The discoveries never stopped. Scientists around the world have continued to chip away at the genetic underpinnings of this heartbreaking disease that steals the mind, leaving the body empty of its former self.

Many roads lead to Alzheimer’s

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’s a saying: Once you’ve seen a person with Alzheimer’s, you’ve seen a person with Alzheimer’s,” said Dr. Richard Isaacson, director of the Alzheimer’s Prevention Clinic at the Brain Health Center at Florida Atlantic University’s Schmidt College. Medicine. “Alzheimer’s disease is a multifactorial disease, consisting of different pathologies, and each person has their own path. The disease appears differently and progresses differently in different people.” A key genetic pathway is APOE ε4, a gene variant responsible for coding for proteins that transport cholesterol to the brain. Having one copy of the gene puts people over the age of 65 at risk, while having two copies is considered the strongest risk factor for later developing Alzheimer’s in this age group. But it is not a given. Some people with APOE e4 do not go on to develop Alzheimer’s, while others without the gene may find themselves with the characteristic signs of tau tangles and beta amyloid plaques. Another pathway to Alzheimer’s is inflammation, “which is common to all chronic diseases,” 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.

Funding boost

To boost 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 finding treatments that target the immune system as well as inflammation in the brain, Edelmayer said, while other research is investigating cell metabolism and how cells use energy. Scientists are also trying to understand more about how brain cells connect and communicate through synapses, and “we’re even seeing research looking at the gut-brain connection, which is another interesting approach,” he said. Researchers are scrambling to find treatment innovations, helped by additional funding in recent years from the public and private sectors, Edelmayer added. The Chicago-based Alzheimer’s Association alone provides more than $300 million in funding for more than 920 projects in 45 countries. “We want to focus on strategies that are both culturally appropriate but also effective and scalable around the world,” Edelmayer said.

Search for existing drugs

Another focus of the research is looking at existing drugs that could prevent Alzheimer’s disease from taking root in the brain. In his lab, Harvard’s Tanzi uses tiny organoids made up of human brain cells that can develop the typical amyloid plaques and tangles of Alzheimer’s in just over a month. Tanzi and Harvard co-creators Doo Yeon Kim and Se Hoon Choi published a landmark paper on their discovery in 2014, dubbing it “Alzheimer in a dish.” Tanzi and his team spent seven years testing drugs that the US Food and Drug Administration has already approved in the “brain” on the plate. Since the FDA has already verified the safety of these drugs, finding a candidate from this group would speed up federal approval of the drug for Alzheimer’s disease, getting the 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-brain creation. “We were able to quickly 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 the MassGeneral Institute for Neurodegenerative Disease in Boston hope to soon begin clinical trials and work with other scientists to see which of the potential candidates might produce results. “It’s all about hitting the right person with the right drug at the right time in their disease course,” he told CNN. “A lot of people may not know this, but after 40 years, almost all of us start to develop the initial pathology of Alzheimer’s, which is the amyloid plaque in the brain and the neurofibrillary tangles,” he continued. “It’s part of life, as most of us start to build up some plaque in our arteries from cholesterol.” In fact, Tanzi estimates that about 30 to 40 million Americans have enough amyloid in their brains right now to benefit from a drug to reduce it — if science had the potential to do it safely and affordably. “I like to say that amyloid is like matches and tangles are like wildfires that spread and spread over decades,” Tanzi said. “And in the process you start big wildfires, that’s neuroinflammation.” By the time a person shows signs of cognitive decline, he added, “the wildfire of neuroinflammation is burning,” and it’s too late to significantly rescue the brain 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’ve lost half the beta cells in your pancreas before we diagnose diabetes.” One of the reasons clinical drug trials in recent decades failed to control amyloid buildup was because many of the study participants were in more advanced stages of the disease when “too much damage had been done,” Edelmayer said. “Removing the amyloid at that time was not necessarily helpful,” he said. “It took us a while to really understand at what point in the disease process we needed to specifically target amyloid with drugs.” Example: The controversial amyloid removal drug aducanumab, sold under the brand name Aduhelm, was only tested in people with mild cognitive impairment. The FDA approved aducanumab for use in 2021, despite the fact that all but one member of an independent panel of experts tasked with reviewing the drug’s effectiveness voted against its approval. While aducanumab removed amyloid, the clinical trial showed only a small improvement in cognition in a subset of patients. Some doctors and medical institutions across the country have decided not to offer aducanumab to their patients after balancing the drug’s weak performance against its cost and significant side effects. In April, Medicare announced that it would only cover the drug’s $56,000-a-year cost if the person enrolled in a study approved by the Centers for Medicare & Medicaid Services. That same month, Biogen, the company that developed the drug, withdrew its approval of the drug 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 about 10, 20 years before symptoms appear,” Tanzi said. “And what about the 6 million people in this country with this disease right now? For them, we have to put out the fire, stop the neuroinflammation, stop the neuron killing.”

Lifestyle interventions

Alzheimer’s disease screening tools will speed up research and help clinicians find Alzheimer’s cases at an early stage. However, most current tests are invasive, such as a spinal tap, or extremely expensive, such as positron emission tomography or PET scans, which insurance companies often refuse to cover. “Ultimately, we need screening tools that are scalable, not invasive, and certainly something that is cost-effective for patients and their families,” Edelmayer said. “A blood test is really the holy grail if we can get there. We’re not there yet, but we’re getting close. Ask me in two years.” Preventative 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 certain types of cognitive training all show impressive results for people who are at the beginning of the disease process. Keeping cholesterol and blood sugar under control at a young age is also key to good brain health. Two recent US studies have shown that such lifestyle interventions, along with drugs, vitamins and supplements, can prevent falls and also improve memory and thinking skills. “There were indeed cognitive improvements at 18 months in both women and men compared to control populations,” said Isaacson, who authored the studies. Even people who carried the Alzheimer’s gene APOE e4, which increases the risk for dementia later in life, saw benefits in cognitive function, he said. More than 25 countries are conducting similar multi-sector lifestyle interventions as part of the World Wide FINGER network, Edelmayer said. FINGER stands for the Finnish Geriatric Intervention for the Prevention of Cognitive Impairment and Disability. People who participated improved their cognition by 25 percent over two years, according to the study. “I’m very careful about using words like cure,” Isaacson said. “But when we use all these different tools early, during the pre-dementia years, I think prevention is cure. And hopefully reducing the risk can delay the pathology long enough that the person dies of something else before it ever develops. dementia”. All these research approaches “bring us to the threshold of a transformative new era…