Effect of reduction in brain amyloid levels on change in cognitive and functional decline in randomized clinical trials: an updated instrumental variable meta-analysis

Objective To update a recently published analysis exploring the causal association between positron emission tomography (PET)-measured change in brain β-amyloid plaque and cognitive decline in patients with Alzheimer’s disease (AD) enrolled in randomized clinical trials (RCTs). Design Updated instrumental variable meta-analysis. Setting Sixteen RCTs were included in this updated meta-analysis versus 14 in the original publication by Ackley et al .[1][1] Data sources were ClinicalTrials.org, Alzheimer Research Forum ([alzforum.org][2]), PubMed and clinical study reports from 2015 to March 1, 2022. Three researchers extracted data from the data sources independently and subsequently resolved any discrepancy. Population RCTs that evaluated β-amyloid targeting therapies and enrolled adult patients with AD dementia or mild cognitive impairment due to AD with data on β-amyloid as measured by PET and clinical outcome measures. Main outcome measures An instrumental variable meta-analysis was performed to compute trial and drug-specific estimates and pooled estimates of the effect of change in PET β-amyloid standard uptake value ratio (SUVR) on cognitive and functional decline with 95% confidence intervals (CIs) and associated p-values. This analysis updated and expanded a prior meta-analysis by Ackley et al .[1][1] using the same methodology and clinical outcome measures: Clinical Dementia Rating–Sum of Boxes (CDR-SB), Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog), and Mini-Mental State Examination (MMSE). Results The reduction of PET-measured β-amyloid induced a statistically significant reduction in cognitive and functional decline. The effect size was characterized by an estimated change (95% CI) of 0.09 (0.034, 0.15) on the CDR-SB; 0.33 (0.12, 0.55) on the ADAS-Cog; and 0.13 (0.017, 0.24) on the MMSE for each decrease of 0.1-unit in PET β-amyloid SUVR. Conclusion This updated instrumental variable meta-analysis of 16 RCTs provides statistically significant evidence of a causal relationship between the reduction in brain β-amyloid plaque and the reduction in cognitive and functional decline in patients with Alzheimer’s disease. ### Competing Interest Statement Changyu Shen, Menglan Pang, Ling Zhu, Audrey Gabelle, Arie Gafson, Ivana Rubino, Shibeshih Belachew and Carl de Moor are employees and shareholders of Biogen inc. Jim E. Galvin MD, MPH is a Professor of Neurology at University of Miami, consultant for Biogen, Alpha Cognition, Eisai, and Cognivue, and has research funding from NIH, and clinical income from patient care. Robert W. Platt, PhD, has an ongoing consulting arrangement with Biogen. ### Funding Statement This work was funded by Biogen. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript [1]: #ref-1 [2]: http://alzforum.org