Amyloid-beta-targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer's disease.

Overview

1. Unit of Epidemiology and Statistics, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
2. Laboratory of Methodology of Systematic Reviews and Guidelines production, Department of Experimental Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
3. U.O.C. Clinica Neurologica Rete Metropolitana (NeuroMet), IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
4. Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
5. Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland
6. Medical Library, Azienda USL - IRCCS di Reggio Emilia, Reggio Emilia, Italy
7. Independent Researcher, Milan, Italy
8. Department of Neurology, Radboud University Medical Centre, Nijmegen, Netherlands
9. Department of Public & Occupational Health, Amsterdam University Medical Centre, University of Amsterdam, Amsterdam, Netherlands

Abstract

Rationale: Alzheimer’s disease is a neurodegenerative disorder and the most common cause of dementia. Aggregated amyloid‐beta protein deposits are implicated in its pathogenesis. Amyloid‐beta‐targeting monoclonal antibodies (sometimes represented as Aβ‐mAbs) are potentially disease‐modifying for Alzheimer’s disease: through the clearance of amyloid in the brain, they may slow cognitive and functional decline.

Objectives: To assess the clinical benefits and harms of amyloid‐beta‐targeting monoclonal antibodies aducanumab, bapineuzumab, crenezumab, donanemab, gantenerumab, lecanemab, ponezumab, remternetug, and solanezumab in people with mild cognitive impairment or mild dementia due to Alzheimer’s disease.

Search methods: We searched CENTRAL, MEDLINE (PubMed), Embase, and two clinical trials registries (Clinicaltrials.gov and WHO International Clinical Trials Registry Platform), and we undertook reference checking and citation research. The most recent search date was 7 August 2025.

Eligibility criteria: We included randomised controlled trials (RCTs) that lasted at least 12 months and compared amyloid‐beta‐targeting monoclonal antibodies with placebo or no treatment in people with mild cognitive impairment or mild dementia due to Alzheimer’s disease. We included both parallel‐group and cluster designs.

Outcomes: Our outcomes of critical importance were: cognitive function; dementia severity; functional ability; any amyloid‐related imaging abnormality (ARIA), which includes oedema (E) and haemorrhage (H); any symptomatic ARIA E and H; symptomatic brain haemorrhage; serious adverse events; and any‐cause mortality. We analysed data at 12, 18, 24, and over 24 months of treatment.

Risk of bias: We used the Cochrane risk of bias tool RoB 2 to assess the risk of bias in outcomes of critical importance.

Synthesis methods: We meta‐analysed results for each outcome within each comparison using the inverse variance method and the random‐effects model. We used GRADE to assess the certainty of evidence for each outcome as very low, low, moderate, or high.

Included studies: Overall, we included 17 studies with 20,342 participants. The mean age of participants in the studies ranged from 70 to 74 years. Seven studies enroled only participants with mild dementia, and one study enroled only participants with mild cognitive impairment. The remaining studies included a mixed population. The mean duration of participants' cognitive impairment ranged from 17 to 52 months.

The 17 studies assessed seven different amyloid‐beta‐targeting monoclonal antibodies: aducanumab (n = 3), bapineuzumab (n = 4), crenezumab (n = 2), donanemab (n = 1), gantenerumab (n = 4), lecanemab (n = 1), and solanezumab (n = 2). All used placebo as a comparison. Eleven studies lasted 18 months, four lasted 24 months, and two lasted more than 24 months.

All studies were funded by the pharmaceutical industry.

Synthesis of results: Below, we report the results of the studies at 18 months.

Cognitive function

Compared to placebo, amyloid‐beta‐targeting monoclonal antibodies probably result in little to no difference in cognitive function as measured by the ADAS‐Cog (Alzheimer's Disease Assessment Scale‐Cognitive) scale (standardised mean difference (SMD) −0.11, 95% confidence interval (CI) −0.16 to −0.06; 13 studies, 9895 participants; moderate certainty).

Dementia severity

Amyloid‐beta‐targeting monoclonal antibodies may result in little to no difference in dementia severity as measured by the CDR‐SB (Clincal Dementia Rating Sum of Boxes) scale (SMD −0.12, 95% CI −0.24 to −0.00; 9 studies, 8053 participants; low certainty).

Functional ability

Amyloid‐beta‐targeting monoclonal antibodies probably result in little to no difference in functional ability as measured on the ADCS‐ADL (Alzheimer's Disease Cooperative Study ‐ Activities of Daily Living) scale (SMD 0.09, 95% CI 0.03 to 0.16; 3 studies, 3478 participants; moderate certainty) and may result in a small increase in functional ability if measured with the ADCS‐iADL (Alzheimer's Disease Cooperative Study‐Instrumental Activities of Daily Living) scale (SMD 0.21, 95% CI 0.10 to 0.32; 1 study, 1252 participants; low certainty) or ADCS‐ADL‐MCI (Alzheimer's Disease Cooperative Study ‐ Activities of Daily Living for Mild Cognitive Impairment) scale (SMD 0.23, 95% CI 0.12 to 0.33; 4 studies, 2802 participants; low certainty).

Adverse events

Amyloid‐beta‐targeting monoclonal antibodies probably result in a small increase in the occurrence of any ARIA E (ARD (absolute risk difference) 107 more per 1000, 95% CI 77 more to 148 more; 11 studies, 13,595 participants; moderate certainty) and probably little to no difference in symptomatic ARIA E (ARD 29 more per 1000, 95% CI 22 more to 38 more; 2 studies, 3522 participants; moderate certainty) or symptomatic ARIA H (ARD 4 more per 1000, 95% CI 1 fewer to 31 more; 1 study, 1795 participants; moderate certainty).

Three studies assessing any ARIA H showed heterogeneous results (I2 = 81%), which prevented pooled analysis.

At 18 months, amyloid‐beta‐targeting monoclonal antibodies do not increase serious adverse events (ARD 6 more events per 1000, 95% CI 10 fewer to 26 more; 9 studies, 11,904 participants; high certainty) or overall mortality (ARD 2 more events per 1000, 95% CI 3 fewer to 11 more; 7 studies, 9733 participants; high certainty).

We judged the overall risk of bias as low for the outcomes of serious adverse events and mortality. We had some concerns about the overall risk of bias for efficacy outcomes, mainly due to the risk of functional unblinding (i.e. participants and investigators correctly guessing whether a participant is receiving the active drug or placebo because of noticeable side effects).

Authors' conclusions: The effect of amyloid‐beta‐targeting monoclonal antibodies on cognitive function and dementia severity at 18 months in people with mild cognitive impairment or mild dementia due to Alzheimer’s disease is trivial, while on functional ability, it is small at best. Amyloid‐beta‐targeting monoclonal antibodies increase the risk of amyloid‐related imaging abnormalities. Both desirable outcomes and adverse events were inconsistently reported in the studies included in the review.

Successful removal of amyloid from the brain does not seem to be associated with clinically meaningful effects in people with mild cognitive impairment or mild dementia due to Alzheimer’s disease. Future research on disease‐modifying treatments for Alzheimer’s disease should focus on other mechanisms of action.

Funding: This Cochrane review was funded in part by the Drug and Medical Devices Governance Area, Regione Emilia‐Romagna, Bologna, Italy.

The publication of this article was supported by "Ricerca Corrente" funding from the Italian Ministry of Health.

Registration: Protocol (2025): PROSPERO registration number CRD420251114325

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

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Data Availability Statement

Data supporting the results of the systematic review, template data extraction forms from Covidence and detailed risk of bias assessment data with consensus responses to the signalling questions in the RoB 2 Excel tool will be made available for users upon request to the review authors.

As part of the published Cochrane review, the following are made available for download for users of the Cochrane Library (see Supplementary material 1: full search strategies for each database; Supplementary material 2: full citation of each unique report for all studies included in the final review; Supplementary material 3: full citation of each unique report for all excluded studies at the full text screen in the final review; Supplementary material 4: full citation of each unique report for all studies awaiting classification in the final review; Supplementary material 5: full citation of each unique report for all ongoing studies in the final review; Supplementary material 6: risk of bias assessments; Supplementary material 7: analysis data, including overall estimates and settings, subgroup estimates, and individual data rows; and Supplementary material 8: data package). Appropriate permissions have been obtained for such use. Analyses and data management were conducted within Cochrane’s authoring tool, RevMan, using the inbuilt computation methods.

Reproduced under the paper's license (CC BY-NC), from the paper cited above.

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Recorded: type, language, journal, volume, issue, pages, dates, 11 authors, 7 MeSH terms, 2 funders, 104 references.

Cite

This paper

Nonino, F., Minozzi, S., Sambati, L., Del Giovane, C., Baldin, E., Bassi, M. C., De Santis, C., Gonzalez-Lorenzo, M., Vignatelli, L., Filippini, G., & Richard, E. (2026). Amyloid-beta-targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer's disease. The Cochrane database of systematic reviews, 2026(4), CD016297. https://doi.org/10.1002/14651858.cd016297

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