A Glimpse of Hope in Alzheimer's Disease?

Hans-Christoph Diener, MD, PhD


May 26, 2023

This transcript has been edited for clarity.

Dear colleagues, I'm Christoph Diener from the Faculty of Medicine at the University Duisburg-Essen in Germany. This video will concentrate on the new developments in the treatment of Alzheimer's disease.

You remember that, until recently, there was no effective treatment for Alzheimer's disease. This started with small molecules targeting different neurotransmitters followed by a number of studies with monoclonal antibodies against amyloid. Most of them failed, but now we have two positive trials for monoclonal antibodies against amyloid in the brain.

Lecanemab and Donanemab

The first study was published in The New England Journal of Medicine in January 2023. This was the lecanemab study. This study recruited 1795 patients with mild cognitive impairment or mild dementia, and they received, twice a week, 10 mg/kg active drug or placebo for 18 months. The inclusion criteria were amyloid PET or biomarkers in the cerebrospinal fluid (CSF).

The study was positive for reducing cognitive decline (the primary endpoint) and all secondary endpoints. For the primary endpoint, there was a 27% slowing in cognitive decline compared with the placebo group. More impressive for me were the amyloid PET data, which showed that 2 of 3 participants no longer had amyloid on PET after 18 months.

There are side effects due to inflammatory reactions of the blood vessels called amyloid-related imaging abnormalities, or ARIA, and they can manifest either as edema or microbleeds. This was the case in 21.5% of patients on active drug compared with 9.5% with placebo, but only 3.5% of patients had symptoms. After the study, in an open-label extension, three patients died — one from cerebral hemorrhage and two following thrombolysis.

Lilly announced, on May 3, 2023, the results of the TRAILBLAZER study with donanemab. This study had similar inclusion criteria as the lecanemab study and had an 18-month observation period.

Overall, 47% of participants showed no worsening of cognitive function compared with 29% on placebo. This result was significant also for the secondary endpoint. ARIA-E, or edema, occurred in 24% and 6% were symptomatic. ARIA-H, or microbleeds, occurred in 31% with active drug vs 13.6% on placebo. This means we now have two new treatments. One is already approved in the US — lecanemab — and the other one most probably will be approved.

Limitations and Questions

We have many unresolved questions. First, is the difference in cognitive function after 18 months clinically meaningful, and how will cognitive function perform if the treatment is continued for many years? Second, are the results only valid for incipient Alzheimer's disease, and if the disease progresses, when should the treatment be terminated?

Third, for diagnosis, you need amyloid PET, tau PET, or biomarkers in CSF. This might be replaced in the future by serum biomarkers. Fourth, the therapy has to be monitored by MRI at least every 3 months because of the risk for ARIA, and it will be very time-consuming for patients and physicians because the infusions have to be given twice a week.

Fifth, which patients are ineligible for the treatment because of potential side effects? These are probably patients who are anticoagulated, patients with multiple microbleeds on imaging, and patients with the APOE genotype.

The cost in the United States is estimated at $26,500 per year. This is equivalent to some of the immunomodulatory treatments in multiple sclerosis, and the big question is whether our healthcare system can afford to treat the majority of or all patients with incipient Alzheimer's disease.


Another very exciting therapeutic approach was published in Nature Medicine last week. This is a tau-targeting antisense oligonucleotide called MAPTRX. This oligonucleotide was investigated in a dose-finding study. It's given intrathecally every 4 or 12 weeks. The study was small, with 34 patients on MAPTRX and 12 on placebo. There was an impressive reduction of tau PET but there were no significant clinical outcomes, as you can imagine, with the small number of patients.

The burning question in the future will be whether we need to combine antibodies against beta amyloid and antisense oligonucleotides against tau protein if a clinical study shows that this approach is valid. We should not forget that the most important aspect of preventing Alzheimer's disease, or preventing its progression, is the treatment of vascular risk factors and a healthy lifestyle.

These are exciting times because, for the first time, we see a glimpse of hope for the treatment of Alzheimer's disease.

I am Christoph Diener from the Faculty of Medicine at the University Duisburg-Essen. Thank you very much for watching and listening.

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