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New Alzheimer’s drug may not be magic bullet for all sufferers

Eli Lilly made world headlines a month ago when it was reported that its drug Donanemab slowed the progression of Alzheimer’s disease by up to 35%. But it is important to interpret these findings cautiously, write South Africa’s Morgan Watson, Jessica Henn and Professor John Joska in Daily Maverick.

The progressive decline seen in many patients with Alzheimer’s, the degenerative brain condition responsible for 60%-80% of all dementia cases in older people, is thought to be due to two key hallmarks.

Both involve proteins normally found in human brains: when protein production, distribution and removal go wrong, the disease state may arise.

Within the medical research world, supporters of the theories of the two-protein pathologies are colloquially referred to as the “Baptists” and the “Taoists”. The “Baptists” believe that beta-amyloid protein forms clumps or plaque in brain tissue, impairing normal nerve functioning. The “Taoists” hold that tau protein, found inside nerve cells, loses its structure, resulting in the formation of non-functional tangles.

With advancing age, both problems are not uncommonly found even in people with typical cognitive function. However, there appears to be a complex relationship between amyloid plaques and tau tangles that may lead to the clinical disease known since 1911 as Alzheimer’s disease.

Amyloid and tau have both been the focus of many clinical trials as prime targets for disease-modifying treatments. The main approach to amyloid plaque clearance in these trials has been through the administration of monoclonal antibodies; clones of your body’s antibodies that are made in a laboratory, meant to stimulate your immune system.

These antibodies are injected into the human study participants at regular intervals, and produce an immune response that labels the amyloid plaque as abnormal. The body then clears out the amyloid.

This process is, however, not without side effects. Previous antibody trials have met with a mixture of celebration (resulting in rushed US Food and Drug Administration approvals), and scepticism (leading to FDA member resignation due to the rushing of approvals).

Donanemab study

In a trial led by Dr Mark Mintun from Eli Lilly, in partnership with the Departments of Neurology, of Radiology and Imaging Sciences, and of Medical and Molecular Genetics and the Indiana Alzheimer Disease Centre, Indiana University School of Medicine, published in the New England Journal of Medicine in 2021, one such monoclonal antibody – Donanemab – was investigated.

Donanemab was developed from a mouse, and modified for use in humans. The discovery of this drug came with a lot of excitement as previous treatments have only been able to prevent the collection of new plaques, as opposed to clearing out old ones.

The Eli Lilly-sponsored trial took place in the US and Canada. Most of the current trials have taken place in high-income countries, and there is a recognition that cohorts from other settings are needed.

The group recruited 257 participants between 60 and 85. They were randomly assigned to either the intervention group (receiving Donanemab) or the placebo, a biologically inactive substance. While the trial generated excitement, it is important to approach the results with caution due to some limitations and nuanced findings.

In this particular study, researchers investigated whether Donanemab improved cognitive performance and daily functioning in people with Alzheimer’s. They used a widely accepted rating scale called the Integrated Alzheimer’s Disease Rating Scale (iADRS) and measured participants’ score at the start of the study and then again, just more than a year later.

Participants treated with Donanemab and placebo both scored 106 on the iADRS at the study’s start. It is important that all participants’ original scores or “baseline measures” are somewhat equal before starting the trial. This means the researchers can assume that any change thereafter is due to the intervention.

One expects that people with dementia will decline in both cognitive performance and activities of daily living over time. Therefore, a lower rate of decline in the treatment group would be a favourable outcome.

Considering this, the investigators did not set out to cure the participants of Alzheimer’s disease, but to slow down its progression by half.

After 76 weeks in the trial, participants treated with Donanemab declined by 6.86 points, while those in the placebo group declined by 10.06 points. In absolute terms, this is a difference of about 3.2 points, and in percentage terms, about 30% less decline.

While this was a statistically significant difference in the rate of decline, the investigators note that this did not achieve the study’s goal to slow disease progression by half. Additionally, they noted that the clinical significance of this small improvement remains to be established.

The potentially small benefit of the treatment was contrasted with the development of amyloid-related brain imaging abnormalities in the intervention group: a quarter of whom developed issues, with 22% of those being symptomatic.

Furthermore, although there was a significant decrease in amyloid plaque levels, this reduction did not translate into improved clinical symptoms related to mental decline or cognitive difficulties.

The study also did not find a significant difference in brain tau load between the intervention and control groups.

Significantly more research needed

These findings raise questions about the direct relationship between amyloid reduction and overall disease progression in Alzheimer’s therapy. In other words, we still don’t really know whether abnormal amyloid plaques are the cause or the effect of Alzheimer’s.

Two limitations were noted by the authors, namely a relatively small sample size, and a lack of representation within the sample. The majority of participants were American and white; eight participants were black, three Asian and another three identified as other.

This further brings into question how applicable the findings are considering that the sample does not match that of the South African population, and ethnic differences have been reported to play a role in Alzheimer’s disease progression.

In summary, while the study on Donanemab’s efficacy in Alzheimer’s disease treatment provided some promising results, it is crucial to interpret these findings cautiously.

Further research is needed to establish the clinical significance, explore potential long-term effects, and determine whether these findings can be applied to various populations.

Ultimately, the search for effective disease-modifying treatments for Alzheimer’s disease continues to be an ongoing and complex endeavour.

Morgan Watson holds a BSc Honours in Psychology, is currently completing her MPhil in Behavioural Medicine and is a Content Developer in the HIV Mental Health Research Unit, Department of Psychiatry and Mental Health, University of Cape Town.
Jessica Henn holds a BSocSc Honours in Psychology, is currently completing her MA in Psychological Research and is a clinical intern in the HIV Mental Health Research Unit, Department of Psychiatry and Mental Health, University of Cape Town.
Professor John Joska is Head of Clinical Services (psychiatry) at Groote Schuur Hospital and Director of the University of Cape Town HIV Mental Health Research Unit.

Study details

Donanemab in Early Alzheimer’s Disease

Mark Mintun, Albert Lo, Cynthia Duggan Evans, Alette Wessels, Paul Ardayfio,
Scott Andersen, Sergey Shcherbinin, JonDavid Sparks, John Sims, Miroslaw Brys, Liana Apostolova, Stephen Salloway, et al.

Published in the New England Journal of Medicine on 6 May 2021


A hallmark of Alzheimer’s disease is the accumulation of amyloid-β (Aβ) peptide. Donanemab, an antibody that targets a modified form of deposited Aβ, is being investigated for the treatment of early Alzheimer’s disease.

We conducted a phase 2 trial of donanemab in patients with early symptomatic Alzheimer’s disease who had tau and amyloid deposition on positron-emission tomography (PET). Patients were randomly assigned in a 1:1 ratio to receive donanemab (700 mg for the first three doses and 1400 mg thereafter) or placebo intravenously every 4 weeks for up to 72 weeks. The primary outcome was the change from baseline in the score on the Integrated Alzheimer’s Disease Rating Scale (iADRS; range, 0 to 144, with lower scores indicating greater cognitive and functional impairment) at 76 weeks. Secondary outcomes included the change in scores on the Clinical Dementia Rating Scale–Sum of Boxes (CDR-SB), the 13-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog13), the Alzheimer’s Disease Cooperative Study–Instrumental Activities of Daily Living Inventory (ADCS-iADL), and the Mini–Mental State Examination (MMSE), as well as the change in the amyloid and tau burden on PET.

A total of 257 patients were enrolled; 131 were assigned to receive donanemab and 126 to receive placebo. The baseline iADRS score was 106 in both groups. The change from baseline in the iADRS score at 76 weeks was −6.86 with donanemab and −10.06 with placebo (difference, 3.20; 95% confidence interval, 0.12 to 6.27; P=0.04). The results for most secondary outcomes showed no substantial difference. At 76 weeks, the reductions in the amyloid plaque level and the global tau load were 85.06 centiloids and 0.01 greater, respectively, with donanemab than with placebo. Amyloid-related cerebral edema or effusions (mostly asymptomatic) occurred with donanemab.

In patients with early Alzheimer’s disease, donanemab resulted in a better composite score for cognition and for the ability to perform activities of daily living than placebo at 76 weeks, although results for secondary outcomes were mixed. Longer and larger trials are necessary to study the efficacy and safety of donanemab in Alzheimer’s disease.


NEJM article – Donanemab in Early Alzheimer’s Disease (Open access)


Daily Maverick article – Despite promising signs, the search for Alzheimer’s treatment is ongoing and complex (Open access)


See more from MedicalBrief archives:


Promising results for new Alzheimer’s drug


Two experimental drugs fail to halt Alzheimer’s disease


Concern over FDA’s fast-track approval of Alzheimer’s drugs


America’s Veteran Affairs shuns controversial Alzheimer’s drug, noting ‘known safety signal’








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