Recent study shows: Antibody drugs for Alzheimer’s shrink the brain

Following the approval of the new Alzheimer’s drugs aducanumab in 2021 and lecanemab in early 2023 by the U.S. Food and Drug Administration (FDA), the third anti-amyloid antibody, called donanemab, is now about to be launched. For example, pharmaceutical company Eli Lilly recently announced preliminary results for the TRAILBLAZER-ALZ-2 trial of donanemab in a press release. Like its “predecessors,” this antibody agent was shown to be effective in eliminating Alzheimer’s-specific amyloid-beta (Aβ) deposits (also known as senile plaques) and caused a slower deterioration of clinical symptoms in early-stage disease patients compared with untreated AD patients [1].

Experts in Alzheimer’s research, on the other hand, view antibody drugs rather critically. Despite demonstrated reduction of Aβ deposits, the benefit to patients remains questionable, as no antibody, including donenamab, has yet succeeded in halting or ameliorating the disease. In all cases, the deterioration of cognitive decline is slowed slightly, but not slowed down. Moreover, the proven “efficacy” in terms of reducing senile plaques is dearly bought with serious, sometimes fatal, side effects.

These side effects, known as ARIA(Amyloid-Related Imaging Abnormalities) in the medical community, manifest as undesirable changes in MRI scans and occur with all anti-amyloid antibodies. In donanemab-treated patients, study physicians observed ARIA in the form of brain edema (fluid accumulation in the brain) in 24.0% of subjects and brain hemorrhage or iron deposition in 31.4% of subjects, which in some cases was fatal. But even if the ARIA are clinically more harmless, this means an enormous additional diagnostic effort for the treating physicians, which is associated with high additional costs – and not least with immense stress for the patients.

ARIA does not appear to be the only side effect of these agents, as an Australian research group found in a recent study. In this study, scientists took a close look at the side effects of anti-Aß antibody drugs (i.e., their potential to trigger ARIA) and their effect on brain volume. The results of this scientific study were published in early 2023 in the medical journal Neurology [2] and are described below.

The authors systematically searched clinical trials for patients enrolled in randomized controlled trials of Aß antibody drugs. An important search criterion was that detailed MRI data (brain images of the patients) were available. This was to detect brain volume changes in regions typical of Alzheimer’s disease, such as the hippocampus (site of episodic memory) and the lateral ventricles (cavities of the brain that contain fluid), as well as shrinkage of total brain volume (brain atrophy).

The meta-analysis of the highest drug dose showed that there was an acceleration of brain atrophy during treatment with the drugs, which varied depending on the class of anti-Aß drugs. While the group of secretase inhibitors (Alzheimer’s drugs) predominantly accelerated hippocampal shrinkage, all ARIA-triggering monoclonal antibodies increased ventricular size. There was a striking correlation between increased ventricular volume and ARIA frequency. The effect on total volume was particularly marked for donanemab and lecanemab: they accelerated brain tissue loss by approximately 5 ^cm3 in treated patients compared with untreated patients. The authors were also able to demonstrate that this tissue loss could not be attributed to the volume-related loss of the (removed) Aß deposits.

The researchers predicted that treatment with these drugs could produce substantial regression to a brain volume typical of Alzheimer’s dementia, starting about eight months earlier than in untreated participants.

Paradoxically, the Australian research team thus found that with brain atrophy, the structural cardinal symptom of Alzheimer’s disease is promoted by all representatives of this drug group. Because brain shrinkage was accelerated, especially in the patients with the side effects, is more than worrisome because about a quarter of the patients suffered from cerebral edema and about a third suffered from cerebral hemorrhage. Thus, approximately half of the participants would be affected by atrophy. Although it is hard to believe, this drug-induced brain atrophy, and thus adverse effects of anti-Asset drugs on brain health, have not been mentioned or investigated in clinical trials to date.

The scientists therefore made an urgent appeal to all the bodies involved, to the pharmaceutical industry and also to the treating physicians: when treating Alzheimer’s patients with ARIA-triggering Aß antibodies, it is essential to pay attention to these volume changes in the future and these drugs should also only be used under critical consideration of the cost-benefit. At “Knowledge stops Dementia” you can read these recommendations again in detail.

Conclusion:

With
Donanemab
the third anti-Aß antibody is about to be approved as an Alzheimer’s drug. But even this drug, which is touted as a “miracle pill,” is not able to slow down Alzheimer’s disease. Rather, an enormously high rate of serious adverse events, known as ARIA for short, also occurred during treatment. In addition to the high health hazard potential, these also bring other problems, such as cost-intensive diagnostic monitoring and patient stress.

Worse, an Australian research team has found via clinical trial imaging data that brain volume depletion is promoted by all members of this drug class – an observation not even mentioned in the clinical trials. This is extremely concerning, as brain tissue loss is the cause of cognitive decline in Alzheimer’s disease, and volume changes are objective evidence of disease progression. Thus, brain-damaging long-term effects of these therapies are unknown!

Against the background that effective, side-effect-free and significantly less cost-intensive
lifestyle-oriented prevention and therapy concepts
are available, this seems almost paradoxical.
Fortunately, with this knowledge and information from “Knowledge stops Dementia”, you have the choice to opt for the right therapy for your mental health!

References:

1. 1. ↑ Lilly’s Donanemab Significantly Slowed Cognitive and Functional Decline in Phase 3 Study of Early Alzheimer’s Disease. Press Release Eli Lilly, May 3, 2023
   2. ↑ Alves F, Kalinowski P, Ayton S. Accelerated Brain Volume Loss Caused by Anti-β-Amyloid Drugs: A Systematic Review and Meta-analysis. Neurology. 2023 May 16;100(20):e2114-e2124. doi: 10.1212/WNL.0000000000207156. Epub 2023 Mar 27. PMID: 36973044; PMCID: PMC10186239.

Image sources:

Contributed image by Christina Victoria Craft on Unsplash