Still, too many people insist on casting the debate over what causes Alzheimer’s as an either-or problem, Nixon said. They chide him, arguing that his beliefs about the importance of the endosomal-lysosomal mechanism must mean that he doesn’t believe amyloid-beta has any role in the disease. “It’s like you can’t hold two relevant ideas in juxtaposition,” he said.
In Alzheimer’s disease, amyloid-beta may be one killer, but there could be a range of toxic accumulating proteins that are equally important in killing the cell, he said. Amyloid-beta is like a banana peel in a garbage can. “There’s a whole host of other garbage that might be even more disgusting than the banana peel,” Nixon said.
Small agrees that it could make the most sense for the endosomal-lysosomal hypothesis, the neuroinflammation hypothesis and the amyloid cascade hypothesis to combine at some point into one larger theory. “You can Occam’s-razor this,” he said.
The implications of taking this broader perspective could reach beyond the Alzheimer’s field. Clues gleaned from Alzheimer’s could help our understanding of other neurodegenerative disorders, such as Parkinson’s disease and amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) — and aging. The reverse could also apply: Weaver often reads the ALS and Parkinson’s literature as well, hoping that their insights “will flip over to our world,” he said.
New Drugs, New Theories
Enthusiasm for explanations beyond the amyloid cascade hypothesis doesn’t mean that people have lost interest in the anti-amyloid drugs now being tested. Aisen and many other researchers are still optimistic that we can build on the moderate success of lecanemab. Even if the drugs address only part of what’s wrong in Alzheimer’s disease, any improvement could be a lifeline for patients.
“Patients need something,” Weaver said. “And I really hope that one of these [ideas] turns out to be right.”
After so many years of drug failures, the lecanemab results were welcome news for Hardy. He flew from London to San Francisco so he could be present when the results were presented at the end of November at the Clinical Trials on Alzheimer’s Disease conference. He could have watched the results from home online, but he wanted to be part of the excitement and “to hear what other people think of the results.”
Even though Hardy helped to launch the amyloid cascade hypothesis decades ago and still believes in its power, he has also always been extremely receptive to evolving ideas.
In 2013, Hardy and his team discovered that mutations in a gene involved in the immune system could increase the risk of developing late-onset Alzheimer’s disease. Since then, he has shifted the focus of his lab to studying microglia. He suspects that amyloid deposits might activate microglia directly to cause damaging inflammation.
To many researchers, the immune system offers an appealingly flexible explanation for Alzheimer’s, one that fits with both the amyloid hypothesis and other ideas. A report in the July 2020 issue of The Lancet listed the variety of known risk factors for dementia, ranging from air pollution to repetitive head trauma to systemic infections. “I mean, it goes on and on,” Weaver said. “They’re different as night and day.”
The thread that connects them, he continued, is the immune system. If you bang your head and damage tissues, the immune system steps in to clean up the mess; if you get infected by a virus, your immune system wakes up to fight it; air pollution activates the immune system and causes inflammation. Studies have shown that even social isolation can lead to inflammation of the brain, and depression is a known risk factor for dementia, Weaver said.
The immune system is also intimately connected to the lysosomal system. “How cells use the lysosomal pathway to internalize, degrade or recycle proteins is critical to how a neuroimmune response may occur,” Young said.
But the endosomal-lysosomal network is also very finely tuned and has a multitude of moving parts that work differently in different types of cells. That makes it trickier to target, Young said. Still, she’s hopeful that there will be a burst of new clinical trials targeting this network in the next few years. Young, Small and Nixon are all working on targeting different aspects of this network.
Part of the allure of the amyloid cascade hypothesis was that it offered a simple solution to Alzheimer’s disease. Some of these other hypotheses bring in extra layers of complexity, but it’s a complexity that scientists — and a growing number of startups — now seem willing to tackle.
Waiting for Relief
Travaglini went back to Alzheimer’s research at a late stage of his doctoral work. In October 2021, he started at the Allen Institute, sifting through slices of brain samples from people who had died of the disease. He and his team are compiling the Seattle Alzheimer’s Disease Cell Atlas — a reference that will detail the effects of the disease on the brain’s diverse mix of cells. As part of that work, they are analyzing changes in the activity of more than a hundred kinds of cells in the cortex during the progression of Alzheimer’s disease.
“The cellular face of the disease is so important, because it puts all of these molecular changes and hypotheses into the context of the cell that they’re actually occurring in,” Travaglini said. If you put amyloid or tau protein on cells in a dish, the cells start to deteriorate and die. “But it’s not been so clear how different kinds of cells are changing.”
His work has already turned up interesting insights, such as the fact that the neurons most vulnerable to the disease are those that have made extra-long connections across the cortex of the brain — where much of our cognitive ability arises. Something about that type of cell could make it more susceptible to the disease, he said.
Travaglini and his co-workers have also seen an increase in the number of cells such as microglia, adding even more evidence to the idea that neuroinflammation is a major part of the process. They have also already uncovered a number of genes that are expressed improperly in the brains of people with Alzheimer’s disease, including genes linked to the lysosomal-endosomal network. Eventually, their work could help to uncover the timing of when things go wrong in specific cells, teasing apart one of the greatest mysteries of the disease.
Travaglini has tried to visit his grandparents as often as possible. A while ago, his grandmother needed to be moved into an assisted-living memory home; his grandfather went too. “He wanted to be with her,” Travaglini said.
They were constant companions since they met in Philadelphia in college; they married more than 60 years ago in Japan, where he was stationed for military service. It has always been hard on him to see her slip away, but it became even harder recently when he too was diagnosed with dementia, although not Alzheimer’s. He would speak lovingly of her, but then add “she doesn’t really like me anymore,” Travaglini said. The family would remind him that wasn’t true, that it was the disease.
Early in the morning of December 1, Travaglini’s grandmother died. She was 91.
Her Alzheimer’s had progressed too far for her to understand what her grandson was working on, but his grandfather at least had a chance to know that Travaglini pursued research in the dementia fields. “He was really proud of that,” Travaglini said.
Family support matters to researchers like Travaglini in more ways than one. Millions of families are volunteering to help test new drugs and new ideas to advance understanding of Alzheimer’s disease, knowing full well that the results likely won’t materialize soon enough to help them.
Until effective treatments are found, Patira will continue to treat the dementia patients in her care by holding their hands through the journey and helping them navigate their evolving relationships with their families. Her patients’ biggest fear is that they will no longer be able to recognize their grandchildren. “That’s painful to think for yourself,” she said. “And that’s painful to think for the loved ones.”
Research in the field, now more open to other alternatives, will continue to move along, with both good and bad news. “Even if the studies don’t work, you learn something from the failures,” Patira said. “It’s frustrating as a clinician, but it’s good for science.”
‘Carol Knew the Implications’
Shortly after Hardy’s discovery that the APP gene was why her family was so afflicted with Alzheimer’s, Carol Jennings quit her job as a teacher to work full-time supporting and advocating for Alzheimer’s disease research. In the following decades, she worked closely with Hardy and then with other researchers at University College London.
Jennings never took the genetic test for the APP mutation that led to her father, three aunts and an uncle — five out of the 11 people in her family — developing Alzheimer’s disease. “She didn’t think it was worthwhile, because there was nothing that we could do,” said Stuart Jennings, Carol’s husband, who is a Methodist minister and historian. “She would say, ‘I could get run over by a bus tomorrow; why worry about something that’s going to happen in 30 years’ time?’” Their two children have likewise not been tested.
In 2012, Carol Jennings was diagnosed with Alzheimer’s disease. She was 58 years old.
Carol Jennings is one of the very small fraction of people whom researchers can look at and say exactly why her brain has deteriorated. The brains of the vast majority of Alzheimer’s patients, whose disease isn’t tied to a specific gene, are more open to interpretation.
“The interesting thing is that the early symptoms were [that] the things that she did badly got worse,” Stuart Jennings said. “We all used to joke she could get lost going from the bedroom to the bathroom.” Eventually, that became literally true. She had always procrastinated, but she became very last-minute.
Then the things she was good at, like packing and organizing, started to deteriorate. It took years for her to get a formal diagnosis, but once she did, it was traumatic for the first couple of days, Stuart said: “Carol knew what the implications were.”
So she started giving instructions. When she dies, she told Stuart, her brain must be donated to the brain bank run by the team at University College London, as the brains of her other afflicted family members have been. She told him that he didn’t have to keep her at home if he couldn’t cope, but he must keep her clean. All the little details were ironed out. “She was brilliant. She got it all organized. I just supported her, really,” Stuart said.
He has managed to keep her at home, and UCL researchers continue to follow the Jennings family. Carol and Stuart’s son John works closely with them now, too.
As he spoke over Zoom, Stuart sometimes patted Carol’s head from his seat beside her, as she lay in bed with a cold. Because of her Alzheimer’s, she can’t get out of bed or talk anymore other than to give yes or no answers to certain prompts. During the conversation, she drifted in and out of sleep — but when she was awake and watching the interview, it didn’t feel as though she was silent.
Maybe in those moments some part of her was back onstage lecturing about Alzheimer’s disease, stringing words together with ease, inspiring and awing an audience. In her talks, she would stress the idea that “this is about families, not about test tubes and labs,” Stuart said. “That was quite powerful, I think, for the drug reps to hear.”
Carol wasn’t bothered that disease-altering treatments didn’t arrive in time to help her — to her, that was a small point. “Carol’s always worked on the principle that it’s for the children and for the next generations,” Stuart said.
Correction: December 8, 2022
This article initially credited the wrong photographer for the photos of Ralph Nixon. Those photos were taken by Karen Dias for Quanta Magazine.
