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

Abstract

PURPOSE We conducted a meta-analysis to evaluate clinically meaningful benefits and harms of monoclonal antibodies targeting amyloid in patients with Alzheimer dementia.

METHODS We searched PubMed, Cochrane CENTRAL, and 5 trial registries, as well as the reference lists of identified studies. We included randomized controlled trials comparing a monoclonal antibody with placebo at a dose consistent with that used in phase 3 trials or for Food and Drug Administration approval. Studies had to report at least 1 clinically relevant benefit or harm. Data were extracted independently by at least 2 researchers for random effects meta-analysis. Changes in cognitive and functional scales were compared between groups, and each difference was assessed to determine if it met the minimal clinically important difference (MCID).

RESULTS We identified 19 publications with 23,202 total participants that evaluated 8 anti-amyloid antibodies. There were small improvements over placebo in the Alzheimer’s Disease Assessment Scale (ADAS)-Cog-11 to -14 score (standardized mean difference = −0.07; 95% CI, −0.10 to −0.04), Mini Mental State Examination score (0.32 points; 95% CI, 0.13 to 0.50), and Clinical Dementia Rating-Sum of Boxes scale score (mean difference =−0.18 points; 95% CI, −0.34 to −0.03), and the combined functional scores (standardized mean difference = 0.09; 95% CI, 0.05 to 0.13). None of the changes, including those for lecanemab, aducanumab, and donanemab, exceeded the MCID. Harms included significantly increased risks of amyloid-related imaging abnormalities (ARIA)-edema (relative risk [RR] = 10.29; number needed to harm [NNH] = 9), ARIA-hemorrhage (RR = 1.74; NNH = 13), and symptomatic ARIA-edema (RR = 24.3; NNH = 86).

CONCLUSIONS Although monoclonal antibodies targeting amyloid provide small benefits on cognitive and functional scales in patients with Alzheimer dementia, these improvements are far below the MCID for each outcome and are accompanied by clinically meaningful harms.

Key words:

INTRODUCTION

The hypothesis that amyloid deposition is part of the causal pathway in the pathogenesis of Alzheimer dementia has led to the development of monoclonal antibodies to reduce this deposition.1,2 In fact, the primary justification for approval of these drugs by the Food and Drug Administration (FDA) is reduced amyloid deposition in the brain.3,4 Their approval despite their failure to provide a clinically significant improvement in cognitive and functional outcomes has resulted in substantial controversy,3-6 including charges of research misconduct in some of the original studies.7

Surrogate outcomes often do not correspond to improvements in patient-oriented outcomes such as reduced mortality or morbidity. For example, 3 large trials in patients with diabetes found that a lower glycated hemoglobin target of 6.5% either did not reduce or increased mortality compared with standard targets of 7.0% to 8.0%.8-10 A clear focus on patient-oriented benefits and harms is thus central to evidence-based practice.11,12 A recent systematic review concluded that patients with dementia most value quality of life, self-efficacy, and avoidance of depression.13

Previous systematic reviews have evaluated the efficacy and harms of monoclonal antibodies targeting amyloid.14-16 These reviews were, however, unable to include several recent studies that were critical to drug approval. The reviews also in some cases included phase 1 and 2 trials that used different doses from those used in later trials, and did not interpret the findings in the context of the minimal clinically important difference (MCID) for each outcome.

Recently, the monoclonal antibodies lecanemab and aducanumab were studied in large randomized controlled trials that found substantial reductions in amyloid deposition but only modest improvements in cognition and function.1,17,18 Significant harms were observed, including symptomatic amyloid-related imaging abnormalities of edema (ARIA-E) and hemorrhage (ARIA-H). We set out to perform a meta-analysis of all randomized controlled trials comparing an anti-amyloid monoclonal antibody with placebo. Our sole focus was on patient-oriented outcomes, which we defined as improved cognition and/or function attaining at least the MCID for each scale, and potentially serious harms such as cerebral edema, hemorrhage, serious adverse events, and mortality.

METHODS

Our protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) as protocol CRD42023392698. The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 statement for reporting systematic reviews (Supplemental Appendix 1).

Inclusion and Exclusion Criteria

We included randomized controlled trials that compared a monoclonal antibody intended to decrease the amount of brain amyloid with placebo. All trials had to enroll adults with cognitive impairment, Alzheimer disease of any severity, or high risk for Alzheimer disease, and had to report at least 1 patient-oriented benefit or harm after a minimum of 1 year. There were no limits by year or language. We excluded trials reporting the results of only a single infusion and phase 1 trials, as well as trials or trial arms using doses lower than those used in phase 3 trials or ultimately approved by the FDA.

Search Strategy

Our PubMed search strategy included terms for each monoclonal antibody identified through a preliminary search of the literature as well as general free text and Medical Subject Heading (MeSH) terms for monoclonal antibodies (Supplemental Appendix 2). We also searched the Cochrane CENTRAL Trials Register, ClinicalTrials.gov, and 4 other clinical trial registries (www.vivli.org, www.clinicalstudydatarequest.com, www.isrctn.com, and yoda.yale.edu). The reference lists of identified studies were also reviewed.

Data Abstraction and Quality Assessment

Titles and abstracts were reviewed in parallel by 2 researchers, at least 1 of whom was a physician. Any study identified as potentially relevant by at least 1 researcher was selected for full text review. Full text review was performed in parallel, again with at least 1 physician researcher for each study, to identify studies meeting our inclusion and exclusion criteria.

Abstraction of study characteristics, assessment of study quality, and abstraction of outcome data were done in parallel by 2 researchers, 1 of whom was a physician. The second physician helped resolve any discrepancies between the first 2 reviewers. The quality assessment used the Cochrane Risk of Bias Tool.19 Details regarding the data preparation for 2 studies requiring slight modifications are given in Supplemental Appendix 2.

Analysis

We performed a random effects meta-analysis of each outcome using the metan procedure in Stata version 17 (StataCorp LLC). For dichotomous outcomes, we calculated relative risks (RRs), 95% CIs, and where relevant, the number needed to treat (NNT) or number needed to harm (NNH). For continuous outcomes, we calculated the mean difference (MD) or when combining similar continuous scales but with different ranges (eg, the Alzheimer’s Disease Assessment Scale Cognitive Subscale-11 items through -14 items [ADAS-Cog-11 through ADAS-Cog-14]), we used the Cohen procedure for calculating summary estimates of the standardized mean difference (SMD).

Forest plots were created for each outcome. Heterogeneity was measured using the I2 statistic.20 Publication bias was assessed using funnel plots for key outcomes using all available studies.

MCID Determination

The MCID is the smallest change in a scale measuring cognition or function that is noticeable by the patient or their caregiver. Jaeschke and colleagues21 estimate that for a 7-point scale, a change of 0.5 points (7% of the range) represents the MCID, with changes of 11.5% to 13.7% representing a moderate effect and 12.3% to 21.0% representing a large change. We determined from the literature the MCID for each scale used in 2 or more studies. Where there was no published MCID, we used 7% of the full range of the scale, for example, a change of at least 1.4 points on a 20-point scale. For SMDs, previous research has concluded that a standardized difference of 0.5 should be considered the MCID.22,23 The range and MCID for each scale are shown in Table 1.

View this table:
Table 1.

Cognitive Scoring Tools and Their MCIDs

RESULTS

Search Results

The results of our literature search are summarized in Supplemental Figure 1 and Supplemental Table 1. We identified 87 studies from PubMed and 71 from other sources, of which 16 were duplicates. A total of 142 records were screened and 41 underwent full text review. We excluded some studies that initially appeared promising but used subtherapeutic doses,34 studied an anti-Tau antibody,35 or were phase 1 studies.36-40 Two studies reported data regarding ARIA-E outcomes for the same pair of phase 3 trials29,41; we used the information from the more detailed report.41 Just before submitting the revised manuscript we added 2 recently published studies that met our criteria.42,43 Ultimately, we included 19 studies with 23,202 participants evaluating 8 anti-amyloid antibodies.

Study Characteristics

Characteristics of the 19 included studies are summarized in Table 2. All studies were industry-funded, placebo-controlled randomized trials. Most were 18 to 19 months in duration, and enrolled patients with mild cognitive impairment or with mild or moderate Alzheimer disease.

View this table:
Table 2.

Characteristics of the 19 Included Studies

Risk of Bias Assessment

The risk of bias assessment for each study is summarized in Table 3. Twelve studies were at high risk for bias because of a lack of complete outcome data (>10% missing). Four studies were at unclear risk for bias because of uncertainty about allocation concealment. The remaining 3 studies were at low risk for bias.

View this table:
Table 3.

Study Quality Assessment Using the Cochrane Risk of Bias Tool19

Potential Benefits

Forest plots of the summary estimates of the SMD for the combined ADAS-Cog-11 through -14 cognitive scores are shown in Figure 1 (individual forest plots for each scale are shown in Supplemental Figures 2-5). The overall improvement with anti-amyloid antibodies over placebo was small (SMD = −0.07; 95% CI, −0.10 to −0.04). Statistically significant improvements in one of these cognitive scores were seen for solanezumab (SMD = 0.07; 95% CI, −0.12 to −0.02), aducanumab (SMD = −0.11; 95% CI, −0.19 to −0.02), and lecanemab (SMD = −0.11; 95% CI, −0.19 to −0.02). For the 2 FDA-approved antibodies, the MD for lecanemab (−1.8 points; 95% CI, −3.1 to −0.52 points) did not exceed the MCID of 4 to 5 points for the ADAS-Cog-14 and the MD for aducanumab (−0.98 points; 95% CI, −1.77 to −0.18 points) did not exceed the MCID for the ADAS-Cog-13 of 3.75 points.24 For donanemab, which is pending FDA approval, the unstandardized MD for change in the ADAS-Cog-13 score was −1.41 points (95% CI, −2.11 to −0.70).

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.

Results for the Mini Mental State Examination (MMSE) cognitive score are shown in Figure 2. The score was improved relative to placebo for all of the anti-amyloid antibodies combined by 0.32 points (95% CI, 0.13 to 0.50). The MMSE was improved by a statistically significant extent but not by a clinically significant extent for solanezumab (MD = 0.53 points; 95% CI, 0.15 to 0.80). For the FDA-approved drugs, the MMSE was not significantly better with aducanumab (MD = 0.25 points; 95% CI, −0.44 to 0.93), while there was a statistically significant benefit for donanemab (MD = 0.49 points; 95% CI, 0.14 to 0.83). None of these improvements exceeded the MCID for the MMSE of 1 to 3 points, however.30

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.

The Clinical Dementia Rating–Sum of Boxes scale (CDR-SB) is a combined cognitive and functional scale with an MCID of 1 to 2 points (Figure 3). Overall, the CDR-SB was improved slightly with the anti-amyloid antibodies compared with placebo (MD = −0.18 points; 95% CI, −0.34 to −0.03). The only individual antibodies with a statistically significant improvement in the CDR-SB were lecanemab (MD = −0.43 points; 95% CI, −0.78 to −0.07) and donanemab (MD = −0.59 points; 95% CI, −0.86 to −0.33). Neither of these differences exceeded the MCID for the CDR-SB of 1 to 2 points, however.30

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.

A forest plot of the summary estimates of the SMDs for the 3 functional scales—the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scale, the Alzheimer’s Disease Cooperative Study–Activities of Daily Living scale for patients with Mild Cognitive Impairment (ADCS-ADL-MCI) scale, and the Disability Assessment for Dementia (DAD)—is shown in Supplemental Figure 6 (forest plots for each scale separately are shown in Supplemental Figures 7-9). Overall, there was a statistically significant improvement in the combined functional scores with the anti-amyloid antibodies compared with placebo (SMD = 0.09; 95% CI, 0.05 to 0.13). Scores were also improved for aducanumab (SMD = 0.14; 95% CI, 0.06 to 0.23) and lecanemab (SMD = 0.19; 95% CI, 0.09 to 0.28) individually. None of these changes exceeded the MCID of 0.5 standardized differences, however.22,23 Forest plots of the summary estimates of the SMDs for the Dependence Scale and for the Neuropsychological Test Battery scale are shown in Supplemental Figure 10 and Supplemental Figure 11, respectively.

None of the studies reported other clinically important outcomes such as functional dependence, placement in memory care units or nursing homes, caregiver burden, or development of aggressive behaviors.

Potential Harms

Overall, there was no significant difference between treatment and control groups with regard to all-cause mortality, as shown in Supplemental Figure 12 (RR = 1.15; 95% CI, 0.85 to 1.56). One drug, bapineuzumab, was associated with a significant increase in mortality (RR = 1.76; 95% CI, 1.03 to 3.00; NNH = 102). There was no significant difference between treatment and control groups in serious adverse events, shown in Supplemental Figure 13 (RR = 1.02; 95% CI, 0.92 to 1.12).

The most frequently reported harms were ARIA-E, symptomatic ARIA-E, and ARIA-H. Those are summarized in the forest plot in Figure 4 (forest plots stratified by drug for each harm are shown in Supplemental Figures 14-16).

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.

Development of any ARIA-H was significantly more common overall in patients given an anti-amyloid antibody (RR = 1.74; 95% CI, 1.24 to 2.44; NNH = 13). This outcome was also significantly more likely for the 2 FDA-approved drugs, lecanemab (RR = 2.33; 95% CI, 1.44 to 3.77; NNH = 9) and aducanumab (RR = 2.94; 95% CI, 2.27 to 3.79; NNH = 8), as well as for donanemab (RR = 2.31; 95% CI, 1.90 to 2.80), than for the other antibodies.

Any ARIA-E was also significantly more common overall in treated patients (RR = 10.29; 95% CI, 7.40 to 14.3; NNH = 9). This was also true for the 2 FDA-approved drugs, aducanumab (RR = 13.1; 95% CI, 9.0 to 18.9; NNH = 3) and lecanemab (RR = 8.1; 95% CI, 4.92 to 13.3; NNH = 9), as well as for donanemab (RR = 6.5; 95% CI, 1.98 to 21.4; NNH = 7).

Finally, symptomatic ARIA-E was distinguished from any ARIA-E in some studies. Although the overall RR was significantly increased for the 3 drugs for which this outcome was reported, the absolute increase was modest (RR = 24.3; 95% CI, 9.9 to 59.9; NNH = 86). It was significantly increased for the FDA-approved drug lecanemab (RR = 52; 95% CI, 3.2 to 852; NNH = 34) and for donanemab (RR = 20.7; 95% CI, 3.1 to 138; NNH = 25), although with broad CIs.

Assessment of Heterogeneity and Publication Bias

Heterogeneity across the studies was generally low, with a few exceptions. The 2 studies of aducanumab had substantial heterogeneity for CDR-SB scores (I2 = 71%) and MMSE scores (I2 = 63%), as well as for ADCS-ADL-MCI functional scale scores (I2 = 56%). Lecanemab had moderate heterogeneity with respect to the ADAS-Cog-14 score (I2 = 47%). Overall there was significant heterogeneity for the outcome of ARIA-H (I2 = 89%), with summary estimates of the relative risk for different drugs ranging from 0.82 (ponezumab) to 2.94 (aducanumab).

Funnel plots for key benefit outcomes (ADAS-Cog-11 to -14, CDR-SB, and MMSE scores) and harm outcomes (ARIA-E and ARIA-H) are shown in Supplemental Figures 17-21. These plots show no evidence of publication bias.

DISCUSSION

We identified 19 reports of 24 studies of monoclonal antibodies targeting amyloid depositions in patients who largely had mild cognitive impairment and mild Alzheimer disease. In no case did the results of any single study, of all combined studies for an individual drug, or of all combined studies overall find a change in cognition or function that exceeded the MCID for that scale. This was also true for lecanemab and aducanumab, the only 2 FDA-approved drugs, and for donanemab, which is pending approval. For their primary outcome of the CDR-SB (MCID = 1 to 2 points),30 the studies found an improvement over placebo of only 0.43 points for lecanemab, 0.18 points for aducanumab, and 0.59 points for donanemab after 18 months of treatment.

We did find, however, that these drugs consistently cause statistically significant and potentially clinically significant increases in harms. The NNH was 13 for any ARIA-H, 9 for any ARIA-E, and 86 for symptomatic ARIA-E. The cost of these drugs is also substantial ($26,500 to $28,200 per year), and the requirement for regular magnetic resonance imaging monitoring adds considerable cost and inconvenience.

Some might argue that a longer study would find a clinically meaningful difference, but the changes we documented were so much lower than the MCIDs that this seems unlikely. For example, the improvement over placebo for the CDR-SB with lecanemab was 0.43 points after 18 months. The MCID for this scale is 1 to 2 points, so assuming a linear improvement in CDR-SB over time, it would take 3 years to get to 0.86 points and 6 years to reach 1.72 points. For aducanumab, with its improvement of only 0.18 points, it would take more than 5 years to reach even a 1-point change, again assuming linearity of effect.

It is possible that treatment earlier in the course of disease would be more beneficial. Indeed, all of the drugs approved or pending approval (lecanemab, aducanumab, and donanemab) were primarily studied in patients with mild cognitive impairment or mild Alzheimer disease, whereas most other drugs were studied in patients with mild to moderate dementia. As noted above, though, none of these drugs achieved the MCID for any benefit outcome. Also, a recent 4.5-year randomized trial of solanezumab in patients even earlier in the clinical pathway (having amyloid deposition but normal cognition) found no benefit at all.43

The FDA has previously argued that decisions about drug approvals should be based on the MCID. Lecanemab and aducanumab, however, were both approved based primarily on their effect on imaging and biomarkers, without any meaningful improvement in clinical outcomes. We feel that this is inappropriate and sets a bad precedent for the agency, not only for Alzheimer disease but also for other conditions wherein intermediate markers are easily measured but may not reliably predict clinical outcomes.

Our analysis had several limitations. All studies enrolled participants who underwent positron emission tomography scanning and/or cerebrospinal fluid analyses for amyloid, studies that are not typically done in current routine clinical practice. The included studies reported average changes on standard cognitive and functional scales, but did not report the percentage of participants achieving clinically meaningful differences in cognition or function from baseline. Such data would be more interpretable for clinicians and patients. Finally, studies had different inclusion criteria for severity of disease at baseline, which is a source of potential heterogeneity.

At best, anti-amyloid monoclonal antibodies, including those approved by the FDA, slightly slow the rate of progression of the dementia. Cognitive enhancers (donepezil, rivastigmine, galantamine, and memantine) also slow the rate of cognitive decline.52,53 Although these older drugs, as monotherapy, do not provide a benefit that exceeds the MCID, at least their safety and cost are much better than those of the newer agents. To our knowledge, no head-to-head comparisons exist, and a search of ClinicalTrials.gov performed February 2, 2023 failed to identify any planned clinical trials comparing cholinesterase inhibitors and anti-amyloid antibodies in adults with dementia.

CONCLUSION

Alzheimer disease causes tremendous suffering in those afflicted, serious burdens to their families and caregivers, and enormous costs to the health care system. Each of these groups hope for effective tools to alleviate these burdens and to extend the time of meaningful life. But our meta-analysis shows that monoclonal antibodies targeting amyloid do not provide a clinically meaningful benefit, are associated with significant harms, and come at a high cost.

Footnotes

  • Conflicts of interest: authors report none.

  • Read or post commentaries in response to this article.

  • Data sharing statement: The authors will make the spreadsheet containing the primary data, along with a data dictionary, available to other researchers who request it. Anyone using the data for further publications should involve the authors in that publication.

  • Supplemental materials

  • Received for publication May 4, 2023.
  • Revision received September 20, 2023.
  • Accepted for publication September 21, 2023.

References

  1. 1.↵
    1. Budd Haeberlein S,
    2. Aisen PS,
    3. Barkhof F, et al.
    Two randomized phase 3 studies of aducanumab in early Alzheimer’s disease. J Prev Alzheimers Dis. 2022; 9(2): 197-210. doi:10.14283/jpad.2022.30
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Chiao P,
    2. Bedell BJ,
    3. Avants B, et al.
    Impact of reference and target region selection on amyloid PET SUV ratios in the phase 1b PRIME study of aducanumab. J Nucl Med. 2019; 60(1): 100-106. doi:10.2967/jnumed.118.209130
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    1. Alexander GC,
    2. Knopman DS,
    3. Emerson SS, et al.
    Revisiting FDA approval of aducanumab. N Engl J Med. 2021; 385(9): 769-771. doi:10.1056/NEJMp2110468
    OpenUrlCrossRef
  4. 4.↵
    1. US Food and Drug Administration
    . FDA’s decision to approve new treatment for Alzheimer’s disease. Published 2021. Accessed Dec 14, 2023. https://www.fda.gov/drugs/our-perspective/fdas-decision-approve-new-treatment-alzheimers-disease
  5. 5.
    1. Karlawish J.
    Aducanumab and the business of Alzheimer disease-some choice. JAMA Neurol. 2021; 78(11): 1303-1304. doi:10.1001/jamaneurol.2021.3123
    OpenUrlCrossRef
  6. 6.↵
    1. Tampi RR,
    2. Forester BP,
    3. Agronin M.
    Aducanumab: evidence from clinical trial data and controversies. Drugs Context. 2021; 10(10): 2021-7-3. doi:10.7573/dic.2021-7-3
    OpenUrlCrossRef
  7. 7.↵
    1. Piller C.
    Blots on a field? Science. 2022; 377(6604): 358-363. doi:10.1126/science.add9993
    OpenUrlCrossRefPubMed
  8. 8.↵
    1. Ismail-Beigi F,
    2. Craven T,
    3. Banerji MA, et al; ACCORD trial group
    . Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010; 376(9739): 419-430. doi:10.1016/S0140-6736(10)60576-4
    OpenUrlCrossRefPubMed
  9. 9.
    1. Duckworth W,
    2. Abraira C,
    3. Moritz T, et al; VADT Investigators
    . Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009; 360(2): 129-139. doi:10.1056/NEJMoa0808431
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Gerstein HC,
    2. Miller ME,
    3. Byington RP, et al; Action to Control Cardiovascular Risk in Diabetes Study Group
    . Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008; 358(24): 2545-2559. doi:10.1056/NEJMoa0802743
    OpenUrlCrossRefPubMed
  11. 11.↵
    1. Slawson DC,
    2. Shaughnessy AF.
    Teaching evidence-based medicine: should we be teaching information management instead? Acad Med. 2005; 80(7): 685-689. doi:10.1097/00001888-200507000-00014
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Slawson DC,
    2. Shaughnessy AF,
    3. Bennett JH.
    Becoming a medical information master: feeling good about not knowing everything. J Fam Pract. 1994; 38(5): 505-513.
    OpenUrlPubMed
  13. 13.↵
    1. Lepper S,
    2. Rädke A,
    3. Wehrmann H,
    4. Michalowsky B,
    5. Hoffmann W.
    Preferences of cognitively impaired patients and patients living with dementia: a systematic review of quantitative patient preference studies. J Alzheimers Dis. 2020; 77(2): 885-901. doi:10.3233/JAD-191299
    OpenUrlAbstract/FREE Full Text
  14. 14.↵
    1. Avgerinos KI,
    2. Ferrucci L,
    3. Kapogiannis D.
    Effects of monoclonal antibodies against amyloid-β on clinical and biomarker outcomes and adverse event risks: a systematic review and meta-analysis of phase III RCTs in Alzheimer’s disease. Ageing Res Rev. 2021; 68: 101339. doi:10.1016/j.arr.2021.101339
    OpenUrlCrossRef
  15. 15.
    1. Lacorte E,
    2. Ancidoni A,
    3. Zaccaria V, et al.
    Safety and efficacy of monoclonal antibodies for Alzheimer’s disease: a systematic review and meta-analysis of published and unpublished clinical trials. J Alzheimers Dis. 2022; 87(1): 101-129. doi:10.3233/JAD-220046
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    1. Lu L,
    2. Zheng X,
    3. Wang S, et al.
    Anti-Aβ agents for mild to moderate Alzheimer’s disease: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2020; 91(12): 1316-1324. doi:10.1136/jnnp-2020-323497
    OpenUrlAbstract/FREE Full Text
  17. 17.↵
    1. van Dyck CH,
    2. Swanson CJ,
    3. Aisen P, et al.
    Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023; 388(1): 9-21. doi:10.1056/NEJMoa2212948
    OpenUrlCrossRefPubMed
  18. 18.↵
    1. Swanson CJ,
    2. Zhang Y,
    3. Dhadda S, et al.
    A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Aβ protofibril antibody. Alzheimers Res Ther. 2021; 13(1): 80. doi:10.1186/s13195-021-00813-8
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Higgins JPT,
    2. Altman DG,
    3. Gøtzsche PC, et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group
    . The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011; 343: d5928. doi:10.1136/bmj.d5928
    OpenUrlFREE Full Text
  20. 20.↵
    1. Higgins JP,
    2. Thompson SG.
    Quantifying heterogeneity in a meta-analysis. Stat Med. 2002; 21(11): 1539-1558. doi:10.1002/sim.1186
    OpenUrlCrossRefPubMed
  21. 21.↵
    1. Jaeschke R,
    2. Singer J,
    3. Guyatt GH.
    Measurement of health status; ascertaining the minimal clinically important difference. Control Clin Trials. 1989; 10(4): 407-415. doi:10.1016/0197-2456(89)90005-6
    OpenUrlCrossRefPubMed
  22. 22.↵
    1. Mouelhi Y,
    2. Jouve E,
    3. Castelli C,
    4. Gentile S.
    How is the minimal clinically important difference established in health-related quality of life instruments? Review of anchors and methods. Health Qual Life Outcomes. 2020; 18(1): 136. doi:10.1186/s12955-020-01344-w
    OpenUrlCrossRefPubMed
  23. 23.↵
    1. Norman GR,
    2. Sloan JA,
    3. Wyrwich KW.
    Interpretation of changes in health-related quality of life: the remarkable universality of half a standard deviation. Med Care. 2003; 41(5): 582-592. doi:10.1097/01.MLR.0000062554.74615.4C
    OpenUrlCrossRefPubMed
  24. 24.↵
    1. Schrag A,
    2. Schott JM; Alzheimer’s Disease Neuroimaging Initiative
    . What is the clinically relevant change on the ADAS-Cog? J Neurol Neurosurg Psychiatry. 2012; 83(2): 171-173. doi:10.1136/jnnp-2011-300881
    OpenUrlAbstract/FREE Full Text
  25. 25.
    1. Salloway S,
    2. Sperling R,
    3. Gilman S, et al; Bapineuzumab 201 Clinical Trial Investigators
    . A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009; 73(24): 2061-2070. doi:10.1212/WNL.0b013e3181c67808
    OpenUrlCrossRefPubMed
  26. 26.
    1. Ostrowitzki S,
    2. Bittner T,
    3. Sink KM, et al.
    Evaluating the safety and efficacy of crenezumab vs placebo in adults with early Alzheimer disease: two phase 3 randomized placebo-controlled trials. JAMA Neurol. 2022; 79(11): 1113-1121. doi:10.1001/jamaneurol.2022.2909
    OpenUrlCrossRef
  27. 27.
    1. Doody RS,
    2. Thomas RG,
    3. Farlow M, et al; Alzheimer’s Disease Cooperative Study Steering Committee; Solanezumab Study Group
    . Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014; 370(4): 311-321. doi:10.1056/NEJMoa1312889
    OpenUrlCrossRefPubMed
  28. 28.
    1. Wang J,
    2. Logovinsky V,
    3. Hendrix SB, et al.
    ADCOMS: a composite clinical outcome for prodromal Alzheimer’s disease trials. J Neurol Neurosurg Psychiatry. 2016; 87(9): 993-999. doi:10.1136/jnnp-2015-312383
    OpenUrlAbstract/FREE Full Text
  29. 29.↵
    1. Salloway S,
    2. Sperling R,
    3. Fox NC, et al; Bapineuzumab 301 and 302 Clinical Trial Investigators
    . Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med. 2014; 370(4): 322-333. doi:10.1056/NEJMoa1304839
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Andrews JS,
    2. Desai U,
    3. Kirson NY,
    4. Zichlin ML,
    5. Ball DE,
    6. Matthews BR.
    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. doi:10.1016/j.trci.2019.06.005
    OpenUrlCrossRef
  31. 31.
    1. Gélinas I,
    2. Gauthier L,
    3. McIntyre M,
    4. Gauthier S.
    Development of a functional measure for persons with Alzheimer’s disease: the disability assessment for dementia. Am J Occup Ther. 1999; 53(5): 471-481. doi:10.5014/ajot.53.5.471
    OpenUrlCrossRefPubMed
  32. 32.
    1. Howard R,
    2. Phillips P,
    3. Johnson T, et al.
    Determining the minimum clinically important differences for outcomes in the DOMINO trial. Int J Geriatr Psychiatry. 2011; 26(8): 812-817. doi:10.1002/gps.2607
    OpenUrlCrossRefPubMed
  33. 33.
    1. Zhu CW,
    2. Bruinsma BG,
    3. Stern Y.
    Utility of the Dependence Scale in dementia: validity, meaningfulness, and health economic considerations. Alzheimers Res Ther. 2018; 10(1): 78. doi:10.1186/s13195-018-0414-7
    OpenUrlCrossRef
  34. 34.↵
    1. Brody M,
    2. Liu E,
    3. Di J, et al.
    A phase II, randomized, double-blind, placebo-controlled study of safety, pharmacokinetics, and biomarker results of subcutaneous bapineuzumab in patients with mild to moderate Alzheimer’s disease. J Alzheimers Dis. 2016; 54(4): 1509-1519. doi:10.3233/JAD-160369
    OpenUrlCrossRef
  35. 35.↵
    1. Teng E,
    2. Manser PT,
    3. Pickthorn K, et al; Tauriel Investigators
    . Safety and efficacy of semorinemab in individuals with prodromal to mild Alzheimer disease: a randomized clinical trial. JAMA Neurol. 2022; 79(8): 758-767. doi:10.1001/jamaneurol.2022.1375
    OpenUrlCrossRef
  36. 36.↵
    1. Farlow M,
    2. Arnold SE,
    3. van Dyck CH, et al.
    Safety and biomarker effects of solanezumab in patients with Alzheimer’s disease. Alzheimers Dement. 2012; 8(4): 261-271. doi:10.1016/j.jalz.2011.09.224
    OpenUrlCrossRefPubMed
  37. 37.
    1. Guthrie H,
    2. Honig LS,
    3. Lin H, et al.
    Safety, tolerability, and pharmacokinetics of crenezumab in patients with mild-to-moderate Alzheimer’s disease treated with escalating doses for up to 133 weeks. J Alzheimers Dis. 2020; 76(3): 967-979. doi:10.3233/JAD-200134
    OpenUrlCrossRefPubMed
  38. 38.
    1. Arai H,
    2. Umemura K,
    3. Ichimiya Y, et al.
    Safety and pharmacokinetics of bapineuzumab in a single ascending-dose study in Japanese patients with mild to moderate Alzheimer’s disease. Geriatr Gerontol Int. 2016; 16(5): 644-650. doi:10.1111/ggi.12516
    OpenUrlCrossRef
  39. 39.
    1. Andreasen N,
    2. Simeoni M,
    3. Ostlund H, et al.
    First administration of the Fc-attenuated anti-β amyloid antibody GSK933776 to patients with mild Alzheimer’s disease: a randomized, placebo-controlled study. PLoS One. 2015; 10(3): e0098153. doi:10.1371/journal.pone.0098153
    OpenUrlCrossRefPubMed
  40. 40.↵
    1. Delnomdedieu M,
    2. Duvvuri S,
    3. Li DJ, et al.
    First-in-human safety and long-term exposure data for AAB-003 (PF-05236812) and biomarkers after intravenous infusions of escalating doses in patients with mild to moderate Alzheimer’s disease. Alzheimers Res Ther. 2016; 8(1): 12. doi:10.1186/s13195-016-0177-y
    OpenUrlCrossRef
  41. 41.↵
    1. Brashear HR,
    2. Ketter N,
    3. Bogert J,
    4. Di J,
    5. Salloway SP,
    6. Sperling R.
    Clinical evaluation of amyloid-related imaging abnormalities in bapineuzumab phase III studies. J Alzheimers Dis. 2018; 66(4): 1409-1424. doi:10.3233/JAD-180675
    OpenUrlCrossRefPubMed
  42. 42.↵
    1. Sims JR,
    2. Zimmer JA,
    3. Evans CD, et al; TRAILBLAZER-ALZ 2 Investigators
    . Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA. 2023; 330(6): 512-527. doi:10.1001/jama.2023.13239
    OpenUrlCrossRefPubMed
  43. 43.↵
    1. Sperling RA,
    2. Donohue MC,
    3. Raman R, et al; A4 Study Team
    . Trial of solanezumab in preclinical Alzheimer’s disease. N Engl J Med. 2023; 389(12): 1096-1107. doi:10.1056/NEJMoa2305032
    OpenUrlCrossRef
  44. 44.
    1. Lacey L,
    2. Bobula J,
    3. Rudell K,
    4. Alvir J,
    5. Leibman C.
    Quality of life and utility measurement in a large clinical trial sample of patients with mild to moderate Alzheimer’s disease: determinants and level of changes observed. Value Health. 2015; 18(5): 638-645. doi:10.1016/j.jval.2015.03.1787
    OpenUrlCrossRef
  45. 45.
    1. Vandenberghe R,
    2. Rinne JO,
    3. Boada M, et al.
    Bapineuzumab for mild to moderate Alzheimer’s disease in two global, randomized, phase 3 trials. Alzheimers Res Ther. 2016; 8(1): 95. doi:10.1186/s13195-016-0189-7
    OpenUrlCrossRef
  46. 46.
    1. Cummings JL,
    2. Cohen S,
    3. van Dyck CH, et al.
    ABBY: a phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. Neurology. 2018; 90(21): e1889-e1897. doi:10.1212/WNL.0000000000005550
    OpenUrlAbstract/FREE Full Text
  47. 47.
    1. Mintun MA,
    2. Lo AC,
    3. Duggan Evans C, et al.
    Donanemab in early Alzheimer’s disease. N Engl J Med. 2021; 384(18): 1691-1704. doi:10.1056/NEJMoa2100708
    OpenUrlCrossRefPubMed
  48. 48.
    1. Ostrowitzki S,
    2. Lasser RA,
    3. Dorflinger E, et al; Scarlet RoAD Investigators
    . A phase III randomized trial of gantenerumab in prodromal Alzheimer’s disease. Alzheimers Res Ther. 2017; 9(1): 95. doi:10.1186/s13195-017-0318-y
    OpenUrlCrossRefPubMed
  49. 49.
    1. Salloway S,
    2. Farlow M,
    3. McDade E, et al; Dominantly Inherited Alzheimer Network–Trials Unit
    . A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat Med. 2021; 27(7): 1187-1196. doi:10.1038/s41591-021-01369-8
    OpenUrlCrossRefPubMed
  50. 50.
    1. Landen JW,
    2. Andreasen N,
    3. Cronenberger CL, et al.
    Ponezumab in mild-to-moderate Alzheimer’s disease: randomized phase II PET-PIB study. Alzheimers Dement (N Y). 2017; 3(3): 393-401. doi:10.1016/j.trci.2017.05.003
    OpenUrlCrossRef
  51. 51.
    1. Honig LS,
    2. Vellas B,
    3. Woodward M, et al.
    Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med. 2018; 378(4): 321-330. doi:10.1056/NEJMoa1705971
    OpenUrlCrossRefPubMed
  52. 52.↵
    1. Veroniki AA,
    2. Ashoor HM,
    3. Rios P, 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(4): e053012. doi:10.1136/bmjopen-2021-053012
    OpenUrlAbstract/FREE Full Text
  53. 53.↵
    1. Takramah WK,
    2. Asem L.
    The efficacy of pharmacological interventions to improve cognitive and behavior symptoms in people with dementia: a systematic review and meta-analysis. Health Sci Rep. 2022; 5(6): e913. doi:10.1002/hsr2.913
    OpenUrlCrossRef
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