Effect of reduction in brain amyloid levels on change in cognitive and functional decline in randomized clinical trials: An instrumental variable meta-analysis.
Alzheimer's disease
amyloid
causal effect
clinical trials
cognitive decline
Journal
Alzheimer's & dementia : the journal of the Alzheimer's Association
ISSN: 1552-5279
Titre abrégé: Alzheimers Dement
Pays: United States
ID NLM: 101231978
Informations de publication
Date de publication:
04 2023
04 2023
Historique:
revised:
08
07
2022
received:
20
05
2022
accepted:
19
07
2022
medline:
17
4
2023
pubmed:
1
9
2022
entrez:
31
8
2022
Statut:
ppublish
Résumé
Whether the reduction in brain amyloid beta (Aβ) plaque alone may substantially slow cognitive and functional decline in patients with dementia or mild cognitive impairment due to Alzheimer's disease (AD) remains debated. An instrumental variable meta-analysis was performed to infer the effect of change in positron emission tomography (PET)-measured Aβ standardized uptake value ratio (SUVR) on cognitive and functional decline. Pooling data from 16 randomized trials demonstrates that each 0.1-unit decrease in PET Aβ SUVR is associated with a reduction (95% confidence interval) by 0.09 (0.034-0.15), 0.33 (0.12-0.55), and 0.13 (0.017-0.24) point in the average change of the Clinical Dementia Rating-Sum of Boxes, the Alzheimer's Disease Assessment Scale-Cognitive Subscale, and the Mini-Mental State Examination, respectively. This meta-analysis provides statistically significant evidence of a likely causal relationship between a reduction in Aβ plaque and a reduction in cognitive and functional decline in patients with AD. A widely cited meta-analysis article concluded amyloid beta reduction does not substantially improve cognition. We identified data inconsistencies in the initial publication and found new trial data. We repeated the meta-analysis after correcting data inconsistencies and adding new trial data. Updated results suggested statistically significant clinical benefit of amyloid beta reduction. Amyloid beta is a viable biological target for the treatment and prevention of AD.
Substances chimiques
Amyloid beta-Peptides
0
Amyloid
0
Types de publication
Meta-Analysis
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1292-1299Subventions
Organisme : NIA NIH HHS
ID : R01 AG071514
Pays : United States
Informations de copyright
© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
Références
Ackley SF, Zimmerman SC, Brenowitz WD, et al. Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis. BMJ. 2021;372:n156. doi: 10.1136/bmj.n156
Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA research framework: toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535-562.
Karran E, Mercken M, De Strooper B. The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011;10:698-712.
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement. 2011;7:263-269.
Jack CR Jr, Knopman DS, Jagust WJ, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol. 2010;9:119-128.
Karran E, De Strooper B. The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics. Nat Rev Drug Discov. 2022;21:306-318.
Thal DR, Rüb U, Orantes M, et al. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology. 2002;58:1791-1800.
Ingelsson M, Fukumoto H, Newell KL, et al. Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology. 2004;62:925-931.
Goate A, Chartier-Harlin MC, Mullan M, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991;349:704-706.
Karlawish J, Grill JD. The approval of Aduhelm risks eroding public trust in Alzheimer research and the FDA. Nat Rev Neurol. 2021;17:523-524.
Siemers ER, Sundell KL, Carlson C, et al. Phase 3 solanezumab trials: secondary outcomes in mild Alzheimer's disease patients. Alzheimers Dement. 2016;12:110-120.
Egan MF, Kost J, Voss T, et al. Randomized trial of verubecestat for prodromal Alzheimer's disease. N Engl J Med. 2019;380:1408-1420.
Sevigny J, Chiao P, Bussière T, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature. 2016;537:50-56.
Wessels AM, Lines C, Stern RA, et al. Cognitive outcomes in trials of two BACE inhibitors in Alzheimer's disease. Alzheimers Dement. 2020;16:1483-1492.
Navitsky M, Joshi AD, Kennedy I, et al. Standardization of amyloid quantitation with florbetapir standardized uptake value ratios to the Centiloid scale. Alzheimers Dement. 2018;14:1565-1571.
Eysenck HJ. Meta-analysis and its problems. BMJ. 1994;309:789-792.
Mangialasche F, Solomon A, Winblad B, et al. Alzheimer's disease: clinical trials and drug development. Lancet Neurol. 2010;9:702-716.
Farrell ME, Chen X, Rundle MM, et al. Regional amyloid accumulation and cognitive decline in initially amyloid-negative adults. Neurology. 2018;91:e1809-e1821.
Grothe MJ, Barthel H, Sepulcre J, et al. In vivo staging of regional amyloid deposition. Neurology. 2017;89:2031-2038.
Yeo JM, Waddell B, Khan Z, et al. A systematic review and meta-analysis of 18F-labeled amyloid imaging in Alzheimer's disease. Alzheimers Dement Diagn Assess Dis Monit. 2015;1:5-13.
Landau SM, Thomas BA, Thurfjell L, et al. Amyloid PET imaging in Alzheimer's disease: a comparison of three radiotracers. Eur J Nucl Med Mol Imaging. 2014;41(7):1398-1407.
Krishnadas N, Villemagne VL, Doré V, et al. Advances in brain amyloid imaging. Semin Nucl Med. 2021;51:241-252.
Cho SH, Choe YS, Kim YJ, et al. Head-to-head comparison of 18F-florbetaben and 18F-flutemetamol in the cortical and striatal regions. J Alzheimers Dis. 2020;76:281-290.
Wolk DA, Zhang Z, Boudhar S, et al. Amyloid imaging in Alzheimer's disease: comparison of florbetapir and Pittsburgh compound-B positron emission tomography. J Neurol Neurosurg Psychiatry. 2012;83:923-926.
Landau SM, Breault C, Joshi AD, et al. Amyloid-β imaging with Pittsburgh compound B and florbetapir: comparing radiotracers and quantification methods. J Nucl Med. 2013;54:70-77.