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Aducanumab - a new antibody therapy against Alzheimer's disease ?

As described in my book on neurodegeneration, the so-called amyloid pathology plays an important role in Alzheimer's disease. This disease already affects around 50 million people worldwide and is as yet untreatable. Various proteins are deposited in the amyloid plaques. In their vicinity, neuronal processes degenerate and inflammatory processes occur. The latter are triggered by numerous inflammatory cells of the brain, the so-called microglia. Since the 1990s, it has been assumed under the keyword "amyloid hypothesis" or "β-amyloid cascade" that the plaques are the essential cause of Alzheimer's disease.

Today, however, we assume that the plaques are rather compensatory. It is likely that it is precisely through the formation of plaques that pathologically high concentrations of soluble precursors of plaques can be rendered harmless. This assumption is supported by the observation that the amyloid plaques are not specific for Alzheimer's disease and occasionally occur in large amounts even in cognitively completely intact elderly people.

An immunohistochemical stain against amyloid in a histological section from the brain of an Alzheimer's patient. It shows the extracellular brownish amyloid plaques (Thanks to A.M. Birkl-Töglhofer, Med. Uni. Graz).

Plaques are formed in particular by Aβ-peptides. These are 39-43 amino acid long peptides that are formed by faulty conversion from a precursor protein, the APP (amyloid precursor protein). Mutations in the APP gene account for only a few percent of Alzheimer's cases. However, Aβ pathology is common and also occurs in sporadic forms with unknown causes. Aβ-peptides are preferentially detectable intracellularly in small transport vesicles called endosomes and are released into the extracellular space by exocytosis. Normally, they are then removed via the nervous fluid or degraded by enzymes.

The 42 amino acid long Aβ42 peptide and the shorter Aβ40 play key roles in Alzheimer's disease. Longer Aβ-peptides tend to assemble more in pairs as a dimer or even multiple times as an oligomer. These then form thin fibers (fibrils) and tend to aggregate. Aggregated Aβ42 peptides attach to cell membranes and form pores that allow charged particles (ions) to enter the cell, thereby disrupting the neuronal metabolism. They also cause hyperexcitability of neurons. Thus, they interfere with long-term potentiation at synapses, which is important for memory formation. In addition, negative effects of Aβ-amyloid on the blood supply have been described, as it constricts brain vessels and impairs cerebrospinal fluid drainage.

Schematic representation of Aβ-peptides (yellowish dots) and the fibrils and plaques made of them. They surround the nerve cells with their processes (

In recent years, therefore, a large number of antibodies (immunoglobulins) against Aβ-peptides have been developed. Interestingly, some of these antibodies were first discovered in healthy people who did not develop Alzheimer's dementia even at an advanced age. Thus, they were intrinsically immunized against plaque formation without ever having been vaccinated. These antibodies were analyzed in more detail and produced for therapy trials in humans. In addition, non-immunologically active substances against Aβ-monomers, oligomers or amyloid aggregates are also being tested in clinical trials. All of them unfortunately without success so far.

Despite these depressing results, however, repeated analysis of the data found that after administration of certain antibodies, specifically directed against Aβ-oligomers and against smaller protein aggregates at relatively high doses (10 mg/kg), improvements in memory function occured in some patients with mild dementia. So perhaps antibodies like aducanumab do slow cognitive decline and reduce the amount of senile plaques.

Although a majority of experts opposed the idea, aducanumab, marketed under the drug name "Aduhelm" by Biogen, was recently approved by the U.S. Food and Drug Administration (FDA) in the United States. This decision has raised eyebrows among critical Alzheimer's researchers, but great hope among many doctors, patients and their families. Other antibodies are now expected to follow. The pharmaceutical company Eli Lill, for example, expects that its similarly acting antibody donanemab will also be approved. In patients treated with this antibody, cognitive decline was apparently delayed by up to 6 months.

It is therefore possible that, in addition to symptomatic treatments with acetylcholine esterase inhibitors and glutamate receptor antagonists, a disease-modifying therapy may finally be available. For now, however, antibody treatment (monthly infusions) should be limited to patients with mild dementia and clearly detectable amyloid plaques. Side effects are possible, such as brain swelling or small hemorrhages. However, the main problem with the approval of Aduhelm was that it was based on a significant decrease in the number of plaques rather than clear evidence of clinical effects. The available data do not show a clear correlation of amyloid plaques in the brain with mental decline.

Complicating matters further, the cost of detecting amyloid deposits using magnetic resonance imaging or PET (positron emission tomography) is added to treatments that cost around €50,000 per year. Alternatively, a blood test may soon be available. The company C2N markets a "PreactivityAD" test that determines the ratio of Aβ42 and Aβ40 peptides as well as the ApoE genotype (a particular ApoE subtype, ApoE4, predisposes to AD).

Despite official FDA approval, potential therapy with Aduhelm remains controversial, and not just because of the price. Indeed, the FDA has conditioned its approval on a "confirmatory study" to ensure that the antibodies actually help patients. For this study, Biogen has nine years to collect results. That's a long time, which also contributed to a panel of the European Medicines Agency (EMA) opposing approval of the drug in Europe for the time being.


Musiek ES, Bennett DA (2021) Aducanumab and the “post-amyloid” era of Alzheimer research? Neuron 109:3045-3047

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