Efficacy and APOE ε4-stratified risk of donanemab in Alzheimer's disease: A systematic review and meta-analysis of randomized clinical trials

Abstract

Background

Donanemab, a monoclonal antibody targeting amyloid-β (Aβ) plaques, has shown the ability to reduce cerebral amyloid burden in early Alzheimer's disease (AD). However, uncertainties remain regarding its clinical relevance, particularly in relation to tau pathology, APOE ε4 genotype, and methodological limitations in existing trials.

Objective

To conduct a systematic review and exploratory meta-analysis to evaluate the efficacy, safety, and tolerability of donanemab in patients with mild to moderate AD.

Methods

We conducted a systematic review and exploratory meta-analysis following PRISMA guidelines. Randomized controlled trials comparing donanemab to placebo in individuals aged ≥65 years with biomarker-confirmed mild to moderate AD were included. Outcomes included cognitive measures (ADAS-Cog13, MMSE, CDR-SB, iADRS, ADCS-iADL) and adverse events (ARIA-E, ARIA-H, infusion reactions, discontinuations). Random-effects models were used to estimate pooled mean difference (MD) or risk ratio (RR) with 95% confidence intervals. Subgroup analyses were performed by baseline tau burden and APOE ε4 genotype.

Results

Three trials (n = 2054) were included. Donanemab modestly reduced cognitive decline compared to placebo: ADAS-Cog13 (MD, −1.86), CDR-SB (MD, −0.36), MMSE (MD, 0.64), and iADRS (MD, 3.19), with similar effects across tau subgroups. The risk of ARIA-E was markedly increased (RR, 12.39), especially among APOE ε4 homozygotes. Infusion reactions (RR, 11.90) and discontinuations (RR, 3.22) were also more frequent.

Conclusions

Donanemab demonstrated modest cognitive benefits, the clinical significance of which remains uncertain. Independent, longer-term trials with rigorous methodology and active comparators are warranted to more clearly define its therapeutic value in the treatment of AD.

Keywords

ADAS-Cog13 Alzheimer's disease amyloid ARIA cognitive decline donanemab meta-analysis monoclonal antibody

Introduction

Alzheimer's disease (AD) is the leading cause of dementia worldwide, affecting more than 50 million individuals, with projections indicating a twofold increase every two decades.^1–3 Cognitive decline is the central clinical feature of AD, progressing gradually and impairing memory, executive function, and independence in activities of daily living.^4,5 Despite advances in research, currently available pharmacological therapies have a limited impact on disease progression.^6,7

In recent years, disease-modifying strategies targeting beta-amyloid deposition have gained prominence.⁸ Donanemab is a monoclonal antibody directed against N-terminal pyroglutamate-modified amyloid-β (Aβ) plaques, developed to facilitate amyloid clearance in the early stages of AD.^9–13 Preliminary randomized clinical trials (RCTs) have demonstrated cognitive stabilization in selected subgroups, particularly in individuals with high amyloid burden and low tau pathology.^9,10,13 However, its safety profile remains a clinical concern, especially regarding the risk of amyloid-related imaging abnormalities (ARIA) and infusion-related reactions.^14–16

Among the known genetic risk factors for AD, the apolipoprotein E (APOE) ε4 allele stands out as the strongest predictor of late-onset AD.¹⁷ Individuals carrying one (heterozygotes) or two (homozygotes) copies of the ε4 allele have an increased risk of developing AD and tend to exhibit earlier disease onset and greater amyloid deposition.^4,18

Recent evidence suggests that APOE ε4 status may also modulate both the efficacy and safety profile of anti-amyloid therapies.^17,19 Donanemab, in particular, may exhibit variable outcomes depending on the APOE genotype.²⁰ Homozygous carriers of the ε4 allele are more susceptible to ARIA, especially vasogenic edema and microhemorrhages, which may limit treatment tolerability and require close monitoring.^13,20,21 Additionally, some studies suggest that the clinical response to donanemab may differ across APOE genotypes, though further investigation is needed to establish genotype-specific efficacy.²²

Emerging data from a network meta-analysis compared Terao and Kodama²³ donanemab with lecanemab, aducanumab, and lithium in patients with mild cognitive impairment or Alzheimer's disease, assessing cognitive efficacy, tolerability, and acceptability in 6547 participants across eight RCTs.²³ The results showed that all active agents outperformed placebo on the Alzheimer's Disease Assessment Scale–Cognitive Subscale (ADAS-Cog), while both donanemab and lecanemab also showed superiority over placebo on the Clinical Dementia Rating–Sum of Boxes (CDR-SB).^24,25 However, donanemab, along with the other anti-amyloid monoclonal antibodies, was associated with lower tolerability and acceptability compared to placebo.^16,26

Although individual trials and indirect comparisons suggest a potential therapeutic role for donanemab, important uncertainties remain regarding the clinical relevance of its effects, particularly in relation to tau pathology and the APOE ε4 genotype. Moreover, discrepancies in methodological rigor and the generalizability of findings across studies justify an independent synthesis of the available evidence.^14,27 Therefore, we conducted a systematic review and exploratory meta-analysis of the available evidence to estimate the efficacy and tolerability of donanemab for the treatment of cognitive impairment in patients with AD.

Methods

This systematic review and meta-analysis was conducted based on the Cochrane Handbook and the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement.^28,29 The protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO) registration number: CRD 420251023460.

Eligibility criteria

This meta-analysis included RCTs that compared donanemab with placebo in elderly individuals (≥65 years) with a clinical diagnosis of AD in mild to moderate stages.^16,30 Eligible studies were required to report at least one predefined outcome of interest related to efficacy or safety/tolerability. Efficacy outcomes included changes in cognitive performance measured by validated scales, such as the ADAS-Cog13, Mini-Mental State Examination (MMSE), CDR-SB and Alzheimer's Disease Cooperative Study–Instrumental Activities of Daily Living (ADCS-iADL).^24,25,31 Safety and tolerability outcomes included treatment-emergent adverse events (TEAEs), discontinuation due to adverse events, amyloid-related imaging abnormalities (ARIA-E and ARIA-H), infusion-related reactions, amyloid-negative population.¹⁵ We excluded case reports, reviews, editorials, letters to the editor, conference abstracts, and studies that did not include a placebo control group or failed to report outcome-specific data relevant to efficacy or tolerability. Non-English language publications were also excluded.

Search strategy, study selection, and quality assessment

A comprehensive literature search was conducted across four electronic databases: PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and SCOPUS from inception to March 2025, using the following search strategy: (“donanemab”) AND (“Alzheimer's disease” OR “mild cognitive impairment”) AND (“cognition” OR “ADAS-Cog” OR “MMSE” OR “CDR-SB”). A Cochrane Highly Sensitive Search Strategy was applied in the MEDLINE, Embase and SCOPUS databases to ensure the search was restricted to RCTs.²⁹ The entire search string is available in the Supplemental Material. Additionally, the reference lists of the included studies were manually screened for additional relevant studies. All retrieved citations were imported into the Rayyan^® platform for systematic screening.³²

The risk of bias for RCTs was assessed using Version 2 of the Cochrane risk-of-bias tool (RoB 2).³³ Two authors independently assessed the studies for data extraction and quality assessment (AMPS & ESF), and any conflict was resolved by a third author (MBSM).

Data extraction

The following data were extracted from each included study: first author, year of publication, study location, study design, sample size, mean age of participants, diagnostic criteria for AD, and baseline cognitive status. Detailed information regarding the intervention (donanemab: dosage, administration route, treatment duration), comparator (placebo), and follow-up period was collected. Primary outcomes included measures of cognitive efficacy (changes in ADAS-Cog13, MMSE, CDR-SB) and safety/tolerability outcomes, such as TEAEs, discontinuation rates due to TEAEs, ARIA-E/H, infusion-related reactions.

Outcomes, definitions, and subgroup analyses

The outcomes analyzed in this review encompassed both efficacy and safety/tolerability domains. Efficacy endpoints included changes in cognitive performance and functional capacity, evaluated through the 13-item version; ADAS-Cog13³⁴ which quantifies cognitive decline in AD; the MMSE, a widely adopted tool for assessing global cognitive function³⁵; the CDR-SB, which integrates cognitive and functional metrics³⁶; the Integrated iADRS, a composite index of cognitive-functional status³⁷; and the ADCS-iADL³⁸; which captures patient capacity in performing routine instrumental tasks.

Safety and tolerability outcomes included the incidence of TEAEs, defined as any undesirable clinical event occurring after the administration of donanemab or placebo, regardless of causality. These outcomes also included adverse events and safety events (deaths, treatment discontinuations and infusion reactions); discontinuations attributed to TEAEs; and ARIA, encompassing both vasogenic edema (ARIA-E) and hemorrhagic manifestations such as microhemorrhages and superficial siderosis (ARIA-H), as detected by magnetic resonance imaging and defined according to radiological criteria.³⁹ All outcomes were evaluated at the 76-week follow-up. Predefined subgroup analyses were conducted to explore potential effect modifiers.

For efficacy endpoints including: ADAS-Cog13, MMSE, CDR-SB, iADRS, and ADCS-iADL stratification was based on baseline tau burden, categorized as low/medium tau versus combined tau groups. For safety outcomes related to ARIA events, subgroup analyses were performed according to APOE ε4 genotype, including homozygous carriers, heterozygous carriers, and noncarriers.

Statistical analysis

The present systematic review and meta-analysis adhered to the updated PRISMA guidelines.²⁹ We calculated pooled effect sizes using mean difference (MD) for continuous outcomes, and risk ratio (RR) with 95% confidence intervals (CI) for dichotomous outcomes.²⁹ All analyses were performed under a random-effects model, accounting for expected clinical and methodological heterogeneity across studies. A p-value < 0.05 was considered statistically significant. Heterogeneity was assessed using the Cochran Q test and quantified with the I² statistic, interpreted as follows: < 40% (low), 40–60% (moderate), and >60% (substantial heterogeneity).²⁹ All statistical analyses were conducted using R software version 4.4.2 (R Foundation for Statistical Computing, Vienna, Austria) with the meta packages.⁴⁰ The DerSimonian and Laird method was employed for estimating between-study variance (τ²) under the inverse variance framework.⁴¹

Results

Study selection

A total of 380 records were identified through database searches from PubMed (31), Scopus (229), Embase (75), and Cochrane Library (45). After removing 197 duplicates, 183 records were screened by title and abstract, resulting in the exclusion of 177 studies. The remaining 6 full-text articles were assessed for eligibility, of which 3 were excluded for being conference abstracts. Ultimately, 3^9,10,13 studies met the inclusion criteria and were included in the final analysis.^28,42 This search process is illustrated in Figure 1.

Figure 1.

PRISMA flow diagram.

Baseline characteristics

The three randomized, multicenter, placebo-controlled trials included in this meta-analysis, conducted between 2015 and 2020 across sites in North America, Europe, Asia, and Australia enrolled a total of 2054 participants, with 1037 (50.5%) allocated to donanemab and 1017 (49.5%) to placebo. Mean age ranged from 66.8 to 78.3 years in the donanemab arms and from 73.0 to 75.4 years in the placebo arms. The proportion of male participants ranged from 42% to 60% across study groups. Baseline MMSE scores ranged from 18.86 (SD 2.41) to 23.6 (SD 3.1) in the donanemab groups, and from 21.67 (SD 4.81) to 23.7 (SD 2.9) in the placebo groups, consistent with mild to moderate cognitive impairment at study entry. All trials required biomarker confirmed AD, with mandatory amyloid PET positivity and, when applicable, tau PET stratification. The prevalence of APOE ε4 carriers in the donanemab groups ranged from 66.7% to 100%. Discontinuation rates were high, reaching up to 37.4% in the donanemab group, primarily due to adverse events, consent withdrawal, or protocol violations. Concomitant use of acetylcholinesterase inhibitors or memantine was permitted and reported in approximately 60% of participants. Strict eligibility criteria, substantial screening failure rates, and high discontinuation frequencies, particularly in the donanemab arm were observed. Baseline characteristics of the included studies and participants are presented in Table 1.

Table 1.

Baseline characteristics of included studies.

Author, y	Groups	Sample Size (n)	Country	Study Design (Year range)	Follow-up (weeks)	Age (mean ± SD)	Sex (M/F)	MMSE, (mean ± SD)	CDR Global, (mean ± SD)	APOE4+^a	Reasons for Selection	Reasons for Exclusion before randomization	Reasons for Exclusion after randomization	Concomitant Treatment
Lowe et al. 2021¹⁰	Donanemab 10 mg/kg Single Dose	7	US and Japan	RCT (2015–2020)	72	78.3 ± 8.4	3/4	21.71 ± 4.23	NA	5/7 (71.4)	Positive florbetapir PET, MMSE 16–30, FCSRT-IR <27, CDR 0.5–2	Amyloid PET below threshold (40/154, 26%), cognitive criteria (33/154, 21.4%), > 4 microhemorrhages (16/154, 10.4%)	Withdrew consent (1/7, 14.3%)	NA
	Donanemab 20 mg/kg Single Dose	7			72	75.6 ± 6.4	4/3	23.57 ± 4.50	NA	5/7 (71.4)			0 (0/7, 0.0%)
	Donanemab 40 mg/kg Single Dose	4			24	75.3 ± 6.7	2/2	23.25 ± 3.86	NA	4/4 (100)			Lost to follow-up (1/4, 25.0%)
	Donanemab 10 mg/kg Q2W	10			72	66.8 ± 8.6	6/4	20.00 ± 3.40	NA	8/10 (80)			Withdrew consent (1/10, 10.0%)
	Donanemab 10 mg/kg Q4W	8			72	73.0 ± 7.8	4/4	18.86 ± 2.41	NA	6/8 (75)			Investigator decision (3/8, 37.5%), Withdrew consent (1/8, 12.5%)
	Donanemab 20 mg/kg Q4W	10			72	71.7 ± 9.2	4/6	19.50 ± 2.93	NA	9/10 (90)			ARIA-E (1/10, 10.0%), Hypertensive crisis (1/10, 10.0%), Withdrew consent (1/10, 10.0%)
	Placebo	15			72	74.5 ± 10.1	4/11	21.67 ± 4.81	NA	10/15 (66.7)			Myocardial infarction (1/15, 6.7%), Withdrew consent (1/15, 6.7%)
Mintun et al. 2021¹³	Donanemab 700–1400mg	131	US and Canada	RCT (2017–2020)	76	75.0 ± 5.6	63/68	23.6 ± 3.1	NA (CDR-SB: 3.6 ± 2.1)	95/131 (72.5)	Age 60–85, early symptomatic AD, MMSE 20–28, amyloid and tau PET positive (but not extensive tau load, SUVR ≤ 1.46)	1683/1955 (86.1%) were excluded: 1563 screening failure due to tau PET not eligible, amyloid PET SUVR <1.17, MMSE out of range, MRI findings, comorbidities. 96 withdrew consent, 6 due to caregiver circumstances, 18 other reasons.	49/131 (37.4%) discontinued Donanemab; adverse events (34/131, 26.0%), withdrawal (2/131, 1.5%), other reasons (13/131, 9.9%)	AchE inhibitors (78/131, 59.5%)
Mintun et al. 2021¹³	Placebo	126	US and Canada	RCT (2017–2020)	76	75.4 ± 5.4	61/65	23.7 ± 2.9	NA (CDR-SB: 3.4 ± 1.7)	92/124 (74.2)			34/126 (27.0%) discontinued Placebo; adverse events (9/126, 7.1%), death (1/126, 0.8%), withdrawal (1/126, 0.8%), caregiver issue (1/126, 0.8%), physician withdrawal (1/126, 0.8%), protocol deviation (1/126, 0.8%), other reasons (20/126, 15.9%)	AchE inhibitors (74/126, 58.7%)
Sims et al. 2023 ⁹	Donanemab 700–1400mg	860	Australia, Canada, Czech Republic, Great Britain, Japan, the Netherlands US and Poland	RCT (2017–2020)	76	73.0 ± 6.2	393/367	22.4 ± 3.8	NA (CDR-SB: 4.0 ± 2.1)	143/860 (16.6)	Age 60–85, early symptomatic AD, MMSE 20–28, amyloid PET ≥37 Centiloids, tau pathology (low/medium or high)	Low tau pathology (1631/8240, 19.8%), Low amyloid pathology (1601/8240, 19.4%), MMSE out of range (1510/8240, 18.3%), P-tau181 pathology (295/8240, 3.6%), MRI findings (234/8240, 2.8%), Withdrew (465/8240, 5.6%), Unreliable (259/8240, 3.1%), Concurrent illness (76/8240, 0.9%), Clinically important abnormality (75/8240, 0.9%), Neurological disease (40/8240, 0.5%), Caregiver issues (21/8240, 0.3%), Other exclusions (397/8240, 4.8%)	Withdrew consent (111/860, 12.9%), Adverse events (50/860, 5.8%), Caregiver issues (21/860, 2.4%), Physician decision (19/860, 2.2%), Death (15/860, 1.7%), Lost to follow-up (11/860, 1.3%), Progressive disease (4/860, 0.5%)	AchE inhibitors or memantine allowed (used in 60.6%)
Sims et al. 2023 ⁹	Placebo	876		RCT (2017–2020)	76	73.0 ± 6.2	373/503	22.2 ± 3.9	NA (CDR-SB: 3.9 ± 2.1)	146/876 (16.6)			Withdrew consent (94/876, 10.7%), Adverse events (21/876, 2.4%), Caregiver issues (20/876, 2.3%), Physician decision (10/876, 1.1%), Death (10/876, 1.1%), Lost to follow-up (11/876, 1.3%), Progressive disease (7/876, 0.8%)	AchE inhibitors or memantine allowed (used in 61.4%)

number/total (%).

AD: Alzheimer's disease; AchE: Acetylcholinesterase; CDR: Clinical Dementia Rating; CDR-SB: Clinical Dementia Rating Sum Box; US: United States; RCT: Randomized Controlled Trial; Q2W: every 2 weeks; Q4W: every 4 weeks; MMSE: Mini Mental State Examination; N: Number of patients; NA: Not available.

Pooled analysis of included studies

Cognitive and functional outcomes

ADAS-Cog13 by tau subgroup

At 76 weeks, donanemab was associated with reduced cognitive decline on the ADAS-Cog13 scale compared to placebo (MD, −1.86; 95% CI, −1.99 to −1.72; I² = 0%; Figure 2). Stratification by baseline tau pathology revealed comparable treatment effects in participants with combined tau (MD, −1.86; 95% CI, −2.05 to −1.67) and those with low/medium tau burden (MD, −1.85; 95% CI, −2.04 to −1.66), with no indication of subgroup interaction (p = 0.96).

Figure 2.

Forest plot of ADAS-Cog13 change at 76 weeks comparing donanemab and placebo, stratified by baseline tau burden (low/medium versus combined).

ADCS-iADL

Donanemab led to a modest but statistically significant preservation of instrumental activities of daily living at 76 weeks relative to placebo (MD, 6.82; 95% CI, 0.16 to 13.48; p = 0.04; I² = 99%; Figure 3). Despite substantial heterogeneity across studies, stratified analyses showed similar effect estimates for both low/medium tau (MD, 8.07; 95% CI, −5.39 to 21.52) and combined tau groups (MD, 5.59; 95% CI, −3.02 to 14.19), without evidence of differential treatment response (p = 0.76).

Figure 3.

Forest plot of change in ADCS-iADL scores at 76 weeks comparing donanemab and placebo, stratified by tau pathology.

CDR-SB

Global cognitive-functional decline was attenuated in the donanemab group compared with placebo at 76 weeks (MD, −0.36; 95% CI, −0.40 to −0.33; p < 0.001; I² = 0%; Figure 4). This benefit was consistent across both trials and tau subgroups. Participants with low/medium tau burden exhibited a pooled effect of −0.36 (95% CI, −0.41 to −0.31), closely mirroring the estimate in the combined tau group (MD, −0.37; 95% CI, −0.46 to −0.28). There was no evidence of effect modification by tau burden (p = 0.87).

Figure 4.

Forest plot of CDR-SB change from baseline to 76 weeks comparing donanemab and placebo across tau subgroups.

iADR

At week 76, donanemab was associated with a significantly reduced rate of decline on the iADRS compared to placebo (MD, 3.19; 95% CI, 2.96 to 3.42; P < 0.001; I² = 0%; Figure 5). Treatment effects were consistent across tau strata, with similar estimates observed in the combined tau group (MD, 3.20; 95% CI, 2.87 to 3.52) and low/medium tau group (MD, 3.19; 95% CI, 2.86 to 3.51). Subgroup interaction was not detected (p = 0.96).

Figure 5.

Forest plot of iADRS scores at 76 weeks comparing donanemab and placebo, stratified by tau status (low/medium versus combined).

MMSE

At 76 weeks, donanemab was associated with a smaller decline in global cognitive function compared to placebo, with a MD of 0.64 points on the MMSE score (95% CI, 0.56–0.71; p < 0.001; I² = 0%; Figure 6). The absence of heterogeneity across studies reinforces the consistency of this observed effect. In stratified analyses by baseline tau burden, results remained stable. Among participants with combined tau, the MD was 0.64 (95% CI, 0.53–0.75), while in the low/medium tau subgroup, the effect estimate was similar (MD, 0.63; 95% CI, 0.52–0.74). No evidence of subgroup interaction was detected (p = 0.92), indicating that the cognitive efficacy of donanemab on MMSE performance is independent of baseline tau pathology.

Figure 6.

Forest plot of MMSE score change at 76 weeks comparing donanemab and placebo, stratified by tau pathology.

Amyloid-related imaging abnormalities

ARIA-E by APOE status

Donanemab was associated with an increased risk of ARIA-E events across all APOE subgroups (Figure 7). Relative risks were elevated among heterozygous ε4 carriers (RR, 12.80; 95% CI, 6.68 to 24.54), homozygous ε4 carriers (RR, 11.92; 95% CI, 5.32 to 26.71), and noncarriers (RR, 16.49; 95% CI, 4.65 to 58.48). The overall pooled estimate indicated a 12.39-fold increased risk of ARIA-E with donanemab (95% CI, 8.92 to 17.21; I² = 0%), with no significant subgroup interaction by genotype (p = 0.96). In individuals with confirmed APOE ε4 positivity, the risk of ARIA-E was increased 9.81-fold (95% CI 5.04–19·08; I² = 0%), with no heterogeneity across studies (p = 0.81), supporting the consistency of the effect in this genetic subgroup (Supplemental Figure 2). In the total population, the pooled RR for ARIA-E favored placebo (RR, 12.87; 95% CI, 8.09–20.49; I² = 0%) (Supplemental Figure 2). The consistency across studies supports the robust association between donanemab and vasogenic edema events. The absolute incidence of ARIA-E also varied by genotype (Supplemental Figure 1), reaching 41.08 (95% CI, 33.89 to 48.67) in homozygous carriers, 25.33 (95% CI, 18.77 to 33.25) in heterozygotes, and 15.23 (95% CI, 11.53 to 19.85) in noncarriers. Subgroup interaction was significant (p < 0.001), indicating differential risk by APOE genotype.

Figure 7.

Forest plot of ARIA-E risk associated with donanemab, stratified by APOE ε4 genotype (noncarrier, heterozygous, homozygous).

The pooled safety analysis revealed a consistently elevated risk of ARIA stratified by APOE Genotype and Amyloid-PET among participants treated with donanemab when compared to placebo (RR, 6.06; 95% CI, 2.83–13.00; I² = 96%) (Supplemental Figure 2). Subgroup-specific patterns further clarified the stratified risk profiles.

ARIA-H events

Donanemab was also associated with an elevated risk of ARIA-H (RR, 3.32; 95% CI, 2.35 to 4.69; I² = 66%; Figure 8). The increased incidence was primarily driven by microhemorrhages (RR, 2.60; 95% CI, 1.46 to 4.65) and superficial siderosis (RR, 5.47; 95% CI, 3.72 to 8.05). Large intracerebral hemorrhages (ICH > 1 cm) were infrequent and not significantly different between groups. In a complementary analysis encompassing ARIA-H subtypes, the pooled effect confirmed the increased incidence of these events with donanemab (RR, 2.91; 95% CI, 2.06–4.11; I² = 0%), with low statistical heterogeneity (p = 0.42) (Supplemental Figure 2).

Figure 8.

Forest plot of ARIA-H risk (including microhemorrhage, siderosis, and ICH > 1 cm) associated with donanemab versus placebo.

Adverse events and safety

There was no significant difference in deaths during follow-up between treatment groups (RR, 0.78; 95% CI, 0.18 to 3.34; I² = 40%; Figure 9). However, discontinuations due to TEAEs occurred more frequently in the donanemab group (RR, 3.22; 95% CI, 2.36 to 4.41; I² = 0%; Figure 8). Infusion reactions were substantially more common with donanemab (RR, 11.90; 95% CI, 2.97 to 47.69; I² = 35%; Figure 8). The overall adverse event risk favored placebo (RR, 2.83; 95% CI, 1.18 to 6.81; p = 0.02; I² = 68%), with moderate between-subgroup heterogeneity (p = 0.03).

Figure 9.

Forest plots of safety outcomes: deaths during follow-up, discontinuations due to treatment-emergent adverse events (TEAEs), and infusion-related reactions.

Amyloid-negative population

In participants with negative amyloid PET imaging, the estimated risk associated with donanemab was highly uncertain (RR 7.42; 95% CI 0·42–130·35; I² = 86%) (Supplemental Figure 2).

Sensitivity analysis

To assess the robustness of findings related to ARIA events and amyloid-PET–defined subgroups, leave-one-out sensitivity analyses were conducted. For amyloid-negative conversion (Supplemental Figure 3), omission of the Sims et al.⁹ study resulted in the highest risk estimate (RR, 30.91; 95% CI, 2.02–474.25), whereas excluding Mintun et al.¹³ yielded the lowest estimate (RR, 1.67; 95% CI, 0.27–10.40). Heterogeneity ranged from 49% to 92%, indicating that results were sensitive to the inclusion of individual studies and that interstudy variability significantly influenced the pooled effect. For the proportion of ARIA-E events (Supplemental Figure 4), omitting Lowe et al.¹⁰ produced a stable estimate (0.25; 95% CI, 0.22–0.27) with no observed heterogeneity (I² = 0%). However, exclusion of Mintun et al.¹³ or Sims et al.⁹ increased heterogeneity to 64% and 73%, respectively, with only minor changes in effect size.

Quality assessment

The risk of bias assessment is summarized in Figure 10 and detailed in Supplemental Table 1. Two trials Mintun et al.¹³ and Sims et al.⁹ were classified as having a high overall risk of bias. Both studies raised concerns in Domain 2 (deviations from intended interventions) and Domain 4 (missing outcome data). Mintun et al.¹³ also showed potential bias in Domain 5 (selection of reported outcomes), while Sims et al. presented additional concerns in Domain 3 (measurement of outcomes) and again in Domain 5. Lowe et al.¹⁰ was assessed as having a lower overall risk; however, it did not report on random sequence generation or allocation concealment (Domain 1). In all trials, protocol modifications related to the occurrence of ARIA were implemented without clearly defined procedures for maintaining blinding. None of the trials explicitly reported the use of intention-to-treat analyses, and strategies for handling missing data were limited or unspecified. Selective reporting of safety outcomes was also noted, including underreporting of ARIA-related complications and mortality.

Figure 10.

Risk of bias assessment of the included studies was conducted using version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB2).

Discussion

In this meta-analysis, we provide the first comprehensive synthesis of the efficacy and tolerability of donanemab for the treatment of cognitive impairment in patients with AD. Given the increasing momentum behind disease-modifying therapies in AD, our primary objective was to consolidate available clinical evidence and deliver a quantitative assessment of donanemab's therapeutic profile, with particular emphasis on stratification by baseline tau burden and APOE genotype.

Consistent with previous research on anti-amyloid monoclonal antibodies such as gantenerumab, lecanemab, and aducanumab,^14,43–46 dose-escalation studies have demonstrated that donanemab induces a rapid and dose-dependent reduction in cerebral amyloid plaques.¹⁰ However, the interpretation of amyloid-PET findings remains a subject of ongoing debate. Experts have raised concerns regarding the anatomical specificity and clinical relevance of PET-detected amyloid reduction, noting that published imaging data frequently demonstrate tracer retention in white matter regions where amyloid deposition is minimal or absent in the early stages of AD. Confirming amyloid clearance in gray matter, where the pathological burden is most relevant, remains technically challenging and subject to methodological limitations.⁴⁷ Moreover, the degree of amyloid reduction attributed to donanemab has not been consistently paralleled by a proportional slowing of cognitive or functional decline, raising questions about the direct clinical utility of anti-amyloid interventions.

Our meta-analysis corroborates these biochemical effects, showing statistically significant improvements in cognitive and functional outcomes, including ADAS-Cog13 (MD, −1.86), CDR-SB (MD, −0.36), MMSE (MD, 0.64), and iADRS (MD, 3.19), compared to placebo. However, the magnitude of these changes, although statistically robust, remains modest and falls below established thresholds for minimal clinically important differences, suggesting that these effects are unlikely to be perceived by patients in their daily functioning. Thus, while donanemab may modestly slow the progression of cognitive decline, this does not appear to translate into perceptible clinical benefit. Moreover, responder rates were not reported in the included trials, preventing the calculation of the number needed to treat. Conversely, the number needed to harm was estimated to be approximately 3, indicating that one in every three patients exposed to donanemab develops ARIA-related adverse events. These findings should be interpreted with caution, particularly in light of ongoing debates regarding the clinical relevance of amyloid-targeted therapies. It is noteworthy that treatment effects were observed regardless of baseline tau burden, suggesting that donanemab's efficacy is not strictly dependent on tau stratification.

Based on these cognitive endpoints, it is essential to contextualize the interpretability of the instruments used. Among them, the iADRS warrants particular consideration. Although it was developed to jointly capture cognitive and functional decline and is increasingly used in anti-amyloid therapy trials the iADRS has yet to be widely adopted in routine clinical practice.^37,48,49 In contrast, more established scales such as the MMSE and CDR-SB are widely validated and integrated into both clinical practice and regulatory frameworks.^35,36 While the iADRS provides valuable complementary information, particularly in research contexts, its limited external validation underscores the importance of relying on globally recognized and routinely applied instruments for primary interpretation and cross-drug comparisons.

However, the efficacy profile of donanemab is tempered by its safety considerations. Treatment was associated with a markedly increased risk of ARIA-E and ARIA-H, particularly among APOE ε4 carriers. The incidence of ARIA-E varied by genotype, with homozygous ε4 carriers exhibiting the highest rates. ARIA-H was similarly elevated, primarily driven by cerebral microhemorrhages and superficial siderosis. These findings were consistent across included trials, strengthening the evidence for a genotype-dependent safety signal.

The safety profile of donanemab aligns with prior findings. In the study by Lowe et al., the drug was generally well tolerated, with ARIA-E being the most commonly reported adverse event, which resolved upon discontinuation of treatment.⁵⁰ The observed rates of ARIA-E fall within the expected range reported for other amyloid-targeting monoclonal antibodies. However, several studies have also documented reductions in brain volume and/or increases in ventricular size among patients treated with anti-amyloid antibodies, including donanemab.^{16,46,51–53} While these morphological changes are often attributed to amyloid plaque removal, their clinical significance remains uncertain. Emerging evidence suggests that such structural alterations may reflect accelerated neurodegeneration or compensatory shifts in brain tissue, with potential adverse functional consequences.⁵⁴

In addition to ARIA, adverse events such as infusion-related reactions and treatment discontinuations were more frequently reported in the donanemab group. Although the pooled mortality rate did not reach statistical significance, several deaths occurred in the context of ARIA-related complications, raising concerns about a potential underestimation of treatment-associated risk. Moreover, the incidence of ARIA-H, particularly cerebral microhemorrhages and superficial siderosis was consistently higher among participants receiving donanemab, reinforcing the need for rigorous safety monitoring.⁵⁵ In amyloid-negative individuals, the safety profile remains uncertain due to limited and heterogeneous data, preventing definitive conclusions and highlighting the need for further investigation in this subgroup.^56,57

Taken together, our findings suggest that donanemab may provide clinical benefits in mitigating cognitive and functional decline in patients with AD, as demonstrated across multiple validated outcome measures.^58,59 While these results are encouraging given the limited therapeutic options for early symptomatic stages of the disease, the observed effect sizes should be interpreted with caution, particularly regarding their clinical relevance. Subgroup analyses stratified by baseline tau burden and APOE ε4 genotype, though informative, are exploratory in nature and should not be used to guide clinical decisions. Their primary value lies in hypothesis generation and in identifying patterns that warrant further investigation in future trials. Larger-scale studies, conducted independently and with extended follow-up, are needed to clarify the clinical value of donanemab, establish its long-term risk–benefit profile, and define its role within an evolving therapeutic landscape. Importantly, the safety profile of donanemab most notably the increased risk of ARIA in genetically predisposed individuals, underscores the need for careful patient selection and rigorous safety monitoring. Further research is warranted to elucidate the long-term impact of donanemab, refine its risk–benefit assessment, and define its role in broader and more diverse patient populations.

It is also essential to consider the methodological quality of the included trials when interpreting donanemab's therapeutic profile. In our meta-analysis, two of the three trials exhibited a high overall risk of bias, primarily due to protocol deviations, incomplete outcome data, absence of intention-to-treat analyses, and selective reporting of outcomes. The occurrence of ARIA led to treatment modifications without clearly defined safeguards to maintain blinding, raising the possibility of functional unblinding and potential inflation of subjective cognitive outcomes. These limitations are consistent with the critical appraisal by Høilund-Carlsen et al.,¹⁴ who reported that the absolute gains on the CDR-SB (0.45 points) and iADRS (3.2 points) represented only 3.7% and 2.3% of their respective scale ranges well below accepted thresholds for clinical relevance and inferior to the benefits observed with conventional therapies such as cholinesterase inhibitors and memantine.^49,60–63 In line with our findings, the Bayesian reanalysis conducted by Høilund-Carlsen et al.¹⁴ indicated a lack of efficacy of donanemab even in the subgroup with low to medium tau burden.¹⁴ Moreover, cumulative safety concerns including treatment-related brain volume loss of up to 6–7 cm³ underscore the need for independent, long-term trials using functional imaging endpoints and standardized adverse event reporting to determine the true clinical value of anti-amyloid therapies.

Limitation

Despite the strengths of this meta-analysis, several limitations should be acknowledged. First, the number of included studies was limited to three RCTs, with most quantitative comparisons based on only two studies.^9,13 While meta-analyses with two studies are methodologically acceptable in emerging research areas, the restricted evidence base reduces statistical power and limits the generalizability of findings. This limitation is particularly relevant for subgroup analyses stratified by tau burden and APOE genotype, requiring cautious interpretation of the results. Second, heterogeneity in study design, inclusion criteria, and outcome reporting across trials may introduce bias and limit the comparability of results. Third, the relatively short follow-up period (maximum of 76 weeks) restricts insights into the long-term efficacy and safety of donanemab, especially regarding sustained cognitive benefits and delayed adverse events. Additionally, the available data on amyloid-negative individuals and underrepresented demographic groups were insufficient, constraining conclusions about donanemab's broader applicability. Fourth, the exclusion of patients who developed symptomatic ARIA during the clinical trials may have resulted in an underestimation of the incidence and clinical severity of these adverse events in real-world practice. The exclusion of patients who experienced early adverse events, such as symptomatic ARIA, may have introduced selection bias and led to an overestimation of the intervention's tolerability and efficacy.⁶⁴ Additionally, the scarcity or absence of robust data on treatment-related structural brain changes, such as volumetric atrophy and ventricular enlargement limits a comprehensive assessment of donanemab's safety profile, particularly regarding its functional and prognostic implications. Fifth, an important limitation is the absence of active comparator groups in the included trials. None of the studies evaluated donanemab against optimized conventional therapies, such as acetylcholinesterase inhibitors or memantine, which limits the contextualization of its efficacy relative to established treatment options. Given that these conventional agents remain widely accessible, cost-effective, and have demonstrated cognitive benefits in early AD, future RCTs should prioritize active comparator arms to more accurately define the therapeutic value of donanemab beyond placebo-controlled settings. Finally, publication bias cannot be entirely ruled out, as negative or inconclusive results may be underreported. An additional potential source of bias relates to unblinding. Since ARIA events occurred exclusively in the donanemab-treated group and often required protocol modifications, there is a risk that both participants and investigators became aware of treatment allocation. This unintentional unblinding may have influenced subjective cognitive assessments, potentially inflating the perceived treatment effect. Future trials should implement rigorous strategies to minimize unblinding-related bias, including the use of blinded outcome assessors and centralized, standardized evaluation protocols.

Conclusion

Donanemab provides questionable cognitive and functional benefits in patients with mild to moderate AD, regardless of baseline tau burden. While these effects are statistically consistent across trials, their magnitude appears modest and may not surpass those achievable with optimized conventional therapies, which remain safer and more cost-effective alternatives. Furthermore, treatment is associated with a significantly increased risk of ARIA and other adverse events, particularly in APOE ε4 carriers, underscoring the importance of careful patient selection and rigorous safety monitoring. In light of these considerations, larger-scale studies, conducted independently and with longer follow-up periods, are essential to clarify the true clinical value of donanemab, establish its long-term benefit-risk profile, and define its role within the therapeutic landscape of AD.

Supplemental Material

sj-docx-1-alz-10.1177_13872877251361044 - Supplemental material for Efficacy and APOE ε4-stratified risk of donanemab in Alzheimer's disease: A systematic review and meta-analysis of randomized clinical trials

Supplemental material, sj-docx-1-alz-10.1177_13872877251361044 for Efficacy and APOE ε4-stratified risk of donanemab in Alzheimer's disease: A systematic review and meta-analysis of randomized clinical trials by Anderson Matheus Pereira da Silva, Luciano Falcão, Filipe Virgilio, Isabelle Rodrigues Menezes, Marianna Leite, Elizabeth Farias, Maria Nascimento, Mariana Lee Han, João Paulo Mota Telles, Eryvelton de Souza Franco and Maria Bernadete de Sousa Maia in Journal of Alzheimer's Disease

Footnotes

Acknowledgments

We thank the Coordination for the Improvement of Higher Education Personnel (CAPES) for the financial support provided through its postgraduate scholarship program.

ORCID iDs

Anderson Matheus Pereira da Silva

Filipe Virgilio

Marianna Leite

Maria Nascimento

Mariana Lee Han

João Paulo Mota Telles

Eryvelton de Souza Franco

Author contribution(s)

Anderson Matheus Pereira Silva: Conceptualization; Formal analysis; Investigation; Methodology; Validation; Writing – original draft; Writing – review & editing

Luciano Falcão Carneiro Filho: Writing – original draft; Writing – review & editing

Filipe Virgilio Ribeiro: Writing – original draft; Writing – review & editing

Isabelle Rodrigues Menezes: Writing – original draft; Writing – review & editing

Marianna Leite: Formal analysis; Writing – original draft; Writing – review & editing

Elizabeth Honorato de Farias: Writing – original draft; Writing – review & editing

Maria Nascimento: Writing – original draft; Writing – review & editing

Mariana Lee Han: Writing – original draft; Writing – review & editing

João Paulo Mota Telles: Writing – original draft; Writing – review & editing

Eryvelton de Souza Franco: Investigation; Supervision; Validation; Visualization; Writing – original draft; Writing – review & editing

Maria Bernadete de Sousa Maia: Conceptualization; Supervision; Validation; Visualization; Writing - review & editing

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Supplemental material

Supplemental material for this article is available online.

References

Feng

Sun

, et al. Global, regional, and national burden of Alzheimer's disease and other dementias, 1990-2019. Front Aging Neurosci 2022; 14: 937486.

Prince

Ali

Guerchet

, et al. Recent global trends in the prevalence and incidence of dementia, and survival with dementia. Alzheimers Res Ther 2016; 8: 23.

McKeown

Turner

Angehrn

, et al. Health outcome prioritization in Alzheimer's disease: understanding the ethical landscape. J Alzheimers Dis 2020; 77: 339–353.

Lyketsos

Carrillo

Ryan

, et al. Neuropsychiatric symptoms in Alzheimer's disease. Alzheimers Dement 2011; 7: 532–539.

Schwarzinger

Dufouil

. Forecasting the prevalence of dementia. Lancet Public Health 2022; 7: e94–e95.

Aisen

Cummings

Doody

, et al. The future of anti-amyloid trials. J Prev Alzheimers Dis 2020; 7: 146–151.

Tatsumi

Nakaaki

Torii

, et al. Neuropsychiatric symptoms predict change in quality of life of Alzheimer disease patients: a two-year follow-up study. Psychiatry Clin Neurosci 2009; 63: 374–384.

Song

Shi

Zhang

, et al. Immunotherapy for Alzheimer's disease: targeting beta-amyloid and beyond. Transl Neurodegener 2022; 11: 18.

Sims

Zimmer

Evans

, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA 2023; 330: 512–527.

10.

Lowe

Willis

Hawdon

, et al. Donanemab (LY3002813) dose-escalation study in Alzheimer's disease. Alzheimers Dement (N Y) 2021; 7: e12112.

11.

Stoiljkovic

Horvath

Hajos

. Therapy for Alzheimer's disease: missing targets and functional markers? Ageing Res Rev 2021; 68: 101318.

12.

Bayer

. Pyroglutamate Abeta cascade as drug target in Alzheimer's disease. Mol Psychiatry 2022; 27: 1880–1885.

13.

Mintun

Duggan Evans

, et al. Donanemab in early Alzheimer's disease. N Engl J Med 2021; 384: 1691–1704.

14.

Hoilund-Carlsen

Alavi

Barrio

, et al. Donanemab, another anti-Alzheimer's drug with risk and uncertain benefit. Ageing Res Rev 2024; 99: 102348.

15.

Hampel

Elhage

Cho

, et al. Amyloid-related imaging abnormalities (ARIA) and their radiological, biological and clinical characteristics: a plain language summary. Neurodegener Dis Manag 2024; 14: 51–62.

16.

Rabinovici

Selkoe

Schindler

, et al. Donanemab: appropriate use recommendations. J Prev Alzheimers Dis 2025; 12: 100150.

17.

Serrano-Pozo

Das

Hyman

. APOE And Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol 2021; 20: 68–80.

18.

Liu

Kanekiyo

, et al. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 2013; 9: 106–118.

19.

Raulin

Doss

Trottier

, et al. Apoe in Alzheimer's disease: pathophysiology and therapeutic strategies. Mol Neurodegener 2022; 17: 72.

20.

Wang

Kowalewski

Koch

. Application of meta-analysis to evaluate relationships among ARIA-E rate, amyloid reduction rate, and clinical cognitive response in amyloid therapeutic clinical trials for early Alzheimer's disease. Ther Innov Regul Sci 2022; 56: 501–516.

21.

Genin

Hannequin

Wallon

, et al. APOE And Alzheimer disease: a major gene with semi-dominant inheritance. Mol Psychiatry 2011; 16: 903–907.

22.

Bradshaw

Georges

. Anti-amyloid therapies for Alzheimer's disease: an Alzheimer Europe position paper and call to action. J Prev Alzheimers Dis 2024; 11: 265–273.

23.

Terao

Kodama

. Comparative efficacy, tolerability and acceptability of donanemab, lecanemab, aducanumab and lithium on cognitive function in mild cognitive impairment and Alzheimer's disease: a systematic review and network meta-analysis. Ageing Res Rev 2024; 94: 102203.

24.

Kueper

Speechley

Montero-Odasso

. The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog): modifications and responsiveness in pre-dementia populations. A narrative review. J Alzheimers Dis 2018; 63: 423–444.

25.

O'Bryant

Waring

Cullum

, et al. Staging dementia using clinical dementia rating scale sum of boxes scores: a Texas Alzheimer's research consortium study. Arch Neurol 2008; 65: 1091–1095.

26.

Cummings

Apostolova

Rabinovici

, et al. Lecanemab: appropriate use recommendations. J Prev Alzheimers Dis 2023; 10: 362–377.

27.

Rashad

Rasool

Shaheryar

, et al. Donanemab for Alzheimer's disease: a systematic review of clinical trials. Healthcare (Basel) 2022; 11: 32.

28.

Page

Moher

Bossuyt

, et al. PRISMA 2020 Explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. Br Med J 2021; 372: n160.

29.

Higgins

JPT

Thomas

Chandler

, et al. Cochrane Handbook for Systematic Reviews of Interventions. 2nd Edition. Chichester, UK: John Wiley & Sons, 2019.

30.

Dubois

Villain

Schneider

, et al. Alzheimer disease as a clinical-biological construct-an international working group recommendation. JAMA Neurol 2024; 81: 1304–1311.

31.

Arevalo-Rodriguez

Smailagic

Roque-Figuls

, et al. Mini-Mental State Examination (MMSE) for the early detection of dementia in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev 2021; 7: CD010783.

32.

Ouzzani

Hammady

Fedorowicz

, et al. Rayyan-a web and mobile app for systematic reviews. Syst Rev 2016; 5: 210.

33.

Sterne

JAC

Savovic

Page

, et al. Rob 2: a revised tool for assessing risk of bias in randomised trials. Br Med J 2019; 366: l4898.

34.

Rosen

Mohs

Davis

. A new rating scale for Alzheimer's disease. Am J Psychiatry 1984; 141: 1356–1364.

35.

Folstein

McHugh

. Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–198.

36.

Morris

. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology 1993; 43: 2412–2414.

37.

Wessels

Andersen

Dowsett

, et al. The integrated Alzheimer's disease rating scale (iADRS) findings from the EXPEDITION3 trial. J Prev Alzheimers Dis 2018; 5: 134–136.

38.

Teng

Manser

, et al. Cross-sectional and longitudinal assessments of function in prodromal-to-mild Alzheimer's disease: a comparison of the ADCS-ADL and A-IADL-Q scales. Alzheimers Dement (Amst) 2023; 15: e12452.

39.

Sperling

Jack, Jr.

Black

, et al. Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup. Alzheimers Dement 2011; 7: 367–385.

40.

Balduzzi

Rücker

Schwarzer

. How to perform a meta-analysis with R: a practical tutorial. Evid Based Mental Health 2019; 22: 153–160.

41.

DerSimonian

Laird

. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–188.

42.

Shamseer

Moher

Clarke

, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. Br Med J 2015; 350: g7647.

43.

Bohrmann

Baumann

Benz

, et al. Gantenerumab: a novel human anti-Abeta antibody demonstrates sustained cerebral amyloid-beta binding and elicits cell-mediated removal of human amyloid-beta. J Alzheimers Dis 2012; 28: 49–69.

44.

Ostrowitzki

Deptula

Thurfjell

, et al. Mechanism of amyloid removal in patients with Alzheimer disease treated with gantenerumab. Arch Neurol 2012; 69: 198–207.

45.

Sevigny

Chiao

Bussiere

, et al. The antibody aducanumab reduces Abeta plaques in Alzheimer's disease. Nature 2016; 537: 50–56.

46.

Swanson

Zhang

Dhadda

, et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer's disease with lecanemab, an anti-abeta protofibril antibody. Alzheimers Res Ther 2021; 13: 80.

47.

Hoilund-Carlsen

Werner

Alavi

. The unsafe profile of lecanemab. J Alzheimers Dis 2025; 105: 62–64.

48.

Wessels

Siemers

, et al. A combined measure of cognition and function for clinical trials: the Integrated Alzheimer's Disease Rating Scale (iADRS). J Prev Alzheimers Dis 2015; 2: 227–241.

49.

Wessels

Belger

Johnston

, et al. Demonstration of clinical meaningfulness of the Integrated Alzheimer's Disease Rating Scale (iADRS): association between change in iadrs scores and patient and caregiver health outcomes. J Alzheimers Dis 2022; 88: 577–588.

50.

Tolar

Abushakra

Hey

, et al. Aducanumab, gantenerumab, BAN2401, and ALZ-801-the first wave of amyloid-targeting drugs for Alzheimer's disease with potential for near term approval. Alzheimers Res Ther 2020; 12: 95.

51.

Sur

Kost

Scott

, et al. BACE Inhibition causes rapid, regional, and non-progressive volume reduction in Alzheimer's disease brain. Brain 2020; 143: 3816–3826.

52.

Zimmer

Shcherbinin

Devous, Sr

, et al. Lanabecestat: neuroimaging results in early symptomatic Alzheimer's disease. Alzheimers Dement (N Y) 2021; 7: e12123.

53.

Novak

Fox

Clegg

, et al. Changes in brain volume with bapineuzumab in mild to moderate Alzheimer's disease. J Alzheimers Dis 2016; 49: 1123–1134.

54.

Alves

Kalinowski

Ayton

. Accelerated brain volume loss caused by anti-beta-amyloid drugs: a systematic review and meta-analysis. Neurology 2023; 100: e2114–e2124.

55.

Lenzer

Brownlee

. Donanemab: conflicts of interest found in FDA committee that approved new Alzheimer's drug. Br Med J 2024; 386: q2010.

56.

Hoilund-Carlsen

Revheim

Alavi

, et al. Amyloid PET: a questionable single primary surrogate efficacy measure on Alzheimer immunotherapy trials. J Alzheimers Dis 2022; 90: 1395–1399.

57.

Hoilund-Carlsen

Alavi

Castellani

, et al.

Alzheimer's amyloid hypothesis and antibody therapy: melting glaciers?

Int J Mol Sci 2024; 25: 20240331.

58.

US Food and Drug Administration. Peripheral and central nervous system drugs advisory committee meeting briefing document: Donanemab for Alzheimer’s Disease, https://www.fda.gov (2023, accessed 15 May 2025).

59.

Knopman

Jones

Greicius

. Failure to demonstrate efficacy of aducanumab: an analysis of the EMERGE and ENGAGE trials as reported by Biogen, December 2019. Alzheimers Dement 2021; 17: 696–701.

60.

Andrews

Desai

Kirson

, et al. Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer's disease clinical trials. Alzheimers Dement (N Y) 2019; 5: 354–363.

61.

Garcia-Ptacek

Jonsson

, et al. Long-term effects of cholinesterase inhibitors on cognitive decline and mortality. Neurology 2021; 96: e2220–e2230.

62.

Habich

Ferreira

, et al. Long-term effects of cholinesterase inhibitors and memantine on cognitive decline, cardiovascular events, and mortality in dementia with Lewy bodies: an up to 10-year follow-up study. Alzheimers Dement 2024; 20: 6740–6754.

63.

Veroniki

Ashoor

Rios

, et al. Comparative safety and efficacy of cognitive enhancers for Alzheimer's dementia: a systematic review with individual patient data network meta-analysis. BMJ Open 2022; 12: e053012.

64.

Kepp

Sensi

Johnsen

, et al. The anti-amyloid monoclonal antibody lecanemab: 16 cautionary notes. J Alzheimers Dis 2023; 94: 497–507.

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