Neurologist Rudy Tanzi was still a graduate student at Harvard Medical School when he helped identify the first gene associated with hereditary Alzheimer’s – amyloid beta-protein precursor, or APP.
“It was the summer of ’86. I was 27 years old,” Tanzi recalls. “I remember thinking that for the first time since Dr. Alois Alzheimer described amyloid in 1906, we now have a clue to its origins.”
The discoveries never stopped. Scientists around the world have continued to chip away at the genetic underpinning of this heartbreaking disease that steals the mind, leaving the body empty of its former self.
An additional 42 genes connected to the development of Alzheimer’s disease were discovered in 2022, bringing the total to 75. Shortly after that revelation, yet another gene called MGMT was identified – and this one might explain why women are two-thirds more likely to be diagnosed with Alzheimer’s than men.
“It’s a female-specific finding – perhaps one of the strongest associations of a genetic risk factor for Alzheimer’s in women,” senior study coauthor Lindsay Farrer, chief of biomedical genetics at Boston University School of Medicine, told CNN in an earlier interview.
With so many genes contributing to the development of Alzheimer’s and other types of dementia, scientists are convinced that each person’s journey may be different.
“There is a saying: Once you have seen one person with Alzheimer’s, you’ve seen one person with Alzheimer’s,” said Dr. Richard Isaacson, director of the Alzheimer’s Prevention Clinic in the Center for Brain Health at Florida Atlantic University’s Schmidt College of Medical.
“Alzheimer’s disease is a multifactorial disease, made up of different pathologies, and each person has their own road. The disease presents differently and progresses differently in different people.”
One key genetic pathway is APOE ε4, a gene variant responsible for encoding proteins that carry cholesterol in the brain. Having one copy of the gene puts people over the age of 65 in danger, while having two copies is considered the strongest risk factor for the future development of Alzheimer’s in that age group.
But it’s not a given. Some people with APOE ε4 don’t go on to develop Alzheimer’s, while others without the gene may find themselves with the hallmark signs of tau tangles and beta amyloid plaques.
Another pathway to Alzheimer’s is inflammation, “which is common to all chronic disease,” Farrer said. Several new genes discovered this year appear to play a role in how the body’s immune system removes damaged cells from the brain.
To bolster research, federal funding in the United States for Alzheimer’s research has increased sevenfold since 2011 to more than $3.4 billion annually, said Rebecca Edelmayer, senior director of scientific engagement for the Alzheimer’s Association.
One focus of research is to find therapeutics that target the immune system as well as inflammation in the brain, Edelmayer said, while other research investigates cell metabolism and how cells use energy.
Scientists are also trying to understand more about how brain cells are connected and communicate through synapses, and “we’re even seeing investigations that are looking at the gut and brain connection, which is another interesting approach,” she said.
Researchers are racing to find breakthroughs in treatment, aided by additional funding in recent years from the public and private sectors, Edelmayer added. The Chicago-based Alzheimer’s Association alone is providing over $300 million in funding for more than 920 projects in 45 countries.
“We want to focus on strategies that are going to be both culturally appropriate but also effective and scalable around the world,” Edelmayer said.
Another focus of research is the examination of existing drugs that might prevent Alzheimer’s from taking root in the brain.
In his lab, Harvard’s Tanzi uses tiny organoids composed of human brain cells that can develop the typical amyloid plaques and tau tangles of Alzheimer’s in just over a month. Tanzi and Harvard co-creators Doo Yeon Kim and Se Hoon Choi published a seminal paper on their discovery in 2014, dubbing it “Alzheimer’s in a dish.”
Tanzi and his team have spent seven years testing drugs that the US Food and Drug Administration has already approved on the “brain” in the dish. Since the FDA has already verified the safety of those drugs, finding a candidate from that group would accelerate federal approval of the drug for Alzheimer’s, thus getting treatments to patients faster, he said.
Tanzi also tested natural products, such as herbs, spices, vitamins, minerals and antioxidants, for their ability to affect the plaques and tangles in his mini-brains creation.
“We were able to rapidly screen every approved drug and over 1,000 natural products,” Tanzi said. “And now we have over 150 identified drugs and natural products that could be tested in clinical trials to hit plaques, tangles or neuroinflammation.”
He and his team at MassGeneral Institute for Neurodegenerative Disease in Boston hope soon to begin clinical trials and collaborate with other scientists to see which of the potential candidates can deliver results.
“It’s all about hitting the right person with the right drug, at the right time in the course of their disease,” he told CNN.
“Many people may not know this, but after 40 years old, just about all of us start to build up the initiating pathology of Alzheimer’s, which is amyloid plaque in the brain and the neurofibrillary tangles,” he continued. “It’s part of life, just like most of us begin to build up a little bit of plaque in our arteries from cholesterol.”
In fact, Tanzi estimates some 30 million to 40 million Americans have enough amyloid in their brains right now to benefit from a drug to lower it – if science had the ability to do so safely and affordably.
“I like to say the amyloid is like the match, and the tangles are like brush fires that propagate and spread over decades,” Tanzi said. “And along the way you’re triggering big forest fires, that’s neuroinflammation.”
By the time a person shows any signs of cognitive decline, he added, “the forest fire of neuroinflammation is blazing,” and it’s too late to rescue the brain significantly and improve thinking and memory skills.
“The elephant in the room is that we wait until the brain deteriorates to the point of dysfunction before we treat this disease,” Tanzi said. “That’s like saying wait until you lose half of the beta cells in your pancreas before we diagnose diabetes.”
One of the reasons clinical drug trials over the last few decades failed to control amyloid buildup was because many of the study participants were in more advanced stages of the disease when “too much of destruction had been done,” Edelmayer said.
“Removing amyloid at that time wasn’t necessarily helpful,” she said. “It has taken us some time to truly understand at what point in the disease process do we need to specifically target amyloid with drugs.”
Case in point: The controversial amyloid-removing drug aducanumab, which sold under the brand name Aduhelm, was only tested on people with mild cognitive impairment. The FDA approved the use of aducanumab in 2021 despite the fact that all but one member of an independent expert panel charged with reviewing the drug’s effectiveness voted against approving it.
While aducanumab did remove amyloid, the clinical trial only showed a small improvement in cognition in one subset of patients. Some doctors and medical institutions around the country decided not to offer aducanumab to their patients after balancing the drug’s weak performance with cost and significant side effects.
In April, Medicare announced it would only cover the drug’s cost of $56,000 a year if the person was enrolled in a study approved by the Centers for Medicare & Medicaid Services. In the same month, Biogen, the company that developed the drug, gave up on getting the drug’s approval in the European Union. By May, the company announced it would stop supporting the drug.
“I want to make it clear to people that to end Alzheimer’s, we need early detection, early intervention some 10, 20 years before symptoms show up,” Tanzi said. “And what about the 6 million people in this country with this disease right now? For them, we need to put out the fire, stop the neuroinflammation, stop the killing of neurons.”
Screening tools for Alzheimer’s would speed up research and assist clinicians in finding cases of Alzheimer’s at an earlier stage. However, most current tests are invasive, such as spinal taps, or enormously expensive, such as positron emission tomography, or PET scans, which insurance companies often refuse to cover.
“In the end, we need screening tools that are going to be scalable, not invasive, and certainly something that is cost-effective for patients and their families,” Edelmayer said. “A blood test really is the holy grail if we can get there. We’re not there yet, but we’re getting closer. Ask me in another two years.”
Preventive methods are a key focus of much of today’s research. Lifestyle changes such as improving exercise, eating a plant-based diet, addressing sleep deficits, reducing stress, improving social connections and engagement and some types of cognitive training are all showing impressive results for people early in the disease process. Keeping cholesterol and blood sugar in check at early ages are also key to good brain health.
Two recent studies in the US have shown such lifestyle interventions, along with medications, vitamins and supplements, can prevent decline and also improve memory and thinking skills.
“There were actually cognitive improvements at 18 months in both women and men when compared to the control populations,” said Isaacson, who authored the studies. Even people who carried the Alzheimer’s gene APOE ε4, which raises risk for late-life dementia, saw benefits in cognition, he said.
More than 25 countries are running similar multidomain lifestyle interventions as part of the World Wide FINGER network, Edelmayer said. FINGER stands for the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability. People who participated improved their cognition by 25% over two years, according to the study.
“I am very cautious to use words like cure,” Isaacson said. “But when we use all of these various tools early, during the years of pre-dementia, I think prevention is a cure. And hopefully risk reduction can delay pathology long enough so that the person will pass away from something else before they ever develop dementia.”
All these research approaches are “bringing us to the threshold of a transformational new era in Alzheimer’s research,” Edelmayer said. “It’s just time right now that we’re up against, especially for those currently living with the disease.”