Review ArticleSystematic Review

Clinically Important Benefits and Harms of Monoclonal Antibodies Targeting Amyloid for the Treatment of Alzheimer Disease: A Systematic Review and Meta-Analysis

Mark H. Ebell, Henry C. Barry, Kanishka Baduni and Gabrielle Grasso
The Annals of Family Medicine January 2024, 22 (1) 50-62; DOI: https://doi.org/10.1370/afm.3050

Article Figures & Data

Figures

  • Figure 1.
    Figure 1.

    Forest plot for the standardized mean differences in ADAS-Cog-11 through ADAS-Cog-14 scores.

    ADAS-Cog-11 = Alzheimer’s Disease Assessment Scale–Cognitive Subscale-11 items; ADAS-Cog-12 = Alzheimer’s Disease Assessment Scale–Cognitive Subscale-12 items; ADAS-Cog-13 = Alzheimer’s Disease Assessment Scale–Cognitive Subscale-13 items; ADAS-Cog-14 = Alzheimer’s Disease Assessment Scale–Cognitive Subscale-14 items; IV =interstudy variance; MCI = mild cognitive impairment.

  • Figure 2.
    Figure 2.

    Forest plot for the mean differences in Mini Mental State Examination scores.

    APOE = apolipoprotein E; DL = DerSimonian-Laird; MCI = mild cognitive impairment; MMSE = Mini Mental State Examination.

  • Figure 3.
    Figure 3.

    Forest plot for the mean differences in the Clinical Dementia Rating–Sum of Boxes scale.

    APOE = apolipoprotein E; CDR-SB = Clinical Dementia Rating–Sum of Boxes scale; DL = DerSimonian-Laird; MCI = mild cognitive impairment.

  • Figure 4.
    Figure 4.

    Forest plot for differences in any ARIA-E, any ARIA-H, and symptomatic ARIA-E.

    APOE = apolipoprotein E; ARIA-E = amyloid-related imaging abnormalities of edema; ARIA-H = amyloid-related imaging abnormalities of hemorrhage; DL =DerSimonian-Laird; MCI = mild cognitive impairment. Note: Separate plots stratified by drug are given in Supplemental Figures 14-16.

Tables

  • Table 1.

    Cognitive Scoring Tools and Their MCIDs

    Scoring ToolRange, PointsMCID, PointsInterpretation
    Cognitive assessments
        ADAS-Cog-110 to 7024324Lower is better
        ADAS-Cog-120 to 80253.5aLower is better
        ADAS-Cog-130 to 85263.75aLower is better
        ADAS-Cog-140 to 90274aLower is better
        ADCOMS-overall0 to 1.97280.14bLower is better
        Neuropsychological test batteryZ scale290.5 SDHigher is better
        MMSE0 to 30301 to 330Higher is better
    Functional assessments
        ADCS-ADL0 to 785.5bHigher is better
        ADCS-ADL-MCI0 to 53173.7bHigher is better
        DAD0 to 100c317b,cHigher is better
    Behavioral disturbance
        NPI-Question0 to 3632832Lower is better
    Combined or global assessments
        CDR-SB0 to 18301 to 230Lower is better
        iADRS0 to 1468.8bHigher is better
        Dependence scale0 to 15331.5 to 233Lower is better

    • ADAS-Cog-11 = Alzheimer’s Disease Assessment Scale–Cognitive Subscale-11 items; ADAS-Cog-12 = Alzheimer’s Disease Assessment Scale–Cognitive Subscale-12 items; ADAS-Cog-13 = Alzheimer’s Disease Assessment Scale–Cognitive Subscale-13 items; ADAS-Cog-14 = Alzheimer’s Disease Assessment Scale–Cognitive Subscale-14 items; ADCOMS = Alzheimer’s Disease Composite Score; ADCS-ADL = Alzheimer’s Disease Cooperative Study–Activities of Daily Living; ADCS-ADL-MCI = ADCS-ADL for patients with Mild Cognitive Impairment; CDR-SB = Clinical Dementia Rating–Sum of Boxes scale; DAD = Disability Assessment for Dementia; iADRS = integrated Alzheimer’s Disease Rating Scale; MCID = minimal clinically important difference; MMSE = Mini Mental State Examination; NPI = neuropsychological inventory; SD = standardized difference.

    • ↵a By extension from study of the ADAS-Cog-11.

    • ↵b Estimated as 7% of the total range for the score.

    • ↵c Percentages (not points).

  • Table 2.

    Characteristics of the 19 Included Studies

    Study and YearSubstudyaDrug and DosingDuration, MosDisease SeverityTreatment Group, No.Placebo Group, No.Age, Mean, Y
    Budd Haeberlein et al,1 2022ENGAGE and EMERGEAducanumab 3 mg/kg q 4 wks18MCI or mild AD (MMSE score ≥24)1,0821,07670.4
    Aducanumab 6 mg/kg q 4 wks1,0961,076
    Salloway et al,25 2009Bapineuzumab 0.15 mg/kg q 3 mos18Mild to moderate AD (MMSE score 16-26)              31              2669.1
    Bapineuzumab 0.5 mg/kg q 3 mos              33              28
    Bapineuzumab 1.0 mg/kg q 3 mos              29              26
    Bapineuzumab 2.0 mg/kg q 3 mos              29              27
    Salloway et al,29 2014Study 301 APOE(−)Bapineuzumab 0.5 mg/kg q 3 mos18Mild to moderate AD (MMSE score 16-26)            314            49372.5
    Bapineuzumab 1.0 mg/kg q 3 mos            307            493
    Bapineuzumab 2.0 mg/kg q 3 mos            141            493
    Study 302 APOE(+)Bapineuzumab 0.5 mg/kg q 3 mos            658            432
    Lacey et al,44 2015Study 301 APOE(−)Bapineuzumab 0.5 or 1.0 mg/kg q 3 mos18Mild to moderate AD (MMSE score 16-26)            621            49372.5
    Study 302 APOE(+)Bapineuzumab 0.5 mg/kg q 3 mos            658            43272.2
    Vandenberghe et al,45 2016APOE(−)Bapineuzumab 0.5 mg/kg q 3 mos18Mild to moderate AD (MMSE score 16-26)            267            34470.5
    Bapineuzumab 1.0 mg/kg q 3 mos            263            344
    APOE(+)Bapineuzumab 0.5 mg/kg q 3 mos18Mild to moderate AD (MMSE score 16-26)            654            439
    Brashear et al,41 2018Study 301 APOE(−)Bapineuzumab, 0.5 mg/kg q 3 mos19Mild to moderate AD (MMSE score 16-26)            337            52472-74
    Bapineuzumab, 1 mg/kg q 3 mos            329            524
    Bapineuzumab, 2 mg/kg q 3 mos            141            524
    Study 302 APOE(+)Bapineuzumab, 0.5 mg/kg q 3 mos            673            448
    Cummings et al,46 2018Crenezumab 15 mg/kg q 4 wks17Mild to moderate AD (MMSE score 18-26)            165              8270.6
    Crenezumab 300 mg q 2 wks            122              62
    Ostrowitzki et al,26 2022CREAD and CREAD2Crenezumab 60 mg/kg q 4 wks24Prodromal or mild AD (MMSE score ≥22)            808            80370.7
    Mintun et al,47 2021TRAILBLAZER-ALZDonanemab 700 mg × 3 then 1,400 mg q 4 wks19Early or mild AD            131            12675.2
    Sims et al,42 2023TRAILBLAZER-ALZ 2Donanemab 700 mg × 3 then 1,400 mg q 4 wks18MCI or mild AD            860            87674
    Ostrowitzki et al,48 2017Gantenerumab 105 mg q 4 wks24Mild AD (MMSE score ≥24)            271            26670.4
    Gantenerumab 225 mg q 4 wks            260            266
    Salloway et al,49 2021Gantenerumab 225 mg then 1,200 mg q 4 wks24Normal but at elevated risk or early AD              52              4043.8
    Swanson et al,18 2021Lecanemab 10 mg/kg biweekly18MCI or mild AD            152            23772b
    Lecanemab 10 mg/kg monthly            253            245
    Van Dyck et al,17 2023Lecanemab 10 mg/kg biweekly18MCI or mild AD            859            87571.2
    Landen et al, 50 2017Cohort MPonezumab 10 mg/kg then 7.5 mg/kg q month18Probable AD              12                667.8
    Cohort QPonezumab 10 mg/kg q 3 mos              12                6
    Doody et al,27 2014EXPEDITION 1Solanezumab 400 mg q 4 wks18Mild to moderate AD (MMSE score 16-26)            506            50674.7
    EXPEDITION 2Solanezumab 400 mg q 4 wks            521            51972.5
    Farlow et al,36 2012Solanezumab 100 mg q 4 wks12Mild to moderate AD (MMSE score 15-26)              10              10NR
    Solanezumab 100 mg weekly              11              10
    Solanezumab 400 mg q 4 wks              10              10
    Solanezumab 400 mg weekly              11              10
    Honig et al,51 2018Solanezumab 400 mg q 4 wks18Mild AD (MMSE score 20-26)1,0571,07273.0
    Sperling et al,43 2023Solanezumab 1,600 mg q 4 wks54Normal cognition with amyloid deposition            564            58372

    • AD = Alzheimer disease; APOE = apolipoprotein E; APOE(+) = carriers of the ApoE mutation; APOE(−) = noncarriers of the ApoE mutation; MCI = mild cognitive impairment; MMSE = Mini Mental State Examination (score range is 0-30); NR = not reported.

    • ↵a Shown where a study had an identifiable name or subgroup other than by dose.

    • ↵b Median.

  • Table 3.

    Study Quality Assessment Using the Cochrane Risk of Bias Tool19

    Study and YearSequence GenerationAllocation ConcealmentBlinding of Personnel and PatientsBlinding of Outcome AssessorsIncomplete Outcome Data (% Missing)Selective Outcome ReportingOther Sources of BiasOverall Risk of Bias
    Brashear et al,41 2018LowLowLowLowLow (0.4)LowLowLow
    Budd Haeberlein et al,1 2022LowLowLowLowLow (0.6)LowLowLow
    Cummings et al,46 2018LowLowLowLowHigh (26)LowLowHigh
    Doody et al,27 2014LowLowLowLowHigh (24.7)LowLowHigh
    Farlow et al,36 2012LowUnclearLowLowLow (4)LowLowUnclear
    Honig et al,51 2018LowUnclearLowLowHigh (14)LowLowHigh
    Lacey et al,44 2015LowLowLowLowHigh (29)LowLowHigh
    Landen et al,50 2017LowUnclearLowLowLow (5.5)LowLowUnclear
    Mintun et al,47 2021LowLowLowLowHigh (32)LowLowHigh
    Ostrowitzki et al,48 2017LowLowLowLowHigh (53.8)LowLowHigh
    Ostrowitzki et al,26 2022LowLowLowLowLow (7)LowLowLow
    Salloway et al,25 2009LowLowLowLowHigh (23.5)LowLowHigh
    Salloway et al,29 2014LowLowLowLowHigh (29)LowLowHigh
    Salloway et al,49 2021LowUnclearLowLowLow (6)LowLowUnclear
    Sims et al,42 2023LowLowLowLowHigh (24)LowLowHigh
    Sperling et al,43 2023LowLowLowLowHigh (28)LowLowHigh
    Swanson et al,18 2021LowUnclearLowLowLow (6.5)LowLowUnclear
    Van Dyck et al,17 2023LowLowLowLowHigh (17)LowLowHigh
    Vandenberghe et al,45 2016LowLowLowLowHigh (49)LowLowHigh

Additional Files

Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Get Permissions

Jump to section

Subjects

Keywords