This has been an exciting time in Alzheimer’s disease (AD) research. While medical news has been largely focused on the pandemic, AD researchers have been developing theories that could completely upend conventional wisdom about the cause of the condition…welcomed a new drug that just might be the first pharmaceutical to slow AD progression…faced fraud allegations that called into question a key research paper…and much more. Here’s what you need to know now.
Pharmaceutical company Eisai unveiled the results of a phase-3 trial of its new AD drug lecanemab in late November 2022. An 18-month study involving 1,795 patients found that participants who had been diagnosed with AD who received this drug experienced 27% less cognitive decline than those receiving a placebo. No previous drug has ever managed to slow AD this way. Lecanemab is an antiamyloid drug designed to remove the protein beta-amyloid that causes the formation of plaques in the brains of AD patients.
But: Questions remain about lecanemab, which was approved by the FDA in January 2023, and will be sold under the name Leqembi. Two participants in the recent trial died from brain hemorrhages believed to be linked to the drug, raising the possibility that its risks might outweigh its benefits.
Medicare will not cover the cost of lecanemab for most patients—though it could later revisit that decision—and paying out of pocket is expected to cost the typical US patient more than $25,000 per year.
And now, some researchers are skeptical that beta-amyloid is even the correct target. In part, these doubts are because earlier attempts to target beta-amyloid have failed to slow or stop AD. One earlier beta-amyloid–targeting drug, aducanumab, received conditional FDA approval in 2021 and now is sold as Aduhelm—but questions remain about whether it benefits patients. Researchers’ opinions range from “Give it a chance” to “Why did they approve this?” The conditional approval means this drug also is not covered for most Medicare patients. Out-of-pocket costs for US patients are around $28,000 per year.
Currently, doctors resort to crude tests of cognitive ability—such as asking patients to spell words backwards—to diagnose AD. But a team of researchers at Germany’s Cancer Research Centre and Centre for Protein Diagnostics recently developed a sensor that can identify signs of AD in patients’ blood up to 17 years before clinical symptoms appear. Advances in the ability to detect AD are crucial, though generally receive less attention than new drugs. It’s likely to be some time before we can be certain about the accuracy or specificity of such blood tests. When a test is claimed to identify signs of a disease 17 years before symptoms appear, it takes 17 years to confirm that those claims are correct.
An article in Science in 2022 suggested that an influential 2006 AD research paper was based on suspicious data. The paper, along with others, played a key role in the theory that beta-amyloid plaques are the primary cause of AD. Result: Some researchers suggest that the past 15 years of AD research has been built on a flawed premise. But: The impact is not as substantial as some claimed. No one study is responsible for 15 years of research—science had largely moved on from that paper even before the allegations.
Still, these allegations have helped call attention to the growing doubts surrounding the idea that an accumulation of beta-amyloid proteins is the primary cause of AD—and that has helped focus attention on alternative ideas.
Because AD research was focused on amyloids, proposed AD studies that lacked an amyloid focus often were rejected by grant committees. That has changed dramatically. Among the proposed alternative causes for AD…
Mitochondria. A paper in Journal of Clinical Medicine by researchers at the European Brain Research Institute and Italy’s Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies is among several to identify a link between AD and dysfunction in mitochondria—the organelles that serve as cells’ energy units. Intriguingly, AD patients appear to experience mitochondrial dysfunction before beta-amyloid protein builds up or other symptoms appear, hinting that the mitochondrial issue might be the trigger of the disease.
Synapses. A paper in Frontiers in Cellular Neuroscience by researchers at the Netherlands’ Utrecht Brain Center reviewed the research into the connection between synapse loss and AD. AD patients experience a loss of synapses—the ends of neurons that send messages to adjacent cells. Research suggests that this synapse loss might be related to changes that occur in patients’ astrocytes—a type of cell found in the brain and spinal cord—hinting that preventing astrocyte changes could become an AD therapy.
Autoimmune dysfunction. If you made a list of key AD risk factors, setting aside age and family history, it would include such seemingly unconnected dangers as repeated head trauma…infections, including dental infections…and exposure to air pollution. But there is a common thread—the immune system plays a role in helping people recover from all of them. Could AD be a result of an immune system problem? That might help explain why beta-amyloid plaques build up in AD patients’ brains. Research by scientists at the Krembil Brain Institute suggests that beta-amyloid plays a role in the brain’s immune system, killing off viruses and bacteria, but it struggles to differentiate between bacteria and brain cells. Perhaps AD is the result of the immune system mistakenly killing brain cells, and beta-amyloid plaques are a consequence.
Which of these theories will turn out to be the Holy Grail that AD researchers have been seeking for decades? Most likely none. There probably is no one solution. It probably is more likely a family of diseases that we haven’t yet figured out how to differentiate. For example, there’s increasing evidence that early-onset AD is different from late-onset. The ultimate solution might turn out to be a cocktail of treatments that involves more than one of these theories and others, and a treatment that targets beta-amyloids could be part of that cocktail.
Good news: After decades where no meaningful Alzheimer’s treatments reached patients, a range of treatments that truly could provide improved outcomes might start to become available, perhaps in as little as three years.
There is evidence that neurological inflammation can be a driver of AD and cognitive decline…and approximately one-third of confirmed COVID patients develop neurological symptoms. Already there is evidence that existing dementia patients diagnosed with COVID experience worsened clinical outcomes.
It will be many years before we know the true scale of this latest AD danger. At this point, we can’t even say which COVID patients are at greatest risk. But there is a real chance that decades from now the pandemic that recently devastated the world could do so again, by potentially doubling global dementia rates.
