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 is now about to be launched: The pharmaceutical company Eli Lilly recently announced preliminary results of the TRAILBLAZER-ALZ-2 study with the new anti-amyloid antibody donanemab in a press release [1].

In the clinical trial, the antibody was tested in 1182 Alzheimer’s patients (65 to 85 years) in the early stages of the disease. After 12 months, amyloid-beta (Aß) deposits were significantly reduced in the majority of patients. Donanemab also slowed patients’ clinical deterioration by 35% at the end of the study at 18 months compared with the untreated control group. What sounds like a high efficacy with “35% slowdown”, and is also described by experts as “clinically relevant”, is however a sham when looked at in a more differentiated way: In the clinical study, cognitive performance in the CDR-SB questionnaire deteriorated by 1.9 points in the control group after 18 months (1). 35% efficacy thus means that the treated patients scored 0.59 points better than the control group, which had been given a placebo. However, a difference of 0.5 points in the evaluation of the CDR-SB is the smallest possible difference that an investigator can document at all in an individual patient!

Experts in Alzheimer’s research also have major concerns: despite proven reduction of Aß deposits, the efficacy and thus the benefit for patients remains questionable, as no anti-amyloid antibody, including donenamab, has yet succeeded in halting or alleviating the disease. In all cases, the deterioration of cognitive decline is slowed slightly, but not stopped. 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 adverse changes in MRI scans in the form of brain edema (fluid accumulation in the brain), brain hemorrhage, iron deposition, and occur with all anti-amyloid antibodies. In donanemab-treated patients, study physicians observed brain edema in 24.0% of subjects and brain hemorrhage or iron deposition in 31.4%, some of which were fatal.

In addition, an Australian research team found in 2023 that treatment with these drugs causes accelerated brain degradation (brain atrophy) and increases the size of brain ventricles (cavities of the brain filled with fluid) [2]. There was a striking correlation between increased ventricular volume and ARIA frequency. Participants with mild cognitive impairment treated with anti-amyloid drugs were predicted to show substantial regression to brain volumes typical of AD, starting approximately eight months earlier than untreated participants!

Paradoxically, this would mean that with the reduction of brain volume, the structural cardinal symptom of Alzheimer’s disease is promoted by all representatives of this group of drugs. Since brain shrinkage was accelerated, especially in the patients with the side effects, this would be more than worrisome since about a quarter of the patients suffered from brain edema and about a third from brain hemorrhage. Thus, approximately half of the participants would be affected by atrophy.

Although it is hard to believe, the long-term consequences of drug-induced brain atrophy and thus adverse effects on brain health have not been mentioned or investigated in clinical trials to date. The scientists therefore made an urgent appeal to physicians to pay attention to these volume changes in the future when treating Alzheimer’s patients with ARIA-triggering Aß antibodies and to use these drugs only after critically weighing the cost-benefit. At “Knowledge stops Dementia” you can read these recommendations again in detail.

Conclusion:

The third anti-dementia drug, donanemab , can’t really do much more than its “predecessors” either. Although it was able to slow mental decline by 35% after 18 months in patients with early Alzheimer’s in the TRAILBLAZER-ALZ-2 study. However, this promising (relative) result looks rather meager in absolute terms and is quite dearly bought with a rather high rate of side effects such as brain edema and hemorrhage. After scientists in a recent study also observed brain shrinkage caused by this group of drugs via the available MRI data, the question finally arises again whether the amyloid-ß protein is the right approach for drug development. Donanemab is therefore no more a breakthrough than its “predecessors” lecanemab and aducanumab – on the contrary, these drugs harbor considerable potential for harm.

All of this appears to be true in light of the fact that effective, side-effect-free and significantly less costly
lifestyle-oriented prevention and therapy concepts.
 are available, almost paradoxical. Fortunately, with this knowledge and “Knowledge stops Dementia,” you have the choice to choose the right therapy for your mental health!

References:

    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.