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Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis

BMJ 2021; 372 doi: https://doi.org/10.1136/bmj.n156 (Published 25 February 2021) Cite this as: BMJ 2021;372:n156

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Instrumental variable meta-analysis of aggregated randomized drug trial data for evaluating proposed target mechanisms

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Re: Effect of reductions in amyloid levels on cognitive change in randomized trials: instrumental variable meta-analysis. Failed anti-amyloid trials raise scientific and ethical questions

Dear Editor

The important report by Ackley et al. has major implications. The authors found no significant effect on cognition of lowering brain beta-amyloid levels in Alzheimer’s disease in 14 clinical trials on a total of 4,596 patients. After a significant reduction in brain beta-amyloid, there was a non-significant change of 0.03 [95% CI ─0.06 to 0.1] points in the MMSE. The MMSE (maximum 30 points) declines by about 0.13 points per year in the community elderly[1], although it declines more rapidly in those with cognitive impairment or dementia.

Considering these results, scientists should question seriously the validity of the basic amyloid hypothesis, as was pointed out more than 10 years ago in relation to earlier trials[2]. The findings should also direct our attention to the prevention of Alzheimer’s disease by slowing down the disease process, for which there are many possible approaches[3-5].

The result also raises an ethical question: is it justifiable to ask patients to undergo yet more trials of anti-amyloid treatments? Finally, we should all question the morality of the drug companies in declining to give these researchers access to data for 20 out of the 34 trials they wanted to study.

1. Clarke R, Birks J, Nexo E, et al. Low vitamin B-12 status and risk of cognitive decline in older adults. Am J Clin Nutr 2007;86(5):1384-91.
2. Smith AD. Why are drug trials in Alzheimer's disease failing? Lancet 2010;376(9751):1466.
3. Smith AD, Yaffe K. Dementia (including Alzheimer's Disease) can be prevented: Statement supported by international experts. J Alzheimers Dis 2014;38(4):699-703.
4. Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 2020;396(10248):413-46.
5. Yu JT, Xu W, Tan CC, et al. Evidence-based prevention of Alzheimer's disease: systematic review and meta-analysis of 243 observational prospective studies and 153 randomised controlled trials. J Neurol Neurosurg Psychiatry 2020;91:1201-09.

Competing interests: No competing interests

10 March 2021
A. David Smith, FMedSci
Professor Emeritus
University of Oxford
Department of Pharmacology, Mansfield Rd. Oxford OX1 3QT