New Alzheimer's Treatments Could Slow Memory Loss—Here's What to Know
The current research around treatment is advancing toward disease-modifying therapies to address the underlying biology of Alzheimer's disease in different ways, explains Brent Forester, MD, Psychiatrist-in-Chief and Chair for the Department of Psychiatry at Tufts Medical Center, Director of Behavioral Health for Tufts Medicine and Professor of Psychiatry.
Here we break down both the existing medications to help with cognitive complaints as well as those still in clinical trials or development.
There are currently two medications that are approved by the Food and Drug Administration (FDA) for the treatment of Alzheimer's: donanemab (brand name Kisunla) and lecanemab (brand name Leqembi). The two recently introduced compounds are anti-amyloid therapeutics, meaning they are designed to stick to and help remove amyloid beta protein.
Abnormal buildup of amyloid plaques in the brain is believed to contribute to memory loss. And while removing these proteins appears to slow disease progression, neither medication will completely stop or reverse Alzheimer's.
'We know for sure based on the research that's been done that when you look at before-and-after of amyloid brain scans, amyloid is high and then it essentially goes completely away after treatment,' confirms Dr. Forester.
Dr. Forester emphasizes that these drugs are most effective when administered in people with early stages of Alzheimer's disease before significant cognitive decline occurs. Once someone is no longer able to function, drive or pay their bills, even if amyloid is removed from the brain, it's too late for the drugs to have a clinically-beneficial effect.
'There's only a [specific] window where these will potentially be beneficial, and that is in the mild cognitive impairment (MCI) stage, where there is mild cognitive impairment and normal functioning, or in the very mild Alzheimer's-type dementia stage where people are just mildly affected from a cognitive and functional standpoint,' explains Dr. Forester.
Right now, these drugs are only approved and available to be delivered through intravenous infusions. That means people are required to come into an infusion center either every other week or once a month to get an hour-long IV treatment, he notes.
There are also side effects associated with the drugs, especially those that may present more serious complications. Dr. Forester says two big concerns are bleeding or swelling of the brain, for which certain genetic factors can increase risk.
Over the next few years, it is likely that Alzheimer's drugs examining specific tangled protein fibers in the brain will advance through clinical trials, predicts Dr. Forester.
'There are also a number of compounds being studied to address other pathways that have not been addressed thus far,' he says. 'These are more directed at inflammation, energy metabolism, oxidative stress—more basic underlying pathways that contribute to the disease.'
There is currently no definitive diagnostic method for Alzheimer's. According to the National Institute on Aging, if cognitive decline is suspected, doctors may ask a patient (or a family member) if they are experiencing certain symptoms and ask questions about their overall health, use of prescription and over-the-counter medicines, diet, past medical problems, ability to carry out daily activities and changes in behavior and personality.
To land on a diagnosis of Alzheimer's, doctors may also:
Conduct tests of memory, problem solving, attention, counting and language
Order blood, urine and other standard medical tests to rule out other conditions
Administer a psychiatric evaluation to determine if depression or another mental health condition is causing or contributing to a person's symptoms
Collect cerebrospinal fluid (CSF) via a spinal tap and measure the levels of proteins associated with Alzheimer's and related dementias
Perform various brain scans
Dr. Forester notes that researchers are also getting 'very close' to having a blood-based biomarker that could be used for clinical practice. The two purposes of a biomarker would be to find the disease early enough that a difference could be made from a treatment perspective, as well as to track the effectiveness of the treatment.
'Once an individual advances past the early dementia stage, these new treatments are ineffective, so it's really important to talk to your doctor right away and ask what could be helpful,' he advises. 'Don't be afraid.'
Advancements in Alzheimer's Treatment: Research is progressing towards disease-modifying therapies for Alzheimer's, focusing on addressing the underlying biology of the disease. Two FDA-approved medications, donanemab and lecanemab, are designed to remove amyloid beta protein, which is believed to contribute to memory loss.
Effectiveness and Administration of Current Drugs: These drugs are most effective in the early stages of Alzheimer's, specifically during mild cognitive impairment (MCI) or very mild dementia stages. They are administered through intravenous infusions, but come with potential side effects like brain bleeding or swelling.
New Medications in Development: Future Alzheimer's treatments may target tangled protein fibers and other pathways like inflammation and oxidative stress. These developments are expected to progress through clinical trials in the coming years.
Testing and Diagnosis: Currently, there is no definitive diagnostic method for Alzheimer's. Diagnosis involves a combination of cognitive tests, medical evaluations and brain scans. Researchers are close to developing a blood-based biomarker for early detection and treatment tracking.
Importance of Early Detection: Early detection is crucial as new treatments are ineffective once the disease progresses beyond the early dementia stage. Patients are encouraged to consult their doctors early if cognitive decline is suspected.
An AI tool helped compile and summarize the key takeaways in this story. The story was then edited by Woman's World staff.
More cognitive decline:
Early Signs of Dementia in Women Doctors Say You Shouldn't Ignore—It Can Even Raise Your Cholesterol
Can Your Vision Predict Your Dementia Risk? Research Suggests It Can
Certain Alzheimer's Risks May Be Within Your Control, Say Doctors: How to Keep Your Mind SharpThis content is not a substitute for professional medical advice or diagnosis. Always consult your physician before pursuing any treatment plan.
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Removal of the tracer was dramatically slower in those who had not slept, compared with those who had. 'It was very evident,' Eide says. 'We were very, very surprised that we saw something after one night of sleep deprivation.' Even more notable was that after all participants were allowed to sleep normally the next night, the clearance of the tracer was still slower in those who had lost the earlier night of sleep. 'You don't compensate by having a good night's sleep,' Eide says. In a subsequent study, Eide and his team found that people who reported chronic poor sleep also showed delayed clearance of the tracer. Moreover, in people with dementia, brain volumes in the frontal, temporal and parietal lobes had shrunk compared with those who slept well. In part because dementia has been previously associated with poor sleep quality, perhaps because of atrophy in the cortex, Eide and his colleagues suspect that chronic sleep disturbance co-occurs with glymphatic dysfunction. There were also clear differences between humans and mice. In the rodents, for example, glymphatic transport was 'an on-off phenomenon,' Eide says—on during sleep and off when the mice were awake. In humans, the process is not as extreme, and changes occur over hours rather than minutes. The work nevertheless demonstrated that human brains, too, get cleaned during sleep—and that 'poor sleep quality is affecting your glymphatic function,' as Eide says. Laura Lewis has lost a lot of sleep in the course of her work because she conducts all-night experiments. 'The sad irony of being a sleep researcher is that you can't follow your own advice,' she says. Lewis has tackled a different piece of the glymphatic problem: the movement of fluids in the human brain that underpin waste clearance. That's how, about seven years ago, she came to be in the control room of an MRI machine very like the one in which she showed me Nick's CSF. Lewis had chosen to measure CSF flow in the brain's fourth ventricle, a small cavity tucked against the cerebellum at the base of the brain. The ventricles produce CSF and act like extra shock absorbers for the fragile brain. For Lewis's purposes, the fourth ventricle was useful because 'it's a kind of choke point.' Sitting as it does at the base of the brain, it provides a summary of what is happening elsewhere—like measuring attendance in a crowded room as people come through the door. In an overnight sleep study published in 2019, Lewis and her colleagues were the first to use MRI to view this process in action. By taking pictures of the brain every 367 milliseconds instead of the standard two or three seconds, they were able to see the movement of cerebrospinal fluid during sleep. At first, Lewis couldn't quite believe it. Typically the significant details of brain imaging require statistics and processing to tease out; they aren't something you can see by eye. 'It was honestly the biggest signal I've ever seen,' Lewis says. 'It was crazy. It's really striking how much you can see that this is happening during sleep.' Lewis delayed publishing the research until she had triple-checked it. It has since been replicated several times. 'When people are sleeping, there are these really huge and slow waves of flow that are pulsing every 20 to 30 seconds in the brain, specifically when we're in non–rapid eye movement sleep,' Lewis says. Using EEG data, she also saw clear patterns of brain activity before each wave. As delta waves of deep sleep and, to some extent, 'theta' waves during intermediate (stage 2) sleep sweep through the brain, transmitting and integrating memories, they also seem to propel pulses of CSF into the brain. Lewis found that CSF also flows when people are awake but less effectively. 'It's always moving a little, but then when you fall asleep, a new cycle starts,' she says. The difference in fluid movement is like the change when a washing machine switches from light jiggling to full-on rotation, at which point more water pours in and out. Lewis's conclusion: sleep, a state that is essential for human health, has a distinct pattern of CSF flow—and that pattern changes as the stages of sleep shift. 'It's not a coincidence,' she says. 'It's actually the same brain circuits that are controlling sleep that seem to also be engaged and controlling the flow.' But what is the source of the elbow grease necessary to do the cleaning? Unlike the blood, which is pumped through the body with great force by the heart, the cerebrospinal fluid is more like water in a bathtub or a slow-moving river with many tributaries. 'Where is the force coming from?' Lewis asks. One possibility is the neurotransmitter norepinephrine, also called noradrenaline. Norepinephrine surges when we wake up. During the day, it focuses attention; it also works to constrict blood vessels. And during non-REM sleep, according to a new study of mice by Nedergaard's group, a lower level of norepinephrine release—not enough to wake the mice but enough to make their blood vessels pulse—propels the movement necessary for CSF to flow. The blood vessels in the brains of these mice dilated and constricted with an amplitude that was 10 times larger during non-REM sleep than during wakefulness, Nedergaard says. And as the blood vessels wax and wane, pushing blood in and out of the brain, CSF flows in and out to fill the expanding and contracting spaces around the blood vessels. 'It seems to be this chain of events where your sleep state changes, and then that changes your blood vessels, and those actively pump the flow of CSF in the brain,' Lewis says. In this way, oscillations in norepinephrine cause waves of CSF to pulse through the perivascular sheaths. But norepinephrine isn't the whole story. In February 2024 Kipnis, neuroscientist Li-Feng Jiang-Xie, and their colleagues at Washington University published a paper showing that, ultimately, it's neurons that provide the energy necessary for cleaning. 'A neuron is a tiny little pump,' says Jiang-Xie, who is now at the University of Pennsylvania. The electrical activity of synchronized neurons, especially during sleep, can propel fluid flow through the brain tissue and help clean waste out. That idea was implied in Lewis's earlier study, but by working in mice, Jiang-Xie and Kipnis were able to show in detail how fluid moved in and out of brain tissue. 'Norepinephrine is basically controlled by neurons' activity,' Jiang-Xie says. These results are 'beautifully aligned with what we found in humans but provide information we couldn't have gotten,' Lewis adds. Meanwhile other research in mice has revealed important distinctions between natural sleep and anesthesia, as well as among anesthetics, all of which affect waste clearance differently. An anesthetized brain does not cycle through phases as it does in sleep. And it turns out that some anesthetics suppress glymphatic function, whereas others enhance it. Furthermore, the influx of cerebrospinal fluid occurs in direct proportion to the power of slow-wave neural activity and in inverse proportion to heart rate, both of which are affected by the drugs used. Those findings help to explain some studies that haven't supported the glymphatic theory. For instance, a 2017 report from researchers at the University of California, San Francisco, described mice anesthetized with avertin, which has since been shown to limit how much cleaning the glymphatic system can accomplish. Five other labs have reconfirmed the initial finding that glymphatic clearance works during sleep. Where does the fluid go? That has been another persistent question. The brain-washing process is made up of four stages, Kipnis says. There is CSF flow into the brain, within the brain, out of the brain along the veins, then into the lymphatic system. His focus has been on the last of these, which is as consequential as everything that comes before it. 'If you wash your house with the same bucket of water, it will not be washing; it will be moving dirt from one place to another,' Kipnis says. The solution is to empty the bucket and bring a new one, which means, in the brain, ensuring that the lymphatic vessels into which the 'dirt' will be dumped are functioning. In 2015 Kipnis and his colleagues found the sewage system: they reported the discovery of lymphatic vessels in the meninges that envelop the brain and spinal cord. These vessels represent an important missing piece of the glymphatic puzzle because they can receive cerebrospinal fluid and interstitial fluid from the brain. They are 'the final outpost,' Kipnis says. 'There is a biological structure at the very end of the whole process.' Once scientists can work out precisely how glymphatic clearance works, they should also begin to see how things go wrong when it doesn't work. Norepinephrine and sleep disruption, for example, are also involved in the development of chronic pain. Higher bursts of norepinephrine lead to wakefulness and seem to shut off the glymphatic system. In consequence, improving the system by reducing norepinephrine levels could possibly also reduce chronic pain. Nedergaard is also exploring the glymphatic system's possible role in psychiatric disorders such as depression and schizophrenia. Eide wants to enhance glymphatic function. The cerebrospinal fluid is an appealing route to deliver drugs to the brain because it bypasses the blood-brain barrier. And the role of norepinephrine is exciting, Nedergaard says. Whether there is too little norepinephrine signaling, as in Alzheimer's, or too much, as in chronic pain or stress, the brain-wave oscillations it controls become inefficient. That recognition might enable us to target treatment by modulating norepinephrine in drug form. There are limits to the possibilities. And until there is a drug that enhances the glymphatic system as well as amyloid beta and tau clearance and slows progression of pathology, no one can definitively say that impaired clearance of brain toxins causes Alzheimer's in humans. In familial early-onset Alzheimer's, amyloid proteins are produced in excess, and clearance may not be able to keep up, no matter how much it is improved. Yet even if enhancing waste clearance only slows the development of Alzheimer's for most patients, that is a big deal. Being able to enjoy five to eight more years of living free of impairment would be a game changer. There may be nonpharmaceutical strategies, too. In the study for which Nick took an afternoon nap, graduate student Joshua Levitt is experimenting with sound stimuli while people are sleeping. His research combines EEG and functional MRI to capture sleep state and brain activity. With Nick and others, he's sending staticky beeps into headphones while subjects are asleep. Given that CSF tends to flow in slow waves and, moreover, that sounds cause more slow-wave activity, this strategy could theoretically affect cerebrospinal flow. 'If we think these things are relevant for great health, then we need to develop ways to actually change them,' Lewis says. Levitt 'is trying to potentially enhance sleep.' Simply understanding the flow of cerebrospinal fluid and how it changes with age is also important. Another graduate student in Lewis's lab, Sydney Bailes, is investigating the differences in flow between adults older than 60 and younger than 40 and the potential implications for waste clearance. It's normal to sleep less as you age and to have fewer slow waves. 'How can we separate just a typical age-related change in sleep versus one that's starting to become an impairment?' Lewis asks. 'We need to disentangle those.' That study is still underway, but so far they have found that older individuals differ from one another more than the younger group does—a pattern that mimics the wider range of cognitive differences in older people versus younger people. 'You'll see some measures that are very clustered together for the young adults and very spread out for the older adults,' Bailes says. But people can surprise. An 80-year-old woman, one of the oldest in the study, stood out. 'Her waves have a much larger amplitude than I typically see in older adults, and they seem to be also pretty consistent,' Bailes says. 'Her CSF flow looked like a young person's CSF.' That's a striking statement. Could it someday become a routine way of evaluating a person's health? Quite possibly. Multiple labs are working toward a noninvasive 'glymphogram' that would reveal how well a person's clearance system is working. Glymphatic function may someday be like hypertension, something to be treated before it turns into a more serious condition. Certainly differences in waste clearance could help explain why some people age healthily and others do not—and then it could pave the way to treatments that enhance clearance in those who need it. The goal is not for everyone to sleep like a baby; sleeping like a thirtysomething would do.
