The Evolving Treatment Landscape for Alzheimer’s

Every year, Alzheimer’s Disease International marks September as Alzheimer’s Awareness Month, presenting an opportunity to challenge stigma, raise awareness and support those affected by Alzheimer’s disease around the world.

In recent years, we have seen significant advances in the development of drugs to tackle Alzheimer’s, particularly in the wake of two decades of largely unfruitful research. Though some such treatments are being hailed as a success, not all researchers remain convinced. Regulators around the world have had differing receptions to the drugs, but despite their problems, research now seems to be trending in a positive direction.

Emerging new treatments

The past two years has seen regulators approve new drugs lecanemab and donanemab to treat Alzheimer’s disease, though their development hasn’t been plain sailing. Both are designed to target a protein called amyloid-beta in the brain that forms abnormal clumps called plaques. These plaques are thought to be the root cause of the disease as part of the “amyloid hypothesis”, though this idea has also been disputed by some.

The first amyloid-targeting antibody to gain approval from the US Food and Drug Administration (FDA) – aducanumab – was given the green light in 2021. But it was not without controversy; three FDA advisors, whose committee had advised against aducanumab’s approval due to a lack of evidence of efficacy, resigned shortly after the decision. Aducanumab’s drugmaker, Biogen, later discontinued the drug in January 2024 to focus on the development of their new offering, lecanemab.

Data from clinical trials suggest that amyloid-targeting drugs like lecanemab and donanemab provide modest benefits for slowing the disease’s progression, mostly during the early stages of the disease. Despite their costs – both risk-wise and financially – their approval heralds some hope for those affected by Alzheimer’s, and it is a positive step after years of trials finding that previous drug candidates failed to impress.

There are several reasons why finding effective drugs to combat Alzheimer’s has been so difficult, as Andrew Doig, a professor of biochemistry at the University of Manchester, told Technology Networks: “Firstly, the target that has received most attention, amyloid-beta, is not at all easy to hit.”

Doig explained that amyloid-beta likely exists in the brain in the form of multiple units stuck together in structures called oligomers. Each different oligomer can vary in toxicity and structure, making finding drugs that effectively bind to them a much more difficult task. “Even if we do have good structures of oligomers, it isn’t clear which would be the most important (i.e., the most toxic). It is also unlikely that a drug would bind to all the toxic forms,” he said.

The complex pathologies in the brain and the mechanisms at play that underpin Alzheimer’s development also make it challenging to target, as the disease’s characteristic brain abnormalities can emerge decades before any apparent symptoms.

“By the time it is diagnosed, it could be too late to treat, as the brain has already undergone significant irreversible damage,” Doig said. To increase the chances of success, patients in the earlier stages of dementia – such as mild cognitive impairment – are now beginning to take center stage for clinical trials.

Amyloid-beta’s other knock-on effects could also indicate that early treatment may be best, Doig explained, as the accumulated amyloid-beta likely kickstarts feedback loops in the brain involving oxidative stress, inflammation and tau – another key protein implicated in Alzheimer’s development. “Once these loops are triggered, removing toxic forms of amyloid-beta may have little effect,” he explained.

Drawbacks for newly approved therapies

Nonetheless, somewhat encouraging data from clinical trials have provided support for the approval of amyloid-targeting antibodies, suggesting they could have modest benefits for slowing down the disease’s progression.

Lecanemab, for example, slows the progression of the disease in its earlier stages, rather than halting or reversing it. “All it does is to slow down the rate at which the disease progresses, as measured by cognitive ability,” Doig explained. “In effect, patients who take lecanemab see a delay in progression to more severe dementia by about six months.”

These antibodies are delivered into a vein with the aim of binding to and clearing the brain’s amyloid-beta plaques; but not all are convinced as to whether this necessarily translates into meaningful benefits for the patients taking it.

“The benefits of lecanemab are so modest as to be undetectable in an individual treated patient,” said Robert Howard, professor of old age psychiatry at University College London. “Although 27% slowing of disease course sounds impressive, this is not strictly what the analysis of the trial data showed.”

Another drawback to these treatments is finding patients who are eligible to receive the drug. This requires undergoing expensive or invasive procedures such as PET scans and lumbar punctures, notwithstanding the eyewatering costs of the drug alone, which the manufacturers have set in the region of $26,500 a year.

“The benefits are small, however, and there are concerns with the drug,” Doig adds, as, even after considering the costs, the drug carries the risk of potentially severe side effects.

“There is a small but real risk that lecanemab can cause brain hemorrhage. A few patients on the trial died in this way,” Doig said, referring to amyloid-related imaging abnormalities (ARIA), which cause potentially fatal microbleeds or clots in the brain.

Weighing the risks versus the benefits is therefore a difficult task. The patients likely to benefit most from the drug are those in the earliest stages of the disease, who, coincidentally, have the most to lose considering the risks.

Weighing the benefits and risks

This decision on whether to approve these drugs has proved arduous for many regulators worldwide, with some taking more conservative stances than others. The FDA was the first to give the green light in July 2023, while the European Medicines Agency (EMA) later decided against its approval in July 2024. The UK was next to follow in the FDA’s footsteps to approve lecanemab. However, they ruled against making it available on the National Health Service, reasoning that the small benefits do not justify the cost – meaning only those able to afford private healthcare can receive it.

Another anti-amyloid antibody, donanemab, which also modestly slows cognitive decline at the risk of ARIA, earned FDA approval in July 2024.

“The benefits are marginal, the costs are high and there is some risk with these drugs, so it is not surprising that many regulatory bodies are saying no,” Doig summarized. “I can understand why some do approve them, however, as we desperately need new therapies for Alzheimer’s, even if they are not especially effective.”

Though further research could provide safer and more effective drug candidates, the approval of these first few drugs may be the starting point to show that we are on the right track. “Patients and carers can take heart that it is possible to slow cognitive decline caused by Alzheimer’s and that amyloid-beta is indeed an appropriate [drug] target,” Doig said. “It therefore points the way to a future where Alzheimer’s can be treated, bringing benefit to millions of people.”

Potential for other treatment avenues

Aside from amyloid-targeting antibodies, there are also other avenues that may be worth pursuing to add more tools to combat the disease.

Doig described these in some of his predictions for the future of research into Alzheimer’s treatments over the coming decade: “We will bring forward a wider range of targets, rather than solely trying to clear amyloid-beta. Tau is next, but anti-inflammatories and antivirals also show promise. Many other pathways are affected by Alzheimer’s and might be useful drug targets.”

Drug repurposing, like that of anti-inflammatories and antivirals, is one such approach that could be used to identify useful drug targets. Repurposing is the process of finding new applications for existing drugs: a significantly cheaper and potentially faster method to find new and effective treatments for many diseases.

“Some therapies aimed at other conditions are showing real benefit for Alzheimer’s. These are the shingles vaccine, Shingrix®, and the anti-obesity drugs, such as semaglutide,” said Doig.

The shingles vaccine targets a protein called HSV-1 that causes both chicken pox and shingles. Doig’s colleague, Ruth Izhaki, pioneered the investigation into the link between Alzheimer’s and HSV-1 for decades. However, her work has only recently gained wider acceptance.

“The Shingrix vaccine seems to be roughly as effective as lecanemab at a much lower cost, without fortnightly administration and the worrying side effects,” Doig said.

Meanwhile, tackling other conditions closely associated with Alzheimer’s could be another promising option to limit the disease’s incidence and progression: “We know that cardiovascular problems in middle age increase the risk of Alzheimer’s later on,” Doig said. “Tackling type 2 diabetes via suppressing appetite shows many benefits, including lowering the risk of Alzheimer’s. These are very exciting recent discoveries which offer cheap and effective ways to reduce Alzheimer’s.”

The first step?

Though the effort to find treatments for Alzheimer’s has not been straightforward, the emergence of these new drugs represents what is hopefully the first step on the journey to safer and more effective treatments. With diagnoses for people aged 65 and over projected to grow to 12.7 million by 2050, the pressing need for breakthroughs to prevent or cure the disease is important now more than ever.

Prof. Andrew Doig was speaking to Dr. Sarah Whelan, Science Writer at Technology Networks.