Corrie Pikul is a health writer and editor in the Boston area. Send comments to magazine@globe.com.For decades, Alzheimer’s has frustrated every effort to cure it, despite often promising efforts. “While we’ve cured Alzheimer’s in a million mice, we still haven’t cured it in humans,” says Dr. Reisa Sperling, who directs the Center for Alzheimer Research and Treatment at Brigham and Women’s Hospital. The need for better approaches has only intensified as the US population ages, increasing the number of Americans vulnerable to the disease.
Sperling, who is also a professor of neurology at Harvard Medical School, is part of a deep bench of Boston-area Alzheimer’s researchers who are building on the region’s rich tradition of medical research. With a high concentration of scientists (especially neuroscientists), treatment centers and hospitals with advanced imaging and other tools, and now, biomedical companies, Boston has emerged as a hotbed of Alzheimer’s study. And while there still isn’t a cure, there is an ever-growing list of notable discoveries to diagnose the disease, alleviate its effects, and potentially prevent it. Sperling, who lost her father to the disease, is optimistic that this will lead to better results for those with Alzheimer’s. “Boston,” she says, “is a great place in which to translate those findings into therapies to help people.” Here are five recent advances.
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1. The Global Research Effort
Alzheimer’s begins changing the brain up to 20 years before a person begins experiencing symptoms. Sperling is one of the leaders of the AHEAD Study, a global research effort that aims to shed light on how the disease develops. It’s recruiting people as young as 55 — the youngest cohort for a late-onset Alzheimer’s prevention trial — who don’t have symptoms of the disease but are at risk for it. Participants will have their brains imaged via positron emission tomography, or PET scans, to look for intermediate or elevated levels of the brain protein amyloid, which has been linked to memory loss associated with Alzheimer’s. Depending on participants' levels, they’ll be assigned to one of two clinical trials to test a drug that might curb cognitive decline. Participants will undergo brain imaging during the four-year study to assess buildup of amyloid as well as levels of another brain protein called tau. They may also receive an experimental drug, BAN2401, that researchers hope can decrease amyloid levels and stave off cognitive decline. (BAN2401 is being developed by Biogen and Eisai, a pharmaceutical company that is funding the study along with the National Institutes of Health.) “The goal of this kind of targeted dosing is intended to prevent people from developing a head full of amyloid,” Sperling says. For more information and to learn about eligibility requirements, go to aheadstudy.org.
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2. Steps Forward in a Blood Test
Researchers have long sought simple, inexpensive blood tests for Alzheimer’s. For starters, they’d make it easier to diagnose the disease, and differentiate it from other types of dementia, at a much earlier age. It would also make screening participants for clinical trials faster and easier, a crucial aid for developing potential therapies.
So it was big news this summer when teams led by researchers at Lund University in Sweden and Washington University in St. Louis released results showing blood tests were able to detect forms of the brain protein tau in people with cognitive decline as precisely as more costly, invasive, and less accessible measures such as PET imaging and testing of cerebrospinal fluid.
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A related type of blood test is being developed by a group of researchers led by Sperling and her Brigham and Women’s colleague Dennis Selkoe. They are looking at whether screening cognitively normal people for a form of tau called NT1 can help predict which of those people will eventually experience cognitive decline. They’ve found that not only are high levels of NT1 associated with changes in memory, but also with “diminished executive function and a greater loss of tissue from the hippocampus, which is important for memory,” says Dr. Jasmeer Chhatwal, one of the researchers, as well as a neurologist at Mass. General and an assistant professor of neurology at Harvard Medical School. A paper explaining their results is forthcoming in the journal Nature Communications. While none of the blood tests is yet ready for clinical use, they could be available in two or three years.
3. A Second Chance for Biogen’s Aducanumab
Hopes for an effective Alzheimer’s drug were dashed in 2019 when Biogen suddenly halted trials for its promising aducanumab drug for reasons of “futility.” The drug, a human monoclonal antibody — made by cloning a white blood cell, the warriors of our immune system — targets beta-amyloid to help prevent the sticky protein from aggregating into plaques, and to remove existing plaques. After promising initial trials, aducanumab seemed to be ineffective at halting the progression of the disease in test subjects with mild Alzheimer’s. But Biogen, based in Cambridge, looked at data gathered in the months leading up to the trial being discontinued, and realized this data told a different story. The company resubmitted its application to the FDA with the new information, and this summer the agency put the drug on the fast track for review. On November 6, the FDA is expected to decide whether aducanumab may actually be the first drug that can reduce cognitive decline caused by Alzheimer’s.
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4. Dance Clubs Might Be Good for the Brain
Regular exposure to rhythmic light and sound bursts might help keep Alzheimer’s from forming, according to research from The Picower Institute for Learning and Memory at MIT. A team of researchers led by institute director Li-Huei Tsai found that when lab mice were put into a dance-club-like environment where they were exposed to pulses of light and sound, it had a remarkably healthy effect on their brains. The researchers knew that high frequency oscillation (patterns higher than 30 hertz) could improve communication between different regions of the brain, but they wanted to see what was actually going on with the cells themselves. They found that when the rodents experienced bursts of light and sound 40 times per second, a rate of 40 hertz, the nerve cells in their brains fired in synchronicity. This boosted the activity of microglial cells, the brain’s immune defenders that can clear amyloid plaques and tau tangles, and even improved blood flow. What’s more, hourlong sessions of 40-hertz pulses over several weeks massively reduced levels of amyloid and tau proteins in their brains, while also improving their learning and memory capacity. “These are really surprising findings,” says Tsai. “We are seeing multiple different cellular responses that are consistent with increased brain health.”
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Tsai and her team at MIT are now in the middle of a small-scale clinical trial that applies these insights to early stage Alzheimer’s patients; the startup Cognito Therapeutics in Cambridge has licensed the technology and is also conducting human studies. Her research group, in collaboration with investigators at MGH, was recently awarded a grant from the Alzheimer’s Association in partnership with Bill Gates to test this approach in people who are at a high risk for Alzheimer’s but don’t yet have any memory deficits.
While lights flashing at 40 hertz may not be appropriate for everyone, most people shouldn’t have issues with it — computer screens refresh at a rate of 60 or 70 hertz. Tsai says the potential is obvious for a prevention technique. She adds, “This type of sensory stimulation may well be the best approach for the prevention of Alzheimer’s.”
5. Smartphone Diagnostics
When researchers study the effectiveness of dementia medications, they typically bring patients in and have them draw overlapping pentagons or maybe complete a maze on paper. “These paper-and-pencil tests are insufficient” for detecting subtle cognitive changes that could suggest risk of future impairment, says Dr. Kathryn V. Papp, an assistant professor of neurology at Harvard Medical School and a neuropsychologist at Brigham and Women’s. So Papp and her team are making memory and thinking tests on smartphones into early warning systems for Alzheimer’s.
Their study sends text messages to participants, asking them to match faces and names or grocery items and prices — everyday acts of simple cognition. Papp has found that when patients take these tests each month, the pitch of their learning curve can be correlated with their risk for Alzheimer’s (those at higher risk tend to have a weaker curve).
Her team has also found performance on these phone-based tasks is related to markers of amyloid and tau in the brain. The phone format has been especially advantageous during COVID times, she notes, when researchers have been limiting the number of people they bring into the clinic. Still to come is comparing the smartphone assessments with blood tests, genotyping, and neuroimaging. These methods all require people to come into a lab, but smartphone assessments could save them an hour or two taking tests when they do. Clinical trials for Alzheimer’s treatments often take four to five years, Papp says. If the smartphone tests are effective, they could greatly accelerate research. “If we can speed up the assessment of cognitive function, that will really speed up a trial and capture the intervention’s effects much more quickly, not to mention save a lot of time and money,” Papp says. “It’d be really impactful for the field.”
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Corrie Pikul is a health writer and editor in the Boston area. Send comments to magazine@globe.com.