鈥淚 have really modest goals. I want to have the largest impact on human suffering of anyone, ever,鈥� says Lou Reese, co-founder of biotechnology company Vaxxinity. He might just pull it off. If everything goes to plan, by 2030 the firm will offer a new drug that will revolutionise our approach to one of the world鈥檚 most feared diseases, and may even lead to its eradication.
That disease is 础濒锄丑别颈尘别谤鈥檚, the most common form of dementia, which causes untold pain to people and their relatives. It and other forms of dementia are seen as a ticking time bomb ready to blow up in the brains of an increasingly elderly population.
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But now it seems there may be a way to defuse this problem. Vaxxinity, which is based in Cape Canaveral, Florida, is working on vaccines designed to halt the progression of 础濒锄丑别颈尘别谤鈥檚 or even stop it from developing in the first place. Several other companies are in the same game and the approach is showing great promise. 鈥淪ociety is entering an era in which the unchecked devastation of 础濒锄丑别颈尘别谤鈥檚 disease is no longer inevitable,鈥� says at Harvard Medical School.
Around 55 million people are living with dementia and that number is projected to rise to about 140 million by 2050, with disastrous consequences for patients, their families and our health and social care systems. In 2021, the World Health Organization estimated that the global cost of dementia by 2030.
There are various types of dementia, but 础濒锄丑别颈尘别谤鈥檚 accounts for the lion鈥檚 share, at 60 to 80 per cent of cases. It is a neurodegenerative condition that destroys the brain and causes people to gradually lose their memories, personalities and independence. As Auguste Deter, the first person diagnosed with the disease, Alois Alzheimer, in 1901: 鈥淚 have, so to speak, lost myself.鈥�
Until recently, little could be done to help people with 础濒锄丑别颈尘别谤鈥檚 find themselves again. Untold numbers of experimental therapies showed initial promise but fell by the wayside. There are on the market, but they barely slow the progression of the disease, let alone cure it.
What causes 础濒锄丑别颈尘别谤鈥檚?
To truly defeat this condition, we need to know what causes it. There have been clues since 础濒锄丑别颈尘别谤鈥檚 was in the early 1900s by the eponymous German psychiatrist while treating Deter. After she died in 1906, Alzheimer dissected her brain and discovered it was riddled with sticky, abnormal protein deposits between neurons and tangles of proteins inside them. The deposits, or plaques, became 鈥� and remain 鈥� the defining feature of the disease. In the 1980s, various researchers . The intracellular tangles, meanwhile, were composed of a modified form of a known protein called tau.
These discoveries led, in 1992, to the . Beta-amyloid normally exists as a soluble and useful protein in the brain, but the cascade hypothesis posits that the key event in 础濒锄丑别颈尘别谤鈥檚 disease is abnormal aggregation of the protein into solid plaques. This then triggers the formation of tau tangles, leading to the dysfunction and death of neurons. Exactly what initiates this cascade is largely unknown. Nonetheless, this quickly became the leading hypothesis for the cause of 础濒锄丑别颈尘别谤鈥檚 disease.
Pharmaceutical firms soon began experimenting with small-molecule drugs designed to target beta-amyloid and break it down. Between 2001 and 2021, dozens of compounds entered clinical trials, yet none made it out alive: they didn鈥檛 work, had toxic side effects, or both. As a result, the amyloid cascade hypothesis fell out of favour, prompting researchers to propose various other causes and mechanisms.
For instance, the pathogen hypothesis suggests the true root cause is bacteria getting into the brain, with the plaques being an immune overreaction to the infection. We know that tau proteins cause neuroinflammation 鈥� an immune flare-up that damages neurons 鈥� so another line of thought is that this is what we truly need to combat. These hypotheses are not mutually exclusive. But still, there has been plenty of disagreement over how 础濒锄丑别颈尘别谤鈥檚 really works. Selkoe describes it as a set of 鈥渞oiling scientific controversies鈥�.
Now, a new line of research is quieting those controversies. There has been a shift towards using the immune system itself to attack the amyloid plaques. One way to accomplish that is with vaccines. The most familiar vaccines are those used to ward off infectious diseases, which largely work by prompting the immune system to make antibodies against the intruder. However, vaccines can also be made to target troublesome proteins such as beta-amyloid.
This idea isn鈥檛 new. In 1999, scientists at Elan Pharmaceuticals and demonstrated that it cleared the protein in a mouse that had been genetically engineered to have 础濒锄丑别颈尘别谤鈥檚-like symptoms. They also developed a 鈥� an injectable antibody made in a test tube 鈥� which had the same effect. Both these immunotherapies were rushed into human trials. Neither worked.
A vaccine for dementia
Nevertheless, the concept lived on and success finally arrived three years ago in the form of a monoclonal antibody developed by biotechnology company Biogen, based in Cambridge, Massachusetts. It works by binding to toxic aggregates of beta-amyloid, prompting immune cells to gobble them up. In June 2021, the US Food and Drug Administration (FDA) . Aducanumab became the first 础濒锄丑别颈尘别谤鈥檚 drug to win approval since 2003.
Biogen has now in favour of a similar monoclonal antibody called lecanemab, which it developed alongside Japanese firm Eisai. In clinical trials, this drug produced significant reductions in cognitive decline in most 鈥� but not all 鈥� of the participants. Likewise, it reduced the decline in their ability to live independently. Last year, the FDA approved it for use in people with early-stage 础濒锄丑别颈尘别谤鈥檚. Another amyloid-busting monoclonal, Eli Lilly鈥檚 donanemab, was also granted FDA approval in July.
According to immunologist at biotech company AC Immune in Lausanne, Switzerland, the success of these drugs was a watershed moment. 鈥淒onanemab and lecanemab finally proved that if you pull out plaque, it will be associated with rescue of cognitive decline,鈥� she says. 鈥淭hat鈥檚 definitely proven.鈥�
Monoclonals appear to have succeeded where small molecule drugs failed and there are various possible reasons why. It could be that those earlier drugs simply didn鈥檛 effectively bind to amyloid. The monoclonals are also more specific, targeting only the amyloid in plaques rather than the natural, soluble form of the protein, which has important biological functions in the brain.
Monoclonal antibodies are far from perfect, however. They disintegrate fairly swiftly in the body, so lecanemab has to be infused intravenously for about an hour once every two weeks. It isn鈥檛 cheap, either, at $26,500 per patient per year. Worse, a significant proportion of those taking it develop serious swelling or bleeding in the brain, or both. In the large-scale, phase III trial of lecanemab, . For donanemab, the number was 24 per cent. These are enormous drawbacks, says . 鈥淭ell me that you鈥檙e going to take a very expensive treatment that takes hours for infusion, that may or may not be slowing the progression of the disease and has a three-out-of-ten chance of causing drug-induced brain swelling?鈥� he says. 鈥淧erfect!鈥�
As if to underscore this point, the European Medicines Agency decided in July on the grounds that the small gains it can bring don鈥檛 outweigh the risk of serious side effects. Biogen has since appealed the decision.
Nonetheless, Reese says he is a 鈥渂ig fan鈥� of the monoclonal approach because it is opening a new frontier in the treatment of 础濒锄丑别颈尘别谤鈥檚. The monoclonals have shown that eliminating amyloid can alleviate symptoms and hence that it is a cause of the disease. 鈥淭he amyloid-beta theory is more or less proven by these antibodies,鈥� says Kosco-Vilbois.
A new era for dementia treatment
This suggests that the other previously attempted approach 鈥� when Elan Pharmaceuticals had a stab at creating an 础濒锄丑别颈尘别谤鈥檚 vaccine 鈥� could be a goer after all. Several companies have been working on this and there are now four vaccines targeting beta-amyloid in clinical trials. The most advanced is Vaxxinity鈥檚 , which is poised to go into a and could be available for use by 2030. The vaccine generates antibodies against toxic aggregates without touching the normal form of beta-amyloid and is designed to be given to people diagnosed with mild 础濒锄丑别颈尘别谤鈥檚. A phase II clinical trial in Taiwan showed that the vaccine is safe and generates a strong immune response. It also slowed cognitive decline by about 50 per cent on average, says Mei Mei Hu, chief executive of Vaxxinity, which is about twice as effective as lecanemab.
There are reasons to believe that vaccines will outperform monoclonal antibodies. Monoclonals are 鈥減assive immunotherapies鈥� 鈥� they don鈥檛 engage the immune system, but merely flood the bloodstream with short-lived antibodies. Vaccines, on the other hand, are active immunotherapies that stimulate the immune system to make its own antibodies. This approach seems to have many advantages. So far, there has been no sign of brain swelling or bleeding with UB-311, says Hu. For reasons unknown, the antibodies it induces appear to be two to three times more efficient at crossing the body鈥檚 protective blood-brain barrier. Vaccines are also cheaper than monoclonals and far simpler to administer. Patients would initially receive four or five injections in the space of a year, then one or two boosters a year thereafter.
Despite widespread optimism about the vaccines, there is always a risk that they will come to grief in late-stage clinical trials through lack of effectiveness, intolerable side effects, or both. Time will tell.
One reason for hope, though, is that there are several ways to deploy the power of vaccines against 础濒锄丑别颈尘别谤鈥檚. There are also vaccines in development against the other villain of the piece, tau tangles. According to the amyloid cascade hypothesis, these are the direct cause of neurodegeneration.
Tau, however, is a tougher nut to crack than beta-amyloid because it is found inside rather than outside cells, meaning that antibodies normally can鈥檛 access it. That is probably why experimental anti-tau monoclonals have all failed, according to Selkoe. But there is a way to sidestep this problem. According to Kosco-Vilbois, tau tangles eventually spill out of neurons and become visible to antibodies. This extracellular phase, which is partly responsible for neurodegeneration, should be treatable. AC Immune has an anti-extracellular tau vaccine, ACI-35.030, in . And even if tau vaccines don鈥檛 work brilliantly on their own, they could be part of a multi-pronged attack combining vaccines that target different parts of both rogue proteins. 鈥淲e can go after multiple targets at one time,鈥� says Reese.
Although we now know that beta-amyloid has a causative role in 础濒锄丑别颈尘别谤鈥檚, there are other physiological consequences of the disease that immune therapies could tackle. It is clear, for example, that plaques and tangles cause neuroinflammation, and emerging evidence suggests this has a significant role in the development of 础濒锄丑别颈尘别谤鈥檚.
at Harvard Medical School is focused on this. He and his team are trialling a monoclonal antibody called foralumab, which was designed to treat multiple sclerosis and Crohn鈥檚 disease. It stimulates a protein cluster, CD3, found on the surface of immune cells known as regulatory T-cells. The drug is administered nasally, which delivers it to lymph nodes in the neck. When the antibody latches on to CD3, it activates T-cells, which then migrate into the brain and damp down inflammation. It has been shown to and was recently cleared to begin human trials. The nasal route has advantages over intravenous infusions of monoclonals. 鈥淭he T-cells naturally go into the brain, so you don鈥檛 have to worry about crossing the blood-brain barrier,鈥� says Weiner.
All this progress on multiple fronts suggests we could be entering a new era where people who develop early-stage 础濒锄丑别颈尘别谤鈥檚 are no longer staring at inevitable decline into the abyss. 鈥淒o I think that stimulating the immune system will work in 础濒锄丑别颈尘别谤鈥檚?鈥� says Weiner. 鈥淚 think the answer is definitely yes.鈥� The benefits could extend to different kinds of dementia, too, many of which are associated with rogue proteins that could be the target of a vaccine.
There may be an even greater prize on the horizon. A invented a few years ago can pick up traces of abnormal tau tangles 20 years before any symptoms of 础濒锄丑别颈尘别谤鈥檚 appear. So the hope is that we could give individuals such a test and vaccinate anyone that requires it, nipping the disease in the bud. 鈥淭he outright prevention of 础濒锄丑别颈尘别谤鈥檚 disease has become a realistic goal,鈥� says Selkoe.
AC Immune鈥檚 anti-tau vaccine is testing this tantalising possibility. The volunteers in the trial haven鈥檛 been diagnosed with 础濒锄丑别颈尘别谤鈥檚 or even its precursor, mild cognitive impairment, but they have been identified via the blood test as being at high risk of developing the condition. Volunteers who are picked up by this test are further screened with a PET scan to confirm that they have abnormal tau in their brains and, if they do, are given the tau vaccine.
Does this raise the prospect that 础濒锄丑别颈尘别谤鈥檚 can be eradicated? Reese, for one, says it absolutely can be. 鈥淚 think of it like polio,鈥� he says. 鈥淎lmost no one in our generation has been personally afflicted by the suffering of polio. It鈥檚 my goal that our kids鈥� and our grandkids鈥� generations have that same foreignness and historical understanding of 础濒锄丑别颈尘别谤鈥檚 and the suffering that it brings.鈥�
Graham Lawton is a staff writer at聽91av
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