THE ALZHEIMER’S ENIGMA

She’s Still Her

Rebecca Chopp thought she knew how she would die.

The former president of Colgate University (2002–09), Chopp was diagnosed with early stage Alzheimer’s disease in spring 2019.

She experienced a period of depression — “I felt like I was diving into Hell,” she writes in her memoir Still Me — and had to come to terms with her career as chancellor of the University of Denver. After making the difficult decision to retire early, Chopp threw herself into Alzheimer’s activism and awareness.  

“One of the hardest parts of processing the diagnosis was the challenge to the very essence of my being,” she says in Still Me. “I do things for myself and take care of myself. It is the deepest personal code I have,” she writes, adding that her favorite T-shirt says “Tell Me What You Think I Can’t Do So I Can Get Started.”

Chopp joined three national boards for Alzheimer’s foundations, co-founded the advocacy group Voices of Alzheimer’s, spoke to the media and universities (including Colgate), and wrote the memoir to give people information about the disease and how to live well.

She thought she knew: “This is my trajectory. It’s written out for me.”

But as the saying goes, “We plan, God laughs.”

Last summer Chopp went in for a routine visit with a neurologist and her world flipped upside down — again.

The doctor told her, “We need to retest you. This is not making sense. After six years, you should be showing more symptoms, no matter how good your genes are, no matter what luck you have, no matter what you’ve done.” Chopp, too, had thought she should be retested going into the appointment that day. “Because of my national and local work in Alzheimer’s, I know the tests have developed; there are now blood biomarkers, better PET scans, and new cognitive tests,” she says. “So I was prepared to ask.”

The blood biomarker test, which looks for tau and amyloid — the two proteins assessed in dementia patients — “came back with nothing — no tau and no significant amyloid plaque,” Chopp says. “And that was shocking. Both [the neurologist] and I expected there to be some, and I assumed we were going to hear, ‘you’re really lucky, it’s progressing really slowly.’ But it indeed came back with at least this biochemical suggestion that I didn’t have Alzheimer’s.”

After months of further testing, including assessments for other cognitive disorders, “my tests indicated that I was perfectly fine,” Chopp says. “I was gobsmacked. I could not get my mind around it.”

The first question, of course, is: What happened?

The short answer is, the doctors don’t know for sure. Chopp went to three different neurologists six years ago, and they all agreed that her scans and tests were indicative of Alzheimer’s. The doctors are hypothesizing now that a lesion on her brain, which they believe has been present since she was in the womb, could have been triggered by the lifestyle that her high-pressure positions demanded over the years (leader of Colgate, Swarthmore College, then University of Denver). She admits that she prided herself on “needing” just a few hours of sleep per night, for example, and the stress of her career could have compounded her symptoms. “But [my neurologist] said, and I would underscore, that is pure speculation.” 

The second question for Chopp was: “Who am I now?”

In Still Me, she recalls how she felt after receiving her Alzheimer’s diagnosis: “How and where I had built so much of my identity was now in the past.” These feelings resurfaced with this latest news. Today, she says, “I chose to use my pain, my frustration to become an advocate and an educator. Then, this goes away, and it was kind of like, what?! Everything I do has to do with this. I am the woman with Alzheimer’s who’s going to try to make a difference. And then all of a sudden, whoops!”

She also worried about how people would perceive her integrity. “That has been the hardest thing,” Chopp says. “I’ve been out there on the front lines, on these national boards representing Alzheimer’s, giving speeches, writing a book…” But “I have had help in thinking about that from a number of people, including neurologists who use my book and other organizations who say the book is still valid. It’s all true and still incredibly helpful.”

Unexpectedly, one emotion Chopp has not felt much of is anger: “These doctors made a good faith effort. And for some reason, my body probably was saying, ‘You can’t do this anymore.’”

She’s now accepted this new stage of her life, with a rededication to her activism work. “I lived thinking I had this disease for many years, and I’ve done a lot of research and put a lot of energy into it. More than ever, I want people to go get tested, learn about your brain, live a healthy life, raise money for research.”

Chopp will continue with her brain-healthy lifestyle by staying active physically, mentally, and creatively. She’s been learning to paint over the years and is now dipping into oil painting, “which I love, love, love. The colors are so beautiful.” Hiking is another one of Chopp’s favorite hobbies, and she goes outdoors a few times a week near her home in Colorado, “which is fun, fun, fun.”

Now that she feels like much of her cognitive ability is restored, she’s started reading philosophy books and novels again. She continues to volunteer, participate in Voices of Alzheimer’s, and give lectures. Chopp says she’s “trying to stay busy, but happy and relaxed.”

Although her case sounds like a fluke or a miracle, Chopp has learned from some doctors and researchers that the situation is not completely unique — there are cases where Alzheimer’s seems to have been reversed or misdiagnosed. She also has heard of, and has friends who have experienced, a misdiagnosis where the patients may have another type of dementia. 

“It’s important to remember that science really didn’t have the tools to do almost any Alzheimer’s diagnosis until the last 10, 15, 20 years,” she says. “Before that, it was very rare, and it usually occurred when people were in the final stages.” Even Chopp’s own mother, for example, wasn’t diagnosed until the disease had progressed to the point where she was having hallucinations.

Chopp’s story motivated Colgate Magazine to reach out to a few alumni working in the field.  

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An App to Detect Early Warning Signs

Anecdotally, Chopp has learned that her case was not entirely unique, but a February article in the Wall Street Journal highlighted an increasing number of patients who had been diagnosed with Alzheimer’s and later found out they did not have the disease. Each case varies, but the phenomenon calls into question: How is Alzheimer’s being diagnosed? 

“Divergent diagnoses for Alzheimer’s are the result of different criteria for diagnosing the disease,” the Wall Street Journal reports. Doctors don’t always agree on whether to rely mainly on the presence of the brain protein amyloid, as the Alzheimer’s Association 2024 criteria for diagnosis suggests; or whether to follow the three-prong criteria established by the International Working Group — the presence of amyloid, tau, and cognitive symptoms. Further complicating diagnoses, symptoms can be varying and subjective and could be caused by something else, like the theory about Chopp’s brain lesion or vascular disease of the brain. Lastly, what if, by the time symptoms present, it’s too late?

Dr. Pankaj Gupta ’88 is a Harvard-trained geriatrician who now works in managed care, and he stresses that “diagnosing Alzheimer’s holistically is essential.” Gupta’s health care technology start-up is developing a patent-pending app that he hopes can be one piece of that puzzle — before it is too late.

Called LexisMD, the app uses machine learning and large language models to detect whether the user is at risk for mild cognitive impairment (MCI) — which, for some, can be an early sign of dementia.

Gupta asserts: “Up to 40% of MCI cases are reversible.” Studies have shown that symptoms can improve with lifestyle changes, including diet, good sleep habits, mental health, and physical activity.

The app is a risk-assessment tool that evaluates your risk of having MCI through language patterns, such as pauses, how long it takes the user to complete a sentence, and word finding. It is not a diagnostic tool, but it could help with prevention by encouraging people to talk to their doctors. 

“When I got into geriatrics, I saw so many patients who already had full-blown dementia,” Gupta says. “That made me think, I want to focus on the stage before dementia.”

Working in managed care, Gupta understands how difficult it can be to navigate insurance and approvals. In fact, that was his motivation to earn an MBA from Cornell and change course after practicing medicine: “I wanted a larger stage because I felt the elderly were disadvantaged. The health care system in this country is like a maze.”

The app, he believes, serves as an easy and accessible tool for people. “There’s so much respected scientific literature about language patterns and MCI,” he says. “So why not make an app that puts it all together to monitor your risk of having MCI — in the comfort of your home and while talking on your cell phone?”

Gupta concludes: “I want this country and the world to be prepared. [I want people to be able to] do estate planning, retirement planning, etc. But the key word is planning — being proactive.”

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Using AI to Assess MRI Scans

Measuring blood-based biomarkers, as was used last summer to reassess Chopp’s case, is one way researchers are hoping to improve Alzheimer’s diagnosis. Another is by using artificial intelligence, which Avi Chandra ’11 is studying as a postdoctoral research associate at Queen Mary University of London.

In the United Kingdom, one in two people will be directly affected by dementia — either through caring for someone with the condition, developing it themselves, or both — according to Alzheimer’s Research U.K. “There are people in this country who are living with dementia but don’t have a diagnosis, and they aren’t getting the treatment or the support they need,” Chandra says.

He’s part of a team, supported by the National Institute for Health and Care Research, that is gauging the efficacy of AI in getting an earlier and more accurate diagnosis of dementia. They’re applying AI to MRI images to pick up subtle patterns in the brain over time — to find small changes that doctors or radiologists might not be able to see. “The technology we’re testing shows about 92% accuracy in predicting whether someone will develop dementia,” Chandra says.

For his part, Chandra has been collecting real-world data by seeing patients in person and gathering data retrospectively from the National Health Service in England. “We’re looking at patients who have been to the memory clinic who have received a diagnosis of some kind of cognitive impairment, and basically we’re seeing if the technology replicates in this real-world cohort,” he explains.

“The aim is to improve the time it takes and the accuracy for getting a dementia diagnosis,” Chandra continues. “In the U.K., patients need to be followed up with for at least one to two years before they can be certain of a dementia diagnosis. This is a crucial period for planning, eligibility, and treatments and support, so we’re trying to give doctors another tool by using AI to hopefully diagnose dementia sooner.”

Independently, Chandra is studying the “modifiable lifestyle risk factors for dementia,” and he’s published papers looking at how those are related to the pathology or neurotoxicity that underlies Alzheimer’s. One of the lifestyle risk factors he’s examined is people who are widowed or divorced. “I found that they had lower memory scores relative to people who were married,” Chandra says. “This was mediated by amyloid beta protein levels, indicating that there might be some neuropathological component or outcome consequence that results from the stress of being widowed or divorced that might increase dementia risk.”

Last year Chandra also published a paper on the relationship between hearing loss and Alzheimer’s. “We found that central hearing loss — not just peripheral, not just detecting a sound, but detecting a sound with background noise or discriminating between two different stimuli in either ear — was linked to tau protein, which is one of the contributing factors, we believe, to the brain cell loss in Alzheimer’s.”

In addition Chandra investigates risk factors related to genetics, ethnicity, and socioeconomic status. “As a postdoc, I do a lot of different things,” he acknowledges.

Outside of his research, Chandra does public engagement work. “It’s important to go beyond the papers and translate them to the real world,” he says. He offers his expertise to the media, and he and a colleague have been visiting South Asian religious centers to give dementia awareness workshops.

At Colgate Chandra was an economics major, but in his sophomore year he took a psychology course and “fell in love with the brain.” He added neuroscience courses to his schedule, conducted lab work with Professor Spencer Kelly, and wrote a thesis with Professor Rebecca Shiner. “Afterward, I knew research was the path I wanted to go down,” he says.

Chandra went on to earn his PhD at King’s College London, and he soon realized, “I wanted to do something that had a societal impact.” Also, his grandmother was diagnosed with dementia, and “I found out firsthand how devastating dementia was.”

Although Chandra is based in the U.K., he’s part of the DEMON network, an international group of people who are collaborating to identify innovative approaches to interdisciplinary dementia research across multiple institutions using data science and AI.

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A Global Lens

Taking a worldwide view of Alzheimer’s could provide valuable insights. At the National Institute on Aging (NIA), Minki Chatterji ’89 is part of the National Institutes of Health’s (NIH) effort to support international research on the disease. “We believe cross-national comparisons of different contexts and how they influence outcomes can help us learn a lot about causes of the disease that will also help older people in the U.S.,” Chatterji says.

As a program officer, she oversees a portfolio of grants to U.S. and international institutions studying aging, specifically Alzheimer’s disease (AD) and Alzheimer’s Disease Related Dementias (ADRD). She also oversees a portfolio of grants on how Medicare and Medicaid influence access, cost, and use of health care by older adults in the U.S., with an emphasis on AD/ADRD. 

The 73 grants in Chatterji’s portfolio are valued at more than $60 million.

The NIA has supported research in more than 50 countries; Chatterji’s portfolio includes studies in Latin America, Europe, Asia, and Africa. Her work has brought her to the Austrian Alps, the American University of Cairo, the All India Institute of Medical Sciences in Delhi, and places in between.

A program officer’s role: “We act as the liaison between the NIH and researchers. We guide investigators through the application process, evaluate scientific aims for alignment with institute priorities, monitor ongoing funded research, and make recommendations on funding decisions.”

Her portfolio includes: “National representative studies, including a set of established cognitive and neuropsychological assessments and informant reports to better characterize cognitive function among older people. These studies also include collection of data on risk factors related to AD/ADRD and dementia. Many of these studies also include collection of AD blood-based biomarkers and genomic data collection.”

Some findings: “We’ve found that dementia prevalence is higher in the U.S. than it is in England, and there are bigger differences if you compare rich people and poor people, or compare less educated with more educated people — those differences are bigger in the U.S. than in England. Another study did a national comparison of negative wealth shocks (when a household loses a lot of money), and they showed that in older adults in the U.S., even if they experienced that wealth shock decades before, their cognition was worse than older adults in England. We hypothesize that this is because, in England, they have a better safety net. In a study in South Africa, they found that giving cash transfers to households slowed memory decline and reduced dementia risk among older adults. There are also a lot of studies recently on pollution, which India has, and it’s fascinating how they found that different types of particulate matter increase the instances of dementia.”

Dementia defined: “Dementia is a general term for cognitive decline, and there are many brain disorders that cause this condition — the most common are Alzheimer’s disease, vascular dementia, Lewy body dementia, and frontotemporal dementia. Most people suffering from clinically diagnosed dementia have mixed pathologies, meaning their dementia is caused by more than one type of brain change.”

An evolving picture: “Our understanding of the biological basis and pathways of AD/ADRD is complex and our understanding is evolving. That’s why, even though we’ve made some advances in treatment, the clinical benefits currently remain modest. However, to crack the nut of the biological basis, NIA is focusing on all different pathways. We don’t know [for example] if amyloid plaque causes the dementia or whether it’s just associated with dementia. Another issue is we need more early diagnosis tools, so we’re funding things like that too.”

The bottom line: “Even though we have some general ideas of risk factors for AD/ADRD — like stress or social connection or environmental factors — we lack large-scale public health strategies. That would save a lot of money, but we’re not there yet.”

Chatterji majored in history and EAst Asian studies at Colgate before earning her master’s in Southeast Asian studies at Cornell and a PhD in demography from UC Berkeley. She says the inspiration for her work was Colgate’s Japan Study Group: “That was really pivotal. It got me interested in foreign cultures, foreign languages, and seeing different parts of the world”

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The Promise of Stem Cell Therapy

If you have a broken refrigerator and your food is spoiling, would you just remove the spoiled food and keep your broken refrigerator? “No, you have to fix the refrigerator,” says Dr. Christopher Duma ’81, a neurosurgeon in Newport Beach, Calif. 

Duma is head of the brain tumor program at Hoag Hospital, where he also performs neurosurgery on patients with Parkinson’s disease. In his free time, he’s invented what he believes might be a fix for Alzheimer’s.

The technique he’s invented injects stem cells into the brain through an Ommaya reservoir, a neurosurgery device the size of a quarter that’s placed under the scalp and allows repeat administration of medicines.

“Alzheimer’s disease [involves] all these different problems: inflammation, P-tau, beta, oxidative stress,” he says. Existing pharmaceuticals aren’t a good treatment option, according to Duma, calling into question their effectiveness and the danger of side effects. “Big pharma is targeting just one of the problems [amyloid plaque]. You need to target everything. And in my neurosurgical mind, I thought, a stem cell is the only thing that can do this.”

He goes on to explain: “Most people do not know that our brains are hollow in the middle, [like] a honeydew melon. [Our brains] have hollow cavities called ventricles, and they produce the cerebrospinal fluid that bathes every nook and cranny of our brains. Cerebrospinal fluid is like spring water, and it’s a constant circulation that’s literally giving us a ‘brainwashing.’ We can use this fluid to deliver the stem cells throughout the entire brain. Interestingly, right next to the ventricle, we all have stem cells sitting there, waiting to be awakened.” There is a barrier at the edge of the ventricle that, as we age, becomes porous. “So if you injected stem cells in there, it’s quite likely it will get through and be able to stimulate those dormant stem cells,” he says. 

Duma continues: “A substance called Wnt is a signaling protein that if it’s being exhibited on a stem cell, that expressing Wnt stem cell can go to another stem cell, and that is the signal for that next stem cell to turn on. Then that stem cell gets turned on and another one gets turned on in the same wave.” The Wnt wave, he says, is “like being at a football game and people start the wave. It is a way to resurrect these little dormant stem cells living in the wall of the ventricle and get them to be active. 

“What we know of stem cells is, once they’re active, they can seek out areas of damage and repair them. That’s their job, and they have all the genetic material to create what they’re supposed to create in that environment. They’re extremely powerful.”

Duma formed Regeneration Biomedical to house lab space and attract investors for clinical trials. His technique uses patients’ own, non-modified stem cells, and he completed a U.S. Food and Drug Administration (FDA) Phase 1 clinical trial with six people. They were all in the middle to advanced stages of the disease and had cognitive mini-mental state examination (MMSE; a test used to check for cognitive impairment) scores as low as a 9 on a scale of 1–30. After one year of injections, some were scoring at 19–20, “a result that has yet to be seen with any existing FDA-approved treatment in the Institutional Review Board–approved research,” according to Regeneration Biomedical’s website. The results have shown “a leveling off” in scores, requiring booster shots every two months for the first two years, “and then potentially at intervals further apart.”

Duma says: “We had zero complications. The patients didn’t even get a headache when we injected the cells. We also saw amyloid PET scan improvement in almost all of them with a single injection. We are also normalizing the tau protein with every single patient.” On the Alzheimer’s Disease Assessment Scale-Cognitive Subscale, patients’ scores also improved. He’s been presenting these findings at conferences around the world.  

The FDA has approved a Phase 2, multicenter trial; Duma has five hospitals on board and is looking for investors. One of his investors in the first trial was the husband of a woman who participated in the trial, “because he saw how well we did with [her],” Duma says.

He hopes this treatment will have potential for other diseases, too, including ALS, multiple sclerosis, Parkinson’s, and even traumatic brain injury. “There is not one neurodegenerative disease that we don’t think we can actually work on,” he says.

An avid musician, Duma started a nonprofit called Music Heals to help patients with Parkinson’s and autism. He’s also the front man for a rock band called The Circle of Willis, named after an anatomical structure in the brain.