Controversial Alzheimer’s drug

AlzheimersLast year a new drug to treat Alzheimer’s arrived on the scene called aducanumab, trade name Aduhelm, made by Biogen in Cambridge Massachusetts. It’s claimed this drug is different to its predecessors because it targets the causative biology of the disease – but it’s not without some controversy. To explain, let’s first look at what we know about the causes of Alzheimer’s, then pick up the story of aducanumab from there.

Although we know quite a lot about the pathology of Alzheimer’s, we still do not know the underlying cause. The three most widely accepted hypotheses concern (1) the formation of plaques between brain neurons, (2) the presence of tangles within the neurones and (3) the loss of a neurotransmitter chemical called acetylcholine. Let’s look at plaques first. Membranes throughout the body, and within the synapses of neurons in particular, contain a protein called amyloid precursor protein, or APP. It has several functions, but within the brain it’s implicated in neurone repair. Like all proteins, APP is subject to turn-over, meaning existing protein is broken down and removed, while new protein is synthesised to replace it. Three enzymes called α- β- and ɣ-secretase digest APP into small fragments which are then eliminated. But if β-secretase predominates, APP is only partly shredded and the remaining fragments clump together into plaques that sit between nerve cells, inhibiting neuronal communication.

While amyloid plaques form outside cells, tangles form inside cells. They originate from structures called microtubules which, amongst several functions, act as highways for nutrients. A protein called tau maintains the structure of microtubules, but tau can become misshaped. This leads to damage to the microtubules and the formation of tangled tau protein. These tangles then block the neuron’s transport system, inhibiting communication between neurones.

The third hypothesis on the cause of Alzheimer’s involves a neurotransmitter chemical called acetylcholine. It’s one of the most important neurotransmitters released in the spaces between one nerve cell and another (called a synapse). Once released, it’s rapidly broken down by an enzyme called acetylcholine esterase. As an aside, nerve agents such as Sarin and VX, inhibit the action of acetylcholine esterase, meaning the acetylcholine transmitter remains in the synapse, constantly firing the nerve cell. With Alzheimers, levels of acetylcholine are lower than normal so the cells do not trigger properly. Current Alzheimer’s drugs such as Rivastigmine, like nerve agents, inhibit acetylcholine esterase (although in not such a drastic way) thus increasing the levels of acetylcholine.

Getting back to the subject of this blog post, aducanumab is an antibody which targets amyloid plaques in the brain (the “mab” part of the name tells you it’s an antibody). The theory is that as aducanumab removes amyloid plaques, so neurones start to communicate again, thus reducing the symptoms of Alzheimer’s. Biogen point out that aducanumab is the first new treatment since 2003, but its action assumes the plaque hypothesis has validity, and that’s not universally accepted. Some scientists believe amyloid plaques are in fact a symptom of the disease, rather than its cause. Sceptics of the plaque hypothesis cite the fact that drugs which target plaques have a poor track record in alleviating symptoms of Alzheimer’s. Others explain the poor track record by pointing out damage to the brain is irreversible and so timing of administration of anti-plaque type drugs is critical. The root cause of Alzheimer’s might, of course, be more complex than any of the single hypotheses. Indeed, a recent study found evidence that cells of the immune system called macrophages clean up amyloid plaques and tau tangles during sleep.

The US Food and Drug Administration (FDA) approved aducanumab contrary to the advice of its scientific advisory board, and since its approval, three members of the board have resigned. (The European Medicines Agency has not approved aducanumab). The drug is available in the United States and the FDA will monitor its efficacy. I guess in time we’ll know which side of the plaque hypothesis is right – if indeed either side is right.

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