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How new treatments might rewrite
"the long goodbye"
"Leese. It's Dad. I need your help."
My father's calling me from the cafeteria at Denver's Presbyterian/St. Luke's Medical Center - the hospital where in 1967 he kicked off a prestigious career as a dashing, 6-foot-3 cardiologist. Dad tells me he's been seeing patients. He just sat down to grab some lunch, but something's wrong. He can't remember where he parked the Jag.
"I think I may have had a little stroke or something."
I do something that would have been unimaginable 6 months earlier. "Your car is in the shop Dad," I lie. "I'll come down in a bit and take you to get it."
Dad sounds relieved. He tells me he has to get back to work, instructs me to page him if I need him, and hangs up.
Four minutes later, the phone rings.
"Leese. It's Dad. I need your help."
By the end of the day, my father has dialed my number 22 times. Each previous call evaporates from his mind as he grows more and more confused about his whereabouts.
Once, he thinks he's at his mountain condo in Winter Park, CO, the place he taught me to ski fearlessly by day and play spirited games of chess by the fireplace at night. Another time, he's at Johns Hopkins University in Baltimore, where he graduated from medical school near the top of his class.
When I can no longer bear to pick up his calls, the messages fill up my voicemail. After my work day ends, I wearily listen to each one, and delete.
At 8 p.m., as I sit wedged between my children on the sofa watching TV, Dad's number pops up on the caller ID.
"Hi Leese. It's been a while."
As I say goodnight and hang up, I picture Dad in his new home, impeccably dressed in his customary sports coat, trousers, and brown loafers. His faded doctor's badge perches on his left breast pocket, where he fastens it every day with pride.
Only Dad is not at work or relaxing at his ski condo. He is in his favorite brown recliner, in a tiny room with one small window, in a locked "memory care" unit. Next to him sits the phone.
Soon, he will forget how to dial it.
Inching Toward Treatments
Dr. Robert Marshall (aka Dr. Bob) was 72, traveling the world and enjoying retirement when, like a half-million people in the U.S. every year, he began the long and slow descent into the haze of Alzheimer's disease.
I watched with aching grief as time erased my Dad bit by bit over the next 12 years.
As a science writer and a daughter, I was desperate for answers. So I took reams of notes. What exactly was going on in my father's brain? Would it happen to me someday? And if it did, could anything fix it?
The answer to that last question -- more than 115 years after Alois Alzheimer first reported a "peculiar severe disease process" in the brain -- is still, heartbreakingly, no.
Alzheimer's is the top cause of dementia. It can impair all the essential qualities that make a human unique: thinking, judgment, language, memory, emotions. Lifestyle changes can lower your chances of getting Alzheimer's, and some medications can manage its symptoms. But nothing on the market today can do what my three siblings and I longed for -- to stop the erosion of my father's memory and even to restore it.
Yet, as we better grasp how memories are formed and why this intricate system goes haywire, some hopeful scientists say that day is drawing tantalizingly near.
Two recent medical advances hold the hope that memory loss, like heart disease, may someday soon be detected and treated early and affordably.
In June 2021, the FDA approved aducanumab (Aduhelm), the first new Alzheimer's drug in 2 decades. It's the first approved medication to target amyloid in people with mild cognitive decline or mild dementia. Amyloid is a sticky protein that is a hallmark of Alzheimer's. Regulators took a hugely controversial path to fast-track Aduhelm based on its ability to remove brain plaques, even though it's unproven that the drug actually slows cognitive decline.
The lack of convincing data, and concerns about brain swelling and bleeding in some patients, prompted an outside advisory committee to recommend against approving Aduhelm, which is given via a monthly IV injection. In January 2022, Medicare said it would not cover the whopping $2,300 per month price tag for Aduhelm except for those enrolled in a clinical trial. Despite the controversy, some experts hope that Aduhelm, a monoclonal antibody that mimics the body's natural immune response to foreign invaders, will open the door to affordable, safer, new medications targeting early drivers of Alzheimer's.
The year before Aduhelm's debut, researchers at the University of Washington in Seattle unveiled the first clinically available blood test to detect possible Alzheimer's. It's not FDA approved or covered by insurance yet. But it, too, is viewed by some as the first of a new vanguard of inexpensive, noninvasive detection tools, akin to cholesterol tests for heart disease.
As for those already in the early grips of forgetfulness, scientists are testing everything from exercise and nutritional supplements to implantable brain stimulators to bring back lost function and to restore the cache of memories.
"I tend to be more hopeful than most," says Nanthia Suthana, PhD, a neuroscientist and an assistant professor in residence at the David Geffen School of Medicine at UCLA. "But I'm optimistic that within our lifetime there could be a neural prosthesis that could benefit even severely memory-impaired individuals."
Unlocking the Mysteries of Memory
Many people assume that memory is stored in a single place, much like money in a bank vault. Actually, you conjure the sights, sounds, smells, and feelings from the past when neurons fire in coordination across different regions of your brain.
Daydreaming about the blazing beach sunset from your last vacation? Your brain retrieves those vivid colors from its visual cortex located in the occipital lobe at the back of your head. Got a favorite song looped in your head? That emanates from the neural cells in your auditory cortex burrowed near your ears.
Researchers also recently discovered specialty cells that add context to your episodic memories, which are when you mentally relive a past experience. "Time cells" stamp your recollections in the right chronology, so you know that your daughter came to visit yesterday, not last month. "Place cells" act as geolocators, guiding you back to your parked car at the mall.
Electrical and chemical signals link these cells together through a complex architecture of synaptic connections. When you go to recall that memory, that original network crackles with life again.
"Your memory of last night's dinner requires the activation of the same constellation of disparate neurons that perceived, paid attention to, and processed your initial experience of that meal," says Lisa Genova, PhD, a neuroscientist and author of Remember: The Science of Memory and the Art of Forgetting.
Central to this process is a seahorse shaped region of the brain called the hippocampus. It first came to scientific light through Henry Molaison, widely known as H.M., perhaps the most famous patient in neuroscience. In an attempt to stop H.M.'s severe epileptic seizures, his surgeon in 1953 carved out chunks of the hippocampus from both sides of his brain.
When H.M., 27, woke up, his seizures were gone. But he was left with permanent amnesia. He forgot new events and facts almost instantly and was unable to make lasting memories. Every day, he said, "is alone in itself." H.M.'s devastating fate kick-started the modern field of memory research.
The hippocampus is essential to convert what would otherwise be fleeting experiences into long-term memories stored in the regions that processed the initial experience via consolidation. As the home of the bulk of our place cells and time cells, the hippocampus lends temporal and spatial context to those memories.
It is, as Genova puts it, "the memory weaver." And without his hippocampus, H.M. was caught in a sort of perpetual groundhog day.
As it turns out, Alzheimer's hits the hippocampus first.
How Life Choices Affect Memory
My father was intellectually voracious. When he was in college, he learned Latin for fun. In his 30s, he taught himself to play piano. He treated patients at a leper colony in Nigeria. He devoured books by John Irving and Tom Wolf, loved art, and delighted in accompanying his grandkids to the theater.
His inquisitive nature, I'm told, probably supplied him with a "cognitive reserve" that buffered him for a time from the ravages of Alzheimer's. Each new lesson or experience strengthens our neural network and protects it from fraying.
"These neural connections are like train tracks that have been clicked together and are super easy to travel on," Genova says. "If you only have 10, and some of them break, it can be hard to get around. But if you have 10,000 tracks you have options."
Research has shown that people with deep cognitive reserves tend to deteriorate more slowly in the early years of Alzheimer's. Or they are simply able to fake it better.
But for all of Dad's cognitive stockpile, his brain had a lot of strikes against it.
He lit his first cigarette at 16 and smoked a pipe for decades. That likely damaged the blood vessels that ferry oxygen to his brain and inflamed his neural tissue.
Dad ate meat, often processed, 7 days a week. The high sodium levels in his beloved bacon and roast beef probably contributed to his high blood pressure, another risk factor for Alzheimer's. He also shunned leafy greens, whose nutrients are proven to protect against brain-cell-killing oxidative stress.
He retired in his 60s so he could travel the world. But ironically, people who retire early are significantly more prone to dementia. One study found that with diminished opportunities for cognitive and social stimulation, new retirees lose about 3 IQ points in the first 2 years.
Then, there was his chronic insomnia -- a condition that I share.
This worries me for two reasons: During sleep, research shows, a cleansing channel of fluids passes through the spaces between our brain cells, providing a midnight wash cycle that ferries away the toxic plaques and tangles that can promote Alzheimer's. Sleep is also the time when the hippocampus gets to work making memories last.
"If you don't sleep," Genova says, "your hippocampus doesn't have time to finish the job."
How Memory Is Lost
I first suspected something was wrong around 2007, when Dad told me he'd been out Jeeping on his favorite mountain pass and had gotten "really turned around." Months later, a good Samaritan found Dad wandering in the dark in a parking lot after he dined out for dinner. The restaurant had closed more than an hour earlier. Dad was divorced and lived alone, so we finally convinced him to move into an assisted living center.
When my husband and I went to empty out his house, we found printed maps stashed everywhere, including one for the grocery store just a mile away. I peg this time as the beginning of his disease. But, in reality, it probably had been smoldering for years.
Research suggests that as many as 2 decades before symptoms arise, misfolded proteins called amyloid plaques begin to form between nerve cells, jamming up the network. Then come hairball-like clusters called tau aggregates, which emerge inside and around neurons, strangling them. As immune cells in the brain, called microglial cells, mount a response to what they see as an internal threat, the brain becomes inflamed, cells die, and the real damage begins.
The process tends to start in a region of the hippocampus called CA1, hitting those "time" and "place" cells hard. Regions where long-term, consolidated memories are already stored are affected much later. This is why Dad could not remember what he had for breakfast, but he could, when I had a minor heart problem, still scan my EKG and give me a spot-on diagnosis.
It would be a few years before doctors officially diagnosed Dad with Alzheimer's, based on a battery of surprisingly low-tech cognitive exams. To truly know for sure, his doctor told us bluntly, we'd have to wait until he died and look at his brain.
Over a tear-filled dinner with my sister later, I was overcome with guilt.
"If only we could have caught it earlier somehow," I said. "Maybe we could have done more to help him."
Quest for Early Detection
When Dad was diagnosed, doctors were only beginning to use PET scans to look for amyloid plaque building up in the brain. The scan, which wasn't covered by Medicare or Dad's supplemental insurance, costs more than $5,000 and would have exposed him to radiation. His doctor advised against it.
More recently, specialized clinics have begun to look for signs of amyloid in cerebrospinal fluid, an uncomfortable and invasive procedure.
In October 2020, C2N Diagnostics in St. Louis unveiled Precivity AD, the first widely available blood test to look for early signs of Alzheimer's. It checks your blood sample for two proteins, amyloid beta 42 and amyloid beta 40, to gauge the amount of plaque in the brain as well as for variants of apolipoprotein E (ApoE) that is a major genetic risk factor for Alzheimer's.
The test, which costs about $1,200, isn't meant to diagnose Alzheimer's on its own. But early studies suggest it's at least as accurate as more expensive or high-tech alternatives.
In one 2019 study of 158 cognitively normal older adults, the blood test caught positive results on PET scans 94% of the time. In some cases, it accurately found high levels of amyloid accumulation beginning in the brain before a PET scan did.
"One can likely detect the earliest pathological stages of Alzheimer's 3 to 5 years earlier than with an amyloid PET scan," says David Holtzman, MD, a neurologist and researcher at Washington University School of Medicine, who co-founded C2N in 2007. "If populations of people in the future are screened with a test like this, it could potentially lead to starting preventative strategies earlier."
Controversial New Drug
Between 2002 and 2012, there were more than 400 clinical trials to evaluate potential Alzheimer's drugs. All save one, memantine (Namenda), failed. Families like ours were left with just five drugs that treated only the symptoms.
Dad tried most of them: Aricept made him so nauseated he quit it after a few weeks. Namenda may have slowed his progression but did not stop it. Dad knew something terrifying was happening to his brain, and he grew depressed, as many with Alzheimer's do. His doctors prescribed antidepressants.
As we languished in search of a cure that didn't exist, Rudolph Tanzi, PhD, director of the Genetics and Aging Research Unit at Massachusetts General Hospital, soldiered on, imagining a day when not only could we detect the underlying pathology of Alzheimer's early, but we also had cheap, easily accessible drugs -- the "statins of Alzheimer's" he calls them -- to treat it.
Tanzi acknowledges that amyloid plaque alone is not the only culprit underlying Alzheimer's. It is, instead, the match that lights the fire. Then come tangles of tau aggregates that wrap around neurons spreading like brush fires, and inflammation, which fully engulfs the forest.
Thus far, he believes, many drugs targeting amyloid have disappointed because they are given too late. But Tanzi says aducanumab, despite its $28,000-a-year price tag and required monthly monitoring with MRI, may benefit some patients, particularly those with a strong genetic tendency toward the disease who show early signs of plaque.
Still, in approving an Alzheimer's drug based on a biomarker (amyloid plaque) instead of symptom reduction, he says the FDA is paving the way for other, cheaper early-intervention drugs that do the same thing.
"In the past, researchers and drug developers had no way forward because the FDA would say, 'If you are not making people cognitively better right now, we are not going to approve your drug,'" he says. Tanzi likens the stance to refusing to approve a cholesterol-lowering medication unless it could cure heart disease.
He and other scientists have identified dozens of compounds that target amyloid, which may help prevent Alzheimer's in people like me with a family history of the disease.
Not only that, Tanzi is optimistic about helping those who are already afflicted with it.
Possible Ways to Restore Memory
Some startups around the country are exploring drugs that could target other later-stage roots of Alzheimer's. One, AZTherapies (Tanzi is an investor), is experimenting with an inhalable, repurposed asthma drug called cromolyn specially formulated to cross into the brain to tamp down inflammation.
Other, early-stage projects are exploring everything from stem cell therapy to nutritional supplements (including nicotinamide riboside, a form of vitamin B3) to jump-start neurogenesis, or new cell formation, in regions of the hippocampus where cells have already died.
Simple aerobic exercise, Tanzi notes, has been shown to not only promote new brain cell growth, but to also boost production of BDNF, or brain-derived neurotrophic factor, a sort of fertilizer for those newborn cells that helps them survive.
With this in mind, we made a point of taking Dad for walks often.
"It may not be the same forest, but we can help regrow some of the trees," Tanzi says. "I am optimistic that some of these things could be used very late in the disease to help someone be a healthier, more functional person."
At UCLA, Suthana just launched a large, federally funded clinical trial of a noninvasive technique called transcranial magnetic stimulation, an FDA-approved treatment for depression, to electrically stimulate the memory centers in the brain in older adults with mild cognitive impairment.
Patients sit back in a chair as a single electric coil on the outside of their skull transmits fast bursts of low-frequency stimulation to a region adjacent to the hippocampus, called the lateral parietal cortex. The procedure takes 10 minutes, 5 days a week for 3 weeks.
Recent human studies have shown that the technique promotes neuroplasticity, the brain's ability to form and reorganize new connections between brain cells. At least one animal study has shown it may actually promote neurogenesis, or the growth of new cells in the hippocampus. And in healthy people without memory loss, it has been shown to improve some measures of recall.
Suthana's study is among the first to test it in people already in the grips of memory loss.
If the trial succeeds, she imagines a day when magnetic stimulation could be used to stall Alzheimer's in its early stages. She also studies deep brain stimulation, a similar but far more invasive technique used with people with Parkinson's. Brain stimulation requires drilling a tiny hole through the skull to insert an electrode deep inside the brain to activate the tissue.
One trial of brain stimulation for Alzheimer's patients famously failed -- a crushing disappointment for people like Suthana. But she suspects the patients may have had too much brain damage already for it to be successful, or it may not have targeted the right region of the brain. In one recent study in epilepsy patients, she found brain stimulation strongly enhanced visual memory.
Suthana believes that it could be possible in the future to fit people with "memory prostheses" to restore their cognitive function, much like artificial legs help people walk after an amputation.
"That may sound crazy, coming from the scientist in me, but I really do," she says, noting that clinical trials for prototypes are already underway.
What Alzheimer's Can't Steal
In Dad's last years, we moved him from a sterile, understaffed, large facility to a brightly lit, 10-room home complete with music therapy, attentive caregivers, and easy access to the outdoors.
"People with Alzheimer's don't lose their ability to feel lonely, angry, loved, happy, and safe. You, as a human being, are more than what you can remember."
- Lisa Genova, PhD, neuroscientist and author
There, he reawakened for a time.
Once, as we sat on the bench in the backyard, he stunned my sister and me with a smooth baritone rendition of "On the Street Where You Live," a show tune he recorded with his band 6 decades earlier. When he couldn't sleep, he charmed a caregiver with an impromptu midnight waltz without missing a step.
Even on his final day, he called me by my name.
These flickers of recognition are not uncommon, Genova says. Some emotions are too deeply rooted for dementia to efface. Alzheimer's steals a lot, but it doesn't erase everything.
"People with Alzheimer's don't lose their ability to feel lonely, angry, loved, happy, and safe," Genova says. "You, as a human being, are more than what you can remember."
Even 2 years after Dad's death, my siblings and I live with the specter that Alzheimer's may come for us someday.
My 85-year-old Mom is remarkably sharp. One of my sisters, out of curiosity, took a test and found that she does not carry the genetic variant (ApoE4) commonly linked to heightened risk of the disease.
That's reassuring. But a twinge of unease can wash over me when I can't recall an acquaintance's name or wander too long in the parking lot. At age 52, I wonder if the match has already been struck, sending embers creeping across my brain.
My older brother, who looks just like Dad, cut back on red meat and slimmed down. My oldest sister, a fellow insomniac, tries mightily to sleep better. My other sister, a therapist who understands the toxic toll of stress on the brain, moved to Australia in pursuit of a more blissful lifestyle.
As for me, I quit smoking and am training for my 14th marathon. I also started graduate school.
None of this, of course, guarantees that we will keep Alzheimer's at bay. So we try to live our lives with vigor and curiosity, a sense of urgency driving us to make the most of our healthy minds while we still can.
My phone rings less often these days. I miss Dad's calls. But I know he'd be proud of how his children have taken charge of our health. Somehow, that makes his absence feel less like a final goodbye.