Alzheimer's advances pose challenges
A new test and new treatments for Alzheimer's disease may offer patients hope but could also raise more questions than they answer, with careful balancing of risks and benefits required.
After years of limited headway in slowing the progression of cognitive symptoms of Alzheimer's disease, the FDA has approved two anti-amyloid therapies for mild dementia or mild cognitive impairment (MCI).
Donanemab was approved in July, following the FDA's summer 2023 approval of lecanemab. The infusions, which reduce amyloid plaques in the brain, represent the leading edge in a wave of drug development for Alzheimer's, the most common form of dementia, which impacts more than six million Americans.
Patients have begun to ask about the new drugs and are desperate for ways to slow early signs of cognitive loss, said ACP Member John N. Mafi, MD, MPH, an internal medicine physician and associate professor of medicine at the David Geffen School of Medicine at UCLA. But the decision to start donanemab or lecanemab is by no means a slam dunk, given various factors that should be weighed and discussed with the patient and care partner, said Dr. Mafi, who coauthored an article published in February in Annals of Internal Medicine that explores how to talk about these drugs with patients.
“Most patients with dementia, their main contact with the health system is still their primary care physician,” he said. “That's why we are really uniquely positioned to take a leadership role in helping patients and families make informed decisions about the tradeoffs in terms of the risks and the benefits and the costs of these therapies.”
In other advances, testing blood for Alzheimer's biomarkers in patients with cognitive symptoms appears closer to more routine clinical use. A recent JAMA study, published online on July 28, identified high diagnostic accuracy for one test when used in a primary care setting.
The test, which calculates an amyloid probability score, is one of a number of blood biomarker tests for detecting amyloid, said Heather Whitson, MD, MHS, professor of medicine at Duke University School of Medicine and codirector of the Duke & UNC Alzheimer's Disease Research Center in Durham, N.C. The Alzheimer's Association has convened a panel of experts to develop clinical guidance on the use of these tests, with an initial focus on patients with cognitive symptoms who have sought out specialty care, said Dr. Whitson, who cochairs the panel.
“The blood-based biomarkers are without a doubt a fantastic advancement,” Dr. Whitson said. “They are going to make diagnosis accessible to a lot of people who could benefit from the new drugs or future drugs that may be even safer or more effective.”
New drug options
Both donanemab and lecanemab reduce amyloid in the brain, and cognitive testing has shown an association with slower cognitive deterioration in patients. For donanemab, that translated to remaining in the MCI or mild dementia stage for 2.47 months to 5.44 months longer during an 18-month period, according to results of the phase 3 industry-funded TRAILBLAZER-ALZ 2 trial, published Aug. 8, 2023, in JAMA. Among a subset of participants with low to medium tau pathology, the drug delayed disease progression a bit longer, 4.36 months to 7.53 months, depending on the cognitive evaluation tool used. In addition, 47% of those participants showed no signs of disease progression after one year compared to 29% of those receiving a placebo. “It doesn't reverse the disease; it doesn't make people better,” said Eric Widera, MD, FACP, coauthor of a related JAMA editorial, also published Aug. 8, 2023, which looked at the donanemab findings. “It just makes them slightly less worse.”
Similarly, the phase 3 industry-funded Clarity AD trial, which studied lecanemab and was published Jan. 5, 2023, in the New England Journal of Medicine, found that patients taking the drug experienced “moderately less decline on measures of cognition and function” at 18 months compared with those taking a placebo. In early 2024, Biogen announced that it would stop manufacturing aducanumab, an earlier anti-amyloid therapy that received accelerated FDA approval in 2021, to focus its resources on lecanemab.
But the measured cognitive difference between the placebo and study groups for both donanemab and lecanemab was relatively narrow, said Dr. Widera, a professor of clinical medicine in the division of geriatrics at the University of California, San Francisco.
“Some would say that it [the cognitive difference] is so small that it's too insignificant,” he said. “Others would say, ‘Hey, that's something, and there's a chance that that will continue to widen past 18 months.’ We just don't really know yet what's going to happen to those individuals.”
While longer-term cognition remains uncertain, recent data provide reason for hope that there may be cumulative benefit, said Kyra O’Brien, MD, MSHP, an assistant professor of neurology at the Hospital of the University of Pennsylvania in Philadelphia who reports serving as an advisor for Eli Lilly. As one example, she referenced data from lecanemab's manufacturer presented this summer at the Alzheimer's Association International Conference in Philadelphia, which showed that in an open-label extension study of patients who had received lecanemab in the Clarity AD trial, slightly more than half who had started the drug in the earliest stage of Alzheimer's, with little to no tau accumulation, improved or hadn't declined in cognition after three years.
“I know there's a lot of skepticism about how effective these are, especially because they are newer therapies,” she said. “But I am actually kind of optimistic.”
For his part, Dr. Widera pointed out that no longer-term data were presented on people who didn't take the drug. “I'd argue that most patients, whether they took the drug or not, may not have declined in cognition if this is the MCI group,” he said, since most people with MCI don't show dramatic progression over the short term.
In addition, Dr. Mafi noted that these results could have been affected by selection bias. “What would be far better would be a longer-term randomized controlled trial to more rigorously answer this question,” he said.
Risks vs. benefits
It's important that primary care physicians educate patients not only about the potential cognitive benefits of the new drugs but also the safety risks and the time-consuming logistics and related costs involved, Dr. Mafi said.
Patients who are considering one of the anti-amyloid drugs will require an extensive workup first, starting with a battery of neurocognitive testing to confirm dementia and assess its severity, as well as magnetic resonance imaging to rule out structural or vascular causes, such as multiple small strokes, he noted. Additional testing could include a lumbar puncture or a positron emission tomography (PET) scan to look for amyloid plaque on the brain, as well as ideally the extent of tau protein, since it's a marker of more advanced disease.
Since the drugs are available only by infusion, they require regular medical visits for administration and related monitoring for potential side effects, raising issues of equity and access. In addition, while Medicare covers both drugs, out-of-pocket costs can be high. For example, Dr. Mafi and colleagues estimated that a Medicare patient without supplementary coverage who is prescribed lecanemab could be responsible for as much as $6,636 annually, according to a study published in the August 2023 JAMA Internal Medicine. According to a Sept. 23 report from KFF, this reflects about 11% of Medicare beneficiaries, Dr. Mafi said.
The drug approval process itself has drawn some scrutiny. In recent months, a BMJ analysis looking at publicly available databases found that physicians on the FDA advisory committee that approved donanemab had financial ties to ongoing Alzheimer's research, including to pharmaceutical companies, according to the findings published on Sept. 25.
When counseling patients, physicians should alert them to any gaps in knowledge, including that the studies for both drugs mostly involved participants who were non-Hispanic White, Dr. Mafi said. Black adults ages 65 years and older are most likely to have Alzheimer's and related dementias (14.7%), followed by Hispanic adults (12.9%) and non-Hispanic White adults (11.3%), according to prevalence data published in 2019 in Alzheimer's & Dementia.
In studies to date, women may not have cognitively benefited from lecanemab as much as men, Dr. Mafi said, adding that neither anti-amyloid drug trial was sufficiently powered to assess cognitive differences between the sexes. “But I think that's something that women should know until more definitive trials are done,” he said.
On the risk front, the greatest concern is the development of amyloid-related abnormalities on imaging, including temporary swelling of the brain or small spots of bleeding. While these changes usually don't cause symptoms, in rare cases more serious or life-threatening complications can occur. About 3% of patients receiving lecanemab developed symptoms severe enough to require urgent treatment, according to a decision aid about the drug that Dr. Mafi and colleagues included in their February Annals article. They also noted that six deaths, three in the Clarity AD trial and three in the TRAILBLAZER-ALZ 2 trial, were potentially attributable to the study drugs and that “patients will need to weigh the risk of this catastrophic event.”
The brain-related risks of the anti-amyloid drugs are higher in patients who are taking anticoagulants or who carry two copies of the apolipoprotein E ε4 (ApoE4) gene variant, according to FDA officials. (Just prior to this article going to press, a New York Times investigation reported that in both drug studies, participants signed consent forms stating that people with certain genetic profiles faced a higher risk of brain injury and that they would be tested. But they were also informed that the genetic results would not be shared with them.)
In her practice, Dr. Whitson recommends ApoE testing for patients interested in the drugs and tends to advise against starting them in those who carry two copies of ApoE4. Given the risks and costs involved, Dr. Whitson described her optimal candidate as “somebody that, if they have a copy of the ApoE4 gene, they only have one copy. And I really do feel that it's [for those with] Alzheimer's disease almost in isolation—that they are a fairly healthy and fit person otherwise—so I can feel like if I just removed that amyloid, I think that's what causing the problem with their brain.”
Biomarker testing
Blood biomarker tests have become more relevant since the approval of the anti-amyloid drugs, said Stephen Salloway, MD, MS, a professor of neurology and psychiatry at Brown University's Warren Alpert Medical School in Providence, R.I., who reports serving as a site principal investigator for aducanumab, phase 2 trials of donanemab, and phase 3 trials of lecanemab and providing consultation to Lilly, Eisai, and Biogen. “We want to diagnose Alzheimer's accurately and early,” he said, noting that the new drugs can be prescribed as early as the MCI stage. “Up until now, there hasn't really been a compelling reason to diagnose early because the treatment options have been limited.”
The JAMA study published on July 28, which looked at the PrecivityAD2 blood test, found that it correctly diagnosed Alzheimer's disease 91% of the time in both primary care and specialty settings. When relying on clinical evaluation alone, including cognitive testing and a CT scan, primary care physicians were correct in 61% of cases and dementia specialists were correct in 73%.
“This is our first major advance with diagnosis that's practical in primary care,” said Dr. Salloway, who coauthored a related JAMA editorial that was also published online on July 28. “PET scans are not practical, routinely anyway. But blood tests are.”
More blood tests are in development that also look good, said Dr. Salloway, who describes the PrecivityAD2 results as among the most reliable data seen to date. PrecivityAD2 and other blood tests for Alzheimer's disease are currently clinically available but are not yet approved by the FDA or routinely covered by insurance, he added.
One benefit of the blood biomarker tests moving forward is that physicians could use them as a first-line diagnostic step, Dr. O’Brien said. “There will be a certain subset of patients with a clearly negative result who you could spare from getting a PET scan or a lumbar puncture,” she explained. For more guidance on the minimal performance criteria for these tests to be clinically useful, she recommended a consensus statement published in July in Nature Reviews Neurology.
Dr. Salloway also sees a potential role for the tests in patients with cognitive symptoms even if they aren't a candidate for or interested in starting an anti-amyloid drug. “Most people want to know what's wrong,” he pointed out. If patients test positive, physicians can discuss other medication options, such as cholinesterase inhibitors, and patients can make related plans regarding finances and other important decisions, he added.
For his part, Dr. Widera is concerned that the biomarker tests will spill over into another population: individuals with a family history and related worries, but no cognitive symptoms themselves. “We don't know what it means [for an asymptomatic person] to have a positive amyloid blood test,” he said. “While it increases your risk for developing dementia in the future, most people won't develop dementia in the future. So what does that mean? And you're putting people through this anxiety and worry.”
Alternative interventions
Even when patients aren't candidates for medication treatment, including cholinesterase inhibitors, physicians can take steps to maximize their cognitive reserve in the near term, including a closer look at their medication regimen, said Matthew Growdon, MD, MPH, a geriatrician and assistant professor of medicine at the University of California, San Francisco. He coauthored a study, published online on July 26 in the Journal of the American Geriatrics Society, which found that older adults with cognitive impairment who lived alone were taking a median of five medications and that nearly half were prescribed at least one high-risk medication, defined as those that had adverse cognitive effects or low tolerance for misuse.
Along with looking at whether the number of medications can be streamlined, physicians may suggest less risky formulations, such as switching a patient with diabetes from insulin to pills if they can still maintain adequate blood glucose control, Dr. Growdon said. For more detailed guidelines and resources, he suggested the website deprescribing.org.
Nearly one in four patients with dementia or their caregivers believe they are taking medications that they no longer need, according to the findings of another study that Dr. Growdon was involved with, published in the June 2022 Journal of the American Geriatrics Society. A majority, 87%, were willing to stop one or more of those medications.
Still, these discussions can be difficult to sort through, Dr. Growdon noted, and some patients may resist and argue, for example, that their insomnia is too severe to drop a sleep medicine.
“Don't let the perfect be the enemy of the good,” Dr. Growdon said. “You can say, ‘Can we space it out more? Can we use half a dose? Can we try to have it used on an as-needed basis rather than an every-night basis?’”
Dr. Mafi noted that the Lancet Commission on dementia recently published a report detailing all the lifestyle modifications, such as improving diet and increasing exercise, that can help reduce the progression of or even prevent dementia. And Dr. O’Brien said that screening for and addressing other potential contributors, such as vision or hearing loss along with mental health challenges and other symptoms, also may help patients bolster their existing cognition.
“Patients' symptoms are better when we treat their insomnia, treat their anxiety and depression,” she said. “They could at least get some symptomatic benefit even if we do expect to see a decline over time because they have some underlying neurogenerative process. There's definitely value in addressing all of these different factors in promoting brain health.”
