9 ± 22.3 ± (63.2)
Cummings et al. Ger- II 300 mg: 122 103 56/66 32/30 8.5 70.3 ± Mild to 3.1 2.4 66 73 wk F1, F2,F5,F6,F7
81/84 36/48 7.2 mod- 78 (64.5) 73 wk F1,F5,F6,F8
2018 [22] many 12/14 5/8 71.2 ± erate 21.7 ± 20.5 ± (63.9) 105 wk F1,F2,F3,F5,F6,F7
11/24 11/6 6.3 69.9 ± AD 2.8 2.2 60
NCT01343966 15 mg/kg: 165 84 168/236 162/247 7.1 117 (71.4)
70.9 ± Mild 21.9 ± 23.4 ± (70.9)
Salloway et al. United II 300 mg: 26 13 6.9 68.9 ± 2.7 2.9 12
8.3 22 (92.3)
2018 [23] States 66.7 ± 21.5 ± 23.5 ± (84.6)
9.5 69.8 ± 2.4 2.9 12
NCT01397578 15 mg/kg: 35 17 7.7 24 (70.6)
71.4 ± 20.8 ± (68.6)
Ostrowitzki Switzer- III 60 mg/kg 409 7.1 70.3 ± 2.3 292
8.4 293 (71.7)
et al. 2022 [32] land (CREAD): 71.0 ± 23.7 ± (72.7)
7.9 70.7 ± 3.0
7.9
NCT02670083 404

Ostrowitzki 60 mg/kg 399 176/231 174/225 71.1 ± 23.6 ± 271 263
et al. 2022 [32] 7.5 2.8
NCT03114657 (CREAD2): (66.9) (65.9)

407

Treatment: Donanemab

Lowe et al. 2021 Singa- Ib 10 mg/kg (sin- 15 3/4 4/15 78.3 ± 74.5 ± Mild to 21.71 ± 21.67 ± 5 (71.4) 10 84 wk F11
gle dose): 7
[30] NCT pore 8.4 10.1 moder- 4.23 4.81 (66.7)

02624778 20 mg/kg (sin- 4/3 75.6 ± ate 23.57 ± 5 (71.4)
6.4
gle dose): 7 4.5

40 mg/kg (sin- 2/2 75.3 ± 23.25 ± 4 (100)
6.7 3.86
gle dose): 4

10 mg/kg 6/4 66.8 ± 20 ± 3.4 8 (80.0)
8.6
(Q2W): 10

10 mg/kg 4/4 73 ± 7.8 18.86 ± 6 (75.0)
2.41 9 (90.0)
(Q4W): 8
19.5 ±
20 mg/kg 3/7 71.7 ± 2.93 Y. Qiao et al.
9.2
(Q4W): 10

Table 1  (continued) Comparative Efficacy and Safety of Monoclonal Antibodies for Alzheimer’s Disease

Study Country Phase Sample size Gender (M/F) Mean age (years) Severity MMSE (baseline) ApoE e4 carriers Follow- Outcome

of AD (%) up F1,F2,F3,F4,F5,F6,F7

EG CG EG CG EG CG Mild EG CG EG CG 76 wk
63/68 61/65
Mintun et al. United II 700–1400 mg: 126 75.0 ± 75.4 ± 23.6 ± 23.7 ± 95 92
131 68/63 65/61 5.6 5.4 3.1 2.9
2021 [31] States (72.5) (74.2)
75.0 ± 75.4 ±
NCT03367403 5.6 5.4

Shcherbinin United II 700–1400 mg: 120 Prodro- 23.5 ± 3 23.77 ± 85 88 72 wk F2,F3.F8
115 mal 2.9 (73.9) (73.9)
et al. 2022 [25] States (MCI)
or mild
NCT03367403 AD

Treatment: Lecanemab

Logovinsky United I 0.1, 0.3, 1, 3, 12 18/18 7/5 70.9 ± 72.1 ± Mild to 23.8 23.5 180 d F1,F2,F3
10, 15 mg/ 10.0 9.2
et al. 2016 [47] States kg (SAD): mod-
36
NCT01230853 erate

AD

0.3, 1, 3, 8 11/13 6/2 70.0 ± 70.0 ± 23.3 24.1
9.97 11.70
10 mg/kg
72

(MAD): 24

Swanson et al. United IIb 2.5 mg/kg 238 315/272 101/137 71 Mild 25.7 ± 26.0 ± 38 (73) 169 (71) 18 mo F1,F2,F5,F6

2021 [42] States biweekly: 52 2.5 2.3

NCT01767311 5 mg/kg 71 25.3 ± 37 (77)
monthly: 48 2.6

5 mg/kg 72 25.6 ± 81 (91)
biweekly: 89 2.3

10 mg/kg 71 25.7 ± 218 (89)
monthly: 2.4
246

10 mg/kg 73 25.6 ± 46 (30)
biweekly: 2.4
152

van Dyck et al. United III 10 mg/kg: 859 875 416/443 411/464 71.4 ± 71.0 ± Mild 25.5 ± 25.6 ± 592 600 18 mo F1,F2,F3,F5,F6,F7,F8
7.9 7.8
2023 [34] States 2.2 2.2 (68.9) (68.6)

NCT03887455

Treatment: Gantenerumab

Ostrowitzki United I 60 mg: 8 4 9/5 1/3 70.9 ± 62.8 ± Mild to 21.8 ± 21.0 ± 4 (57.1) 4 (100) 28 wk F8

et al. 2012 [35] States 8.1 3.5 mod- 3.6 2.5

NCT00531804 200 mg: 6 66.5 ± erate 22.0 ± 5 (83.3)
8.4
AD 1.6

177

Table 1  (continued) 178

Study Country Phase Sample size Gender (M/F) Mean age (years) Severity MMSE (baseline) ApoE e4 carriers Follow- Outcome
of AD (%) up F1,F2,F3,F4,F5,F6,F8
104 wk F2,F3,F4,F5,F8
EG CG EG CG EG CG Mild to EG CG EG CG
69.5 ± mod- 25.7 ± 4 y
Ostrowitzki United III 105 mg: 271 266 NA NA 70.3 ± erate 25.7 ± 70.5 69.8
7.0 7.5 AD 2.3 2.1 (13.6) (12.9)
et al. 2017 [40] States
71.3 ± 44.2 ± DIAD 25.7 ± 26.68 ± 70.1 13 (32)
NCT01224106 225 mg: 260 7.1 9.6 2.2 3.97 (12.5)

Salloway et al. United III Gantenerumab 40 31/21 18/22 46.0 ± 27.10 ± 16 (31)
225– 21/29 10.8 3.45
2021 [50] States 1200 mg: 52
42.5 ±
NCT01760005 Solanezumab 9.5
400–
1600 mg: 50 26.72 ± 14 (28)
4.11

Treatment: Ponezumab

Landen et al. United I 0.1 mg/kg: 4 11 15/11 8/3 69.0 ± 71.8 ± Mild to 22.5 ± 21.5 ± 1 (25) 1 (9.1) 1 y F1
8.1 7.0
2013 [46] States mod- 2.5 3.4
70.0 ± 72.2 ±
NCT00455000 0.3 mg/kg: 4 3.7 7.1 erate 24.3 ± 2 (50)

72.0 ± AD 1.7
7.5
1 mg/kg: 4 21.3 ± 3 (75)
66.5 ± 3.6
11.8
3 mg/kg: 6 22.7 ± 2 (33)
72.1 ± 3.3
8.0
10 mg/kg: 8 21.9 ± 1 (12.5)
65.7 ± 2.8
6.4
Miyoshi et al. Japan I 0.1 mg/kg: 3 5 7/8 2/3 Mild to 16.33 ± 21.2 ± 2 (66.7) 4 (80) 1 y F1
2013 [45] 67.7 ±
NCT00607308 8.1 mod- 3.21 3.56

0.5 mg/kg: 3 72.3 ± erate 19.67 ± 1 (33.3)
11.5 AD
1.53
61.3 ±
1 mg/kg: 3 18.4 18.33 ± 0

50.3 ± 1.53

7.5
5 mg/kg: 3 20.67 ± 1 (33.3)
6.11

10 mg/kg: 3 24.67 ± 2 (66.7)
1.53

Y. Qiao et al.

Table 1  (continued) Comparative Efficacy and Safety of Monoclonal Antibodies for Alzheimer’s Disease

Study Country Phase Sample size Gender (M/F) Mean age (years) Severity MMSE (baseline) ApoE e4 carriers Follow- Outcome
of AD (%) up

EG CG EG CG EG CG Mild to EG CG EG CG 24 mo F2,F6
13/12 11/13 70.0 ± mod- 21.0 ±
Landen et al. United II 0.1 mg/kg: 25 24 70.8 ± erate 21.5 ± N N
8.2 7.8 AD 2.9 3.4
2017(a) [36] States
71.9 ± 70.4 ± Mild to 21.4 ± 21.9 ±
NCT00722046 0.5 mg/kg: 25 10/15 9.4 10.3 mod- 3.6 3.4
erate
1 mg/kg: 25 14/11 72.2 ± 71.3 ± AD 20.8 ± 20.8 ±
8.4 8.5 3.0 2.99
3 mg/kg: 32 32 12/20 15/17
70.5 ± 65.8 ± 22.5 ± 22.5 ±
8.5 mg/kg: 31 14/17 8.9 8.3 2.5 4.04

Landen et al. United II 10 mg/kg 6 8/4 3/3 71.8 ± 20.9 ± 10 (83) 3 (50) 18 mo F3,F4,F6
7.3 3.1 11 (92) 5 (83)

2017(b) [41] States (Cohort Q):
65.1 ± 22.5 ±
NCT00945672 12 7.4 2.75

10 mg/kg/ 6 9/3 1/5 69.8 ± 21.2 ±
7.5 3.04
7.5 mg/kg

(Cohort M):

12

Treatment: Solanezumab

Farlow et al. United II 100 mg Q4W: 10 24/28 71.2 ± 9.2 Mild to 20.2 ± 3.8 39 (75) 1 y F6
10 mod-
2012 [43] States erate
100 mg QW: AD
NCT00329082 11

400 mg Q4W:
10

400 mg QW:
11

179

Table 1  (continued) 180

Study Country Phase Sample size Gender (M/F) Mean age (years) Severity MMSE (baseline) ApoE e4 carriers Follow- Outcome
of AD (%) up

EG CG EG CG EG CG EG CG EG CG

Doody et al. United III 400 mg Q4W 506 207/299 219/287 75.0 ± 74.4 ± Mild to 21 ± 4 21 ± 3 266 288 18 mo F1,F2,F3,F5,F6,F7
(EXPEDI- 519 397/446 377/467 7.9 8.0 mod- 21 ± 3
2014 [38] States TION 1): 325 erate 21 ± 3 (57.3) (61.3)
506 1072 457/600 441/631 72.5 ± 72.4 ± AD
NCT00905372 61 18/47 22/39 8.0 7.8 23 ± 3
400 mg Q4W
Doody et al. (EXPEDI- 71.5 ± 72.5 ± 22.6 ± 263 281
2014 [38] TION 2): 7.9 7.9 2.9
NCT00904683 521 (56.8) (59.5)
72.7 ± 73.3 ± 21.6 ±
400 mg Q4W 7.8 8.0 Mild 22 ± 3 2.5 155 183
(EXPE-
DITION 75.2 ± 73.2 ± Mild 22.8 ± (54.6) (61.4)
2-mild): 322 7.1 7.2 2.8
Honig et al. 11 coun- III 712 685 76 wk F4,F5,F6
2018 [51] tries 400 mg Mild 22.5 ±
NCT01900665 IV every 2.9 (69.3) (66.3)
4 weeks:
Nakamura et al. Japan III 1057 50.8 61 184 wk F2,F3,F4,F5
2017 [29]
NCT00905372, 400 mg
NCT00904683, IV every
NCT00904683 4 weeks: 65

AD Alzheimer’s disease, ADAS-cog14 Alzheimer’s Disease Assessment Scale, ADCS-ADL Alzheimer’s Disease Cooperative Study–Activities of Daily Living, AE adverse event, ARIA-E amy-

loid-related imaging abnormalities characterized by edema and effusion, ARIA-H amyloid-related imaging abnormalities characterized by cerebral microhemorrhages, CDR-SB Clinical Demen-
tia Rating scale–Sum of Boxes, CG control group, DIAD dominantly inherited Alzheimer’s disease, EG experimental group, F1: any AE, F2 ARIA-E, F3 ARIA-H, F4 MMSE, F5 CDR-SB, F6
ADAS-cog14, F7 ADCS-ADL, F8 PET-SUVr, IV intravenously, MAD multiple ascending dose, MCI mild cognitive impairment, MMSE Mini–Mental State Examination, PET-SUVr standard-
ized uptake value ratio of amyloid positron emission tomography, NA not available, QW every week, Q2W every 2 weeks, Q4W every 4 weeks, SAD single ascending dose, SD standard devia-
tion

Y. Qiao et al.

Comparative Efficacy and Safety of Monoclonal Antibodies for Alzheimer’s Disease 181

Fig. 2  Risk of bias graph and risk of bias summary

4 Network Analysis of Outcomes 4.2 Change in CDR‑SB

4.1 Change in MMSE In the evaluation of the CDR-SB, 14 RCTs were included
with a total of 13,835 patients. The higher the score, the
In the evaluation of the change in MMSE from baseline, greater the damage. There were eight interventions: adu-
11 studies were included with a total of 9897 patients, with canumab, bapineuzumab, crenezumab, donanemab, gan-
higher scores indicating better mental performance. There tenerumab, lecanemab, placebo and solanezumab. A total
were seven interventions including aducanumab, bapineu- of 28 direct or indirect comparisons were generated by
zumab, crenezumab, donanemab, gantenerumab, placebo, the NMA, which revealed that aducanumab (MD −0.58,
and solanezumab. In terms of MMSE score, aducanumab 95% CI − 0.69 to − 0.48), lecanemab (MD − 0.34, 95%
was significantly more effective than placebo (MD 0.93, CI − 0.49 to − 0.18), and solanezumab (MD −0.34, 95%
95% CI 0.39–1.41), as shown in Supplementary table S2 CI − 0.35 to − 0.33) had significantly lower CDR-SB
(see ESM). No significant differences were found among scores compared with placebo, indicating a statistically
the other meta-analysis pairs. The results of the rank- significant difference (Supplementary table S3, see ESM).
ing according to SUCRA values were that aducanumab According to the SUCRA values, aducanumab (99.37%)
(87.01%) ranked first in MMSE score change, followed by had the highest likelihood of being the best treatment
solanezumab (64.03%) and donanemab (63.80%) (Table 3). for decreasing CDR-SB score, followed by solanezumab
The cumulative probability showed that aducanumab was (74.69%), whereas donanemab (5.38%) had the lowest

associated with the greatest benefit on MMSE score, as probability (Table 3). The cumulative probability showed
shown in Fig. 5a.

182 Y. Qiao et al.

Fig. 3  Network graphs of randomized controlled trials comparing the ease Assessment Scale–cognitive subscale (ADAS-cog), d Alzhei-
mer's Disease Cooperative Study–Activities of Daily Living (ADCS-
efficacy of monoclonal antibodies (mAbs) in the treatment of Alzhei- ADL), e standardized uptake value ratio of amyloid positron emission
mer’s disease: a Mini-Mental State Examination (MMSE), b Clinical tomography (PET-SUVr)
Dementia Rating scale–Sum of Boxes (CDR-SB), c Alzheimer's Dis-

that aducanumab is related to the maximum benefit on 4.4 Change in ADCS‑ADL
CDR-SB, as shown in Fig. 5b.
Seven of the included articles including a total of 8931
4.3 Change in ADAS‑cog participants reported the change in ADCS-ADL score of
six interventions: aducanumab, crenezumab, donanemab,
Results for change in ADAS-cog score were obtained from lecanemab, placebo, and solanezumab, with a lower score
14 RCTs covering eight treatment regimens and involving meaning greater functional loss. A total of 15 direct or
12,252 participants, with higher scores indicating greater indirect comparisons were generated by the NMA, which
impairment. The eight interventions were aducanumab, revealed that aducanumab (MD 0.91, 95% CI 0.16–1.66),
bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab (MD 2.00, 95% CI 0.39–3.59), and solan-
lecanemab, placebo, and solanezumab. A total of 28 direct ezumab (MD 1.35, 95% CI 1.31–1.39) were more effec-
or indirect comparisons were generated by the NMA, which tive than placebo according to ADAS-cog (Supplementary
revealed that aducanumab (MD − 0.82, 95% CI − 1.35 to table S5, see ESM). The results of the ranking according
− 0.29), donanemab (MD − 1.78, 95% CI − 3.52 to − 0.01), to SUCRA values were that lecanemab (87.24%) exhib-
gantenerumab (MD − 0.94, 95% CI − 1.35 to − 0.53), ited the highest efficiency on ADCS-ADL, whereas cren-
lecanemab (MD − 1.09, 95% CI − 1.69 to − 0.49) and solan- ezumab (9.83%) exhibited the lowest efficiency (Table 3).
ezumab (MD − 0.9, 95% CI − 1.63 to − 0.17) were asso- The cumulative probability showed that lecanemab was
ciated with a significant decrease in ADAS-cog compared associated with the greatest benefit on ADCS-ADL, as
with placebo (Supplementary table S4, see ESM). Accord- shown in Fig. 5d.

ing to SUCRA curve analysis, donanemab (88.5%) was
the most effective in terms of ADAS-cog score, and cren- 4.5 Change in Amyloid PET SUVr
ezumab (16.17%) was the least effective of the treatments
examined (Table 3). The cumulative probability showed Nine articles providing data on the changes of amyloid
that donanemab was associated with the greatest benefit on protein PET SUVr from baseline, including a total of 1095
ADAS-cog, as shown in Fig. 5c. participants in eight interventions (aducanumab, bapineu-
zumab, crenezumab, donanemab, gantenerumab, lecanemab,

Comparative Efficacy and Safety of Monoclonal Antibodies for Alzheimer’s Disease 183

Fig. 4  Network graphs of randomized controlled trials comparing abnormalities characterized by edema and effusion (ARIA-E) and c
cerebral microhemorrhages (ARIA-H)
the safety of monoclonal antibodies (mAbs) in the treatment of Alz-
heimer’s disease: a adverse events (AE), b amyloid-related imaging

Table2  Assessment of local inconsistency by node-split method

Outcomes Comparisons Direct comparisons results Indirect comparisons Network comparisons p values
results (OR 95% CrI)
(OR 95% CrI) results (OR 95% CrI) 0.580
0.576
MMSE Gantenerumab vs placebo − 0.0548 (− 1.12, 1.02) − 1.47 (− 6.48, 3.45) − 0.113 (− 1.18, 0.927) 0.576
CDR-SB Solanezumab vs gantenerumab − 0.892 (5.59, 3.86) 0.516 (− 0.863, 1.91) 0.416 (− 0.923, 1.73) 0.550
Solanezumab vs placebo 0.569 (− 0.296, 1.44) − 0.865 (− 5.82, 4.09) 0.531 (− 0.329, 1.38) 0.571
Gantenerumab vs placebo − 0.066 (− 0.57, 0.45) 0.87 (− 2.2, 4) − 0.043 (− 0.54, 0.47) 0.582
Solanezumab vs gantenerumab 0.64 (− 2.5, 3.8) − 0.28 (− 0.95, 0.39) − 0.25 (− 0.88, 0.42)
Solanezumab vs placebo − 0.22 (− 0.62, 0.22) 0.68 (− 2.4, 3.8) − 0.20 (− 0.60, 0.23)

CDR-SB Clinical Dementia Rating scale–Sum of Boxes, CrI credible interval, MMSE Mini Mental State Examination, OR odds ratio

placebo, and solanezumab). At first glance, one can conclude PET (Supplementary table S6, see ESM). In the analysis
that aducanumab (MD − 0.17, 95% CI − 0.27 to − 0.07) and of the curative effect of SUCRA, donanemab scored the
donanemab (MD − 0.37, 95% CI − 0.57 to − 0.17) were highest in SUCRA (99.00%) in the amyloid protein PET
more effective than placebo. On the contrary, solanezumab SUVr, ranking first, while solanezumab (0.6%) performed
(MD 0.55, 95% CI 0.14–0.95) was associated with a signifi- worst (Table 3). The cumulative probability showed that
cant increase in the risk of abnormal imaging of amyloid donanemab was associated with the greatest benefit on amy-
loid PET SUVr, as shown in Fig. 5e.

184 Y. Qiao et al.

Rank ADAS-cog14 Alzheimer’s Disease Assessment Scale, ADCS-ADL Alzheimer’s Disease Cooperative Study–Activities of Daily Living, AE any adverse event, ARIA-E amyloid-related imaging 4.6 Adverse Events (Subjects With Any TEAE)
abnormalities characterized by edema and effusion, ARIA-H amyloid-related imaging abnormalities characterized by cerebral microhemorrhages, CDR-SB Clinical Dementia Rating scale–Sum
2 7 6 1 3 5 4 8 of Boxes, MMSE Mini Mental State Examination, PET-SUVr standardized uptake value ratio of positron emission tomography, SUCRA​surface under the cumulative ranking area

Amyloid 4 82.81 24.30 6 37.43 3 99.00 69.61 1 42.28 5 43.97 0.60 Discontinuation rates for adverse events were reported in
PET SUVr 19 trials, involving 12,867 patients with nine treatments
(%) (aducanumab, bapineuzumab, crenezumab, donanemab,
gantenerumab, lecanemab, ponezumab, placebo, and solan-
Rank 2 ezumab). Relative to the other types of mAbs, bapineuzumab
(OR 1.3; 95% CI 1.05–1.6) and lecanemab (OR 2.16; 95%
ADCS-ADL (%) 3 50.97 9.83 1 62.24 2 87.24 7 17.61 4 71.11 CI 1.83–2.55) can increase the significant risk of adverse
events during treatment compared with placebo. However,
Rank 6 8 5 regarding gantenerumab (OR 0.61; 95% CI 0.38–0.97), there
was a significantly reduced risk for adverse events (Sup-
ADAS-cog (%) 1 64.40 plementary table S7, see ESM) and lecanemab (OR 2.16;
6 21.26 95% CI 1.83–2.55) exhibited the lowest safety (Table 3).
Rank 4 16.17 The results of the ranking according to SUCRA values were
8 88.50 that gantenerumab (89.12%) exhibited the highest safety,
7 45.21 followed by ponezumab (84.91%), solanezumab (56.43%),
3 79.80 placebo (56.02%), aducanumab (55.34%), donanemab

5 21.04 (47.85%), crenezumab (36.65%), bapineuzumab (22.89%),
2 63.62 and lecanemab (0.79%) (Table 3). The cumulative probabil-
ity showed that gantenerumab was associated with minimal
CDR-SB (%) adverse effects, as shown in Fig. 6a.

4.7 ARIA‑E

1 99.37 4 30.03 6 58.47 5.38 5 25.66 74.19 7 32.22 2 74.69 In total, 16 studies with 18,300 patients were included in
the analysis of the events with ARIA-E, involving eight
Rank 3 treatments—aducanumab, bapineuzumab, crenezumab,
donanemab, gantenerumab, lecanemab, placebo, and
MMSE (%) 7 87.01 43.38 3 29.53 8 63.80 5 37.43 2 24.82 1 64.03 solanezumab. The incidence of ARIA-E associated with
mAbs against Aβ was significantly higher in bapineu-
Rank - 6 4 zumab (OR 30.29; 95% CI 19.88–48.89), aducanumab
(OR 15.09; 95% CI 11.51–20.20), gantenerumab (OR
ARIA-H (%) 7 14.55 3 67.14 4.93 6 45.90 4 37.05 1 80.38 60.80 2 89.26 14.78; 95% CI 6.36–43.88), donanemab (OR 12.26;
95% CI 6.58–25.19), and lecanemab (OR 8.32; 95% CI
Rank 8 5 5.50–13.15) compared with placebo in the treatment
of AD (Supplementary table S8, see ESM). According
Table 3  The SUCRA values of each treatment AE (%) Rank ARIA-E (%) 27.71 to SUCRA curve analysis, placebo (95.75%) exhibited
2.92 the lowest risk of ARIA-E, followed by solanezumab
66.38 (82.67%), and bapineuzumab (2.92%) exhibited the
38.26 highest risk of ARIA-E (Table 3). The cumulative prob-
29.75 ability showed that solanezumab was associated with the
56.57 least ARIA-E adverse effects except placebo, as shown
95.75 in Fig. 6b.
82.67
4.8 ARIA‑H
Aducanumab 55.34 5 Bapineuzumab 22.89 8 Crenezumab 36.65 7 Donanemab 47.85 6 Gantenerumab 89.12 1 0.79 9 56.02 4 Ponezumab 84.91 2 Solanezumab 56.43 3
Fourteen articles were included in the analysis for the

Treatment Lecanemab Placebo events of ARIA-H, involving 10,565 patients and eight
interventions—aducanumab, crenezumab, donanemab,
gantenerumab, lecanemab, ponezumab, placebo, and solan-
ezumab. The NMA revealed that a higher risk of ARIA-H in
aducanumab (OR 4.44; 95% CI 3.75–5.28), donanemab (OR

Comparative Efficacy and Safety of Monoclonal Antibodies for Alzheimer’s Disease 185

Fig. 5  Rank of the cumulative probabilities for basic parameters: a Cooperative Study–Activities of Daily Living (ADCS-ADL), e stand-
Mini-Mental State Examination (MMSE), b Clinical Dementia Rat- ardized uptake value ratio of amyloid positron emission tomography
ing scale–Sum of Boxes (CDR-SB), c Alzheimer's Disease Assess- (PET-SUVr)
ment Scale–cognitive subscale (ADAS-cog), d Alzheimer's Disease

5.77; 95% CI 3.39–10.26), gantenerumab (OR 1.81; 95% CI events, ARIA-E, and ARIA-H. In this study, NMA may have
1.32–2.49), and lecanemab (OR 2.12; 95% CI 1.60–2.83) a potential publication bias, as shown in Fig. 7.
was statistically different compared with placebo in the treat-
ment of AD (Supplementary table S9, see ESM). According 5 Discussion
to SUCRA curve analysis, solanezumab (89.26%) exhibited
the lowest risk of ARIA-H, followed by placebo (80.38%), A total of 21,087 subjects from 33 studies were included
and donanemab (4.93%) exhibited the highest risk of ARIA- in the network analysis in which the efficacy and safety of
H (Table 3). The cumulative probability showed that solan- mAbs against Aβ in the treatment of mild or moderate AD
ezumab was associated with the lowest ARIA-H adverse were investigated. The results of a pairwise meta-analysis
effects, as shown in Fig. 6c. found that aducanumab exerted better efficacy compared
with other interventions in improvements of MMSE and
4.9 Publication Bias CDR-SB scores, with SUCRA values of 87.01% and 99.37%,
respectively. Donanemab, with respective SUCRA values
Funnel plots are used to show the publication bias of the of 88.50% and 99.00%, showed superior performance over
evaluation scales, including MMSE, CDR-SB, ADAS-cog, other therapies in improving ADAS-cog scores and amyloid
ADCS-ADL, the change of amyloid PET-SUVr, adverse

186 Y. Qiao et al.

Fig. 6  Rank of the cumulative probabilities for a adverse events (AE), b amyloid-related imaging abnormalities characterized by edema and
effusion (ARIA-E) and c cerebral microhemorrhages (ARIA-H)

PET-SUVr. Additionally, lecanemab, with a SUCRA value most beneficial effects, followed by solanezumab, but bap-
of 87.24%, may be the most beneficial option for slowing ineuzumab, crenezumab, and gantenerumab had no effect
down the decline in ADCS-ADL scores. However, our on the improvement of clinical outcomes [54]. A previous
findings also highlight the increased risk of adverse events NMA included five interventions, involving 5141 patients;
associated with these treatments, notably ARIA. Apart from it was reported that aducanumab and solanezumab were
solanezumab, all other mAb therapies increased the risk of significantly superior to placebo in MMSE [55]. These two
ARIA. Meanwhile, compared with the placebo group, the NMAs reported similar comparative results regarding adu-
application of gantenerumab, ponezumab, and solanezumab canumab and solanezumab. Aducanumab is a whole human
did not statistically increase the risk of AEs. In interpret- IgG 1 mAb isolated from elderly donors with cognitive
ing SUCRA rankings, it's crucial to consider their statisti- health as the first disease-modifying therapy (DMT) for
cal uncertainties and dependence on the quality of included AD [56]. Aducanumab binds to amyloid plaques and high
studies; these rankings are relative and sensitive to methodo- molecular weight amyloid oligomers, and it also stimulates
logical variations in NMA. microglia to clear Aβ in a dose- and time-dependent manner
accompanied by a slowing of cognitive impairment based
Considering the efficacy profile, we showed the changes on MMSE and CDR-SB [57]. The original statement dis-
in MMSE, ADAS-cog, CDR-SB, ADCS-ADL, and amy- cusses the approval of aducanumab and lecanemab based
loid PET SUVr. Although the NMA was not ideal given on their ability to reduce Aβ rather than their impact on
the lack of head-to-head studies among the interventions cognitive functions. Previous analysis revealed that, despite
(i.e., only against placebo; a star-shaped network), except statistically significant results, the effect of these medica-
for a three-arm experiment, interesting results were found. tions on cognitive performance is relatively minor and
According to the ranking probabilities, aducanumab lacks clinical significance [54, 58, 59]. In addition, a study
performed most effectively, followed by solanezumab, of 196 patients with AD showed a similar result, that is,
donanemab, and bapineuzumab, and gantenerumab was aducanumab reduced Aβ plaques, and it slowly decreased
superior to crenezumab regarding MMSE scores. When clinical indicators of patients [60]. Similarly, when assessed
we chose the improvement of CDR-SB score as the effi- by ADAS-Cog, another cognitive subscale, the cognitive

cacy outcome, aducanumab was still ranked ahead of other improvement with donanemab was more obvious than with
anti-Aβ mAbs. In 2017, a previous meta-analysis of a total other mAbs. ADAS-Cog was designed as a standard tool in
of 17 clinical studies revealed that aducanumab exerted the

Comparative Efficacy and Safety of Monoclonal Antibodies for Alzheimer’s Disease 187

key clinical trials related to attention, concentration, non- cognitive function among patients with mild or moderate
verbal memory and practice, which is used to evaluate the AD has been observed. At the same time, their efficacy
cognitive aspects of AD [61, 62]. Only a phase II trial of showed considerable variation, with each mAb exhibiting a
donazumab was involved in our NMA, and Mintun et al. distinct profile of efficacy and associated risks for potential
considered no definitive conclusions could be drawn regard- adverse effects.
ing the difference between groups in the change in ADAS-
Cog score [31]. At the same time, lecanemab, aducanumab, In a safety assessment, amyloid-related imaging abnor-
and solanezumab also improved ADAS-Cog scores, which malities (ARIA), ARIA-E, and ARIA-H, were selected for
had been confirmed in another meta-analysis [63, 64]. Like comparison between immunotherapy and placebo. Draw-
most measures of functioning used in AD, ADCS-ADL ing on the findings of recent studies, the risk-to-benefit
was developed as an interview-based, informant-reported ratio of anti-Aβ mAbs in Alzheimer's disease continues to
measure of level of independence in specific tasks to assess be unfavorable [58, 63, 73]. Several articles suggest that
basic as well as instrumental living skills [65]. In our study, amyloid-β, as a barrier protein, has a unique sealant which
lecanemab achieved better results on ADCS-ADL from the can prevent immune-mediated brain tissue damage, and
perspective of SUCRA rankings, followed by solanezumab, thus assume the main anti-pathogenic function. Therefore,
and donanemab was superior to aducanumab. A recent sys- the risk of amyloid-β deficiency can lead to a series of com-
tematic review and meta-analysis of anti-amyloid-β mAbs plications, such as downstream bleeding and edema, which
in phase III clinical trials indicated that aducanumab and should be paid attention to [74]. In addition, the risk of
lecanemab significantly improved ADCS-ADL-MCI scores, ARIA increased with the dose of the antibodies, suggesting
consistent with our findings [66]. Lecanemab is a human- a relationship between the efficacy of amyloid clearance and
ized IgG1 of the mouse mAb158, defined as the second the imaging abnormality. In the current NMA, compared
FDA-approved anti-amyloid drug to treat AD after aduca- with the placebo group, most of the mAbs significantly
numab, and supposedly the only one that shows a statis- increase the risk of ARIA-E and ARIA-H. According to
tically significant clinical benefit [47, 67]. A multicenter, the ranking results, the best alternatives were gantenerumab

double-blind, phase III trial showed that after 18 months, and solanezumab, which showed the lowest rates of adverse
according to the ADCS-MCI-ADL evaluation, compared events (subjects with any TEAE) and ARIAs. Jeremic
with placebo, lecanemab delayed the progress of AD by et al. suggested that solanezumab was the only drug that
37%, and the gap was increasing [34]. The amyloid cas- did not increase ARIA-E risk [66]. Recent studies revealed
cade hypothesis postulates that the amyloid precursor that the lack of specific targeting Aβ oligomers or block-
protein (APP) is broken down to form Aβ, and the imbal- ing their toxicity is a serious defect in immune therapeutic
ance between Aβ generation and Aβ clearance results in approaches: solanezumab, ponezumab, and lecanemab are
an abnormal accumulation of amyloid-β plaques in various targeted to soluble Aβ; bapineuzumab and crenezumab rec-
regions of the brain [68, 69]. As for the data of amyloid ognize all three forms of Aβ; and aducanumab, donanemab,
PET-SUVr, results from our NMA showed donanemab had and gantenerumab bind AβOs and fibrils. In SCarlet RoAD,
the highest SUCRA value in reducing the amyloid burden, at doses of 105 and 225 mg every 4 weeks, gantenerumab
followed by gantenerumab and aducanumab; other mAbs was chosen to minimize the risk of any adverse events inci-
were inferior to placebo. Among these antibody molecules, dence [40]. However, compared with the positive results
donanemab was very effective in reducing florbetapir amy- of the phase Ib trial for aducanumab [24], it shows that the
loid PET signal and amyloid load but depended on per- dose of gantenerumab may be too low to obtain substantial
cent change [30, 31]. Patients with higher levels of Aβ clinical benefit. Because anti-amyloid treatments have been
at baseline experienced a more obvious reduction, while associated with ARIA with edema or hemorrhage and raised
those with lower initial Aβ levels might achieve complete some safety concerns [75], we compared immunotherapies
clearance of amyloid. However, according to the results of versus placebo. Solanezumab that also recognizes soluble,
a previous meta-analysis, cognitive improvement was not monomeric amyloid has showed the least risk of ARIA-
found across the donanemab phase I/II trials, measured by E and ARIA-H incidence among immunotherapies. The
MMSE, ADAS-Cog, and CDR-SB scores [70]. Research incidence of ARIAs was 0.9% and 0.4% for solanezumab
indicated that mAbs used in AD treatments, such as adu- and placebo, respectively, indicating that solanezumab did
canumab, gantenerumab, and solanezumab, have differ- not induce ARIAs, thus displaying its great tolerability
ent specificities for various forms of amyloid-β. They can and safety [38]. Lecanemab ranked lowest in terms of AEs
influence the effectiveness at various stages or under vary- in our study, but in clinical trials of lecanemab, the inci-
ing conditions of amyloid-β accumulation, which might dence of brain swelling (referred to as ARIA-E) was 12.6%,
explain the variations in their therapeutic outcomes [71, whereas in the clinical trials of donanemab, this rate was
72]. Overall, the efficacy of these mAbs in improving 24% [25, 34].

188 Y. Qiao et al.