My father is at the Selkoe Laboratory at Brigham and Women’s Hospital. And he is at work.
That may seem improbable given that, in March 2022, my father died of Alzheimer’s disease. But, since he died, my father has helped pioneer the validation of effective treatments that weren’t available for him; research conducted on his brain tissue is helping scientists understand how to (hopefully) improve upon the recently FDA-approved lecanemab and develop even more effective treatment for Alzheimer’s disease.
Over the years my mother, sisters, and I cared for my dad, we focused on navigating immediate obstacles. We stood next to him at social gatherings, so we could jump in if he needed help holding a conversation. We researched tracking devices to keep him safe if he wandered. We learned to understand him when he went weeks without speaking. Medications helped manage symptoms, but not slow or reverse the disease. As my dad’s Alzheimer’s advanced, I’d imagine two lines sloping upward: one the progression of my father’s disease and one the curve of scientific innovation; my father’s disease always racing faster than scientists’ ability to understand and stop it.
In the 1990s, Dennis Selkoe and other leading scientists hypothesized that Alzheimer’s Disease is started by the accumulation of a clumped protein—amyloid—in the brain, and that removing amyloid could prevent cognitive decline. While this theory, known as the Amyloid Hypothesis, has been the basis for much of Alzheimer’s research, early trials attempting to target the amyloid did not slow memory decline, perhaps because they did not remove much amyloid.
The FDA’s 2021 approval of Aduhelm, the first medication to drive lower amyloid levels in patients’ brain, was unfortunately clouded by controversy. Poor decision-making by its manufacturer led to a prematurely ending two trials. Incomplete and conflicting data, as well as high rates of temporary brain swelling, left serious questions of Aduhelm’s efficacy that were compounded by a much-criticized FDA approval process.
Regardless, Aduhelm was not suitable for my father, who, by the time of its approval, had progressed to advanced Alzheimer’s, past the point where scientists believe amyloid removal might be effective.
Before he was sick, my father, the ultimate caregiver, was never frustrated. If he saw a problem, he focused on a solution. When I was a child, he designed a perfect step stool. The legs, brace, and seat joined together perfectly to offer you this: step up, you cannot tip and fall. He would balance like a flamingo on one foot on the seat’s edge, delighting in how the stool improbably distributed the weight from his six-foot frame.
In the first several years of his sickness, he made nearly a hundred stools for kids he knew.
As we cared for my dad, we tried to offer him what he had offered us: a solid foundation to stand on. When he took off on a walk, I quietly trailed behind. If he decided to swim, I jumped in the pool clothed, reveling in seeing him enjoy the feeling of warm water and the sound of his grandchildren splashing.
As his Alzheimer’s progressed, we struggled to offer him appropriate support. He grew frustrated, unable to work around his new limitations. We’d find him jiggling a broken hinge, aware it needed to be fixed but unable to identify a solution. In that moment, I’d feel a sharp pang in my chest—one of pain and pride; I loved that he was still a problem solver, and I wanted to support him in solving this particular one.
We had three weeks from when doctors told us my father was dying until he died. In those blurry days, as my mother, sisters, and I went from thinking he would live several years to understanding he would not be alive for much longer, we decided to donate his brain for Alzheimer’s research.
That first week the idea of donating my dad’s brain popped into my head. I called my mother and asked what she thought. She seemed put off by the idea, mentioning the Jewish tenet that you should bury the body whole.
Knowing nothing about brain donation, I googled “brain donation” and saw a list of places that accepted brain tissue. I pictured my dad’s unaccompanied brain being sent across the country in a padded envelope to a lab that I didn’t know. I felt like we’d be abandoning him. I dropped the topic.
A few weeks later, one of my sisters called and asked again, “Should we think about donating dad’s brain?”
She emailed Seth Gale, my dad’s neurologist, to ask if we could learn about the process. My dad had made a stool for Seth’s children not long after Seth diagnosed him. The next morning, three days before my father died, my sisters, my mother, Seth and I zoomed.
In the years my dad was sick, no one suggested brain donation. I imagine it is impossibly hard for a medical professional to bring up the topic. My sisters and I do not know why we thought of it except, perhaps, that the act of watching my dad die made us ask ourselves, “Is there something we should be doing?”
Seth explained the process without assuming we’d ultimately decide to do it. Repeatedly, he told us, “You don’t have to do this.”
Seth said that if we made the donation, my father’s brain would stay at the Brigham and Women’s Hospital, where he was treated. I realized we would know where his brain was and who had it. My mother, who had been concerned about burying his body whole, called me after and said “if I had a tumor, I’d remove it and then one day, I’d be buried without it. This isn’t any different.” After Seth dropped off the Zoom, my mother, sisters, and I took a minute to talk. Each of us knew he would want the opportunity to help people. The answer was clear.
I asked Seth to connect me to the brain donation team. Andrew Stern, a physician-scientist in the Selkoe Lab, called me to talk about logistics.
Two weeks prior, I had leaned my head to my dad’s and told him “Dad, you are dying. But it’s ok. We are here. We are all ok and we will take care of one another.” Now, I crouched on my dad’s bed, put my head on his, and said “Dad, you are taking care of people. You are donating your brain so this doesn’t happen to other families. ”
Three days later, at my father’s bedside, I texted Andrew to let him know my father had died. Andrew called the funeral home and ensured the team at the hospital was ready. That evening, when I emailed my father’s obituary to family and friends, I bcc’d Andrew. If he had my father’s brain, he would know my father.
I told my dad he was helping, but the help felt abstract. I had no sense of what the research might look like or how quickly his brain would be put to work.
On Nov. 29, 2022, at the 15th Clinical Trials on Alzheimer’s Disease (CTAD) Eisai presented its large Phase III randomized control trial of lecanemab, an anti-amyloid medication. The results showed that lecanemab slowed the decline of cognitive function, functional capacity, and quality of life for patients with early Alzheimer’s compared to a placebo. Like Aduhelm but unlike preceding medications, lecanemab wiped amyloid from patients’ brains. Importantly, unlike Aduhelm, lecanemab completed its clinical trials as intended and had much lower rates of swelling or bleeding. These results are understood to confirm that removing amyloid helps prevent cognitive decline. On Jan. 6, 2023, lecanemab (now branded Leqembi) was approved by the FDA. Lecanemab may become the first change in the standard of care for early Alzheimer’s patients in nearly 20 years. (Current Medicare policy makes lecanemab hard to access for most patients, though that will hopefully change soon.) The mechanism underlying lecanemab, unlike any of the treatments available to my father, has the potential to halt the disease. This is a giant leap for Alzheimer’s research.
The study shows that lecanemab can work but questions remain about how it works—in particular scientists are still learning the exact size and shape of amyloid that is so injurious to the brain. At the same conference, Andrew Stern and Dennis Selkoe presented the first images that illustrate in detail—down to the individual atom—exactly what lecanemab sticks to in the human brain, and, perhaps, how scientists can improve upon this advance.
I know these images well. They are images of lecanemab bound to amyloid fibrils, tiny stick-shaped protein clumps, from my father’s brain.
In Sept. 2022, Dennis and Andrew invited my family to the Selkoe Laboratory. Dennis and Andrew walked us through scientists’ understanding of Alzheimer’s, the Amyloid Hypothesis, and then images showing how lecanemab bound to amyloid from my father’s brain tissue. My dad is now fuel for the curve of scientific innovation.
As Andrew and Dennis detailed their research, they referenced my dad by name, like a colleague.
My father, who died of Alzheimer’s, who did not have disease-modifying drugs available to him has, in Dennis and Andrew’s hands, demonstrated how Alzheimer’s could potentially be stopped. In collaboration with Dennis and Andrew, he is solving his most frustrating problem. He gets a chance to build for others the foundation he didn’t have. There, in the Selkoe Lab, looking at images of lecanemab bound to my dad’s brain tissue, I could see my dad balancing like a flamingo on the edge of a step stool.
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Contributor: Rebecca Leventhal