New Medication, Staging Criteria Signal a Potential Shift in Alzheimer’s Care

“These medications have given us hope and they’ve given our families hope,” Elizabeth J. Santos, M.D., M.P.H., president-elect of the American Association for Geriatric Psychiatry, told Psychiatric News. However, the FDA guidance leaves open the question of how to obtain the needed amyloid-confirming PET scans to determine when to discontinue donanemab. These scans are largely unavailable in non-research settings and rarely ever covered by insurance, added Santos, who is also the clinical chief of the Division of Geriatric Mental Health and Memory Care at the University of Rochester.

“Every time a new medication comes on the market that has a very specific indication, like this one does, it pushes insurance companies to allow us to do these advanced kinds of tests, and that’s a great thing for patient care,” Santos said.

Eric Widera, M.D., director of hospice and palliative care at the San Francisco VA Medical Center, said the new antibody-based medications may be right for some patients who have access to the specialists needed to provide the ongoing care they require. However, the evidence is clear that the new don’t make people with Alzheimer’s better, but rather they will be “slightly less worse off” than they otherwise would have been, according to Widera, who is also a clinical professor in the Division of Geriatrics at the University of California, San Francisco. “The disease still progresses, and we don’t know what happens to people after 18 months.”

As with lecanemab, donanemab carries a significant risk of brain hemorrhaging and edema, which is referred to on the label’s boxed warning as so-called “amyloid-related imaging abnormalities (ARIA),” which in rare cases may cause serious and life-threatening intracerebral hemorrhages or focal neurologic deficits that can mimic ischemic stroke. People who carry two copies of the Alzheimer’s risk gene ApoE ε4 have a higher incidence of this serious adverse event, so genetic testing is needed prior to initiation of treatment.

Tampi pointed out that obtaining monthly infusions of donanemab requires treatment by geriatric psychiatry or geriatric neurology specialists along with numerous MRI scans at set intervals to assess for ARIA.

“You cannot do this from the primary care office or in smaller hospitals, where you don’t have the support to decide who is the right candidate or obtain the necessary follow-up to rule out side effects,” Tampi said. “That’s the main issue: How many patients can really get access when you look at how many patients have Alzheimer’s in this country?”

Donanemab’s approval came just one week after the Alzheimer’s Association issued revised criteria for the diagnosis and staging of Alzheimer’s disease, calling for the use of amyloid-assessing biomarkers --rather than traditional cognitive and functional testing.

According to the new criteria, which were issued in Alzheimer’s & Dementia, early biomarkers that can diagnose the disease even in asymptomatic individuals include amyloid-assessing PET scans, “approved” cerebrospinal fluid assays, and certain plasma biomarkers. The revision states that an abnormal amyloid biomarker result is sufficient to establish a diagnosis of Alzheimer’s and to inform clinical decision making throughout the disease continuum.

“Defining diseases biologically, rather than based on syndromic presentation, has long been standard in many areas of medicine—including cancer, heart disease and diabetes—and is becoming a unifying concept common to all neurodegenerative diseases,” lead author Clifford Jack Jr., M.D., a professor of radiology at the Mayo Clinic in Rochester, Minnesota, said in a statement. “An unchanging principle is that effective treatment will always rely on the ability to diagnose and stage the biology driving the disease process.”

“This is industry defining what a disease is,” Widera told Psychiatric News. “The industry has billions of dollars at stake by expanding the definition of Alzheimer’s.” Yet there’s still a lot of work to be done to validate these biomarkers and what impact they may have on Alzheimer’s progression, particularly for asymptomatic individuals.

One-third of the workgroup that crafted the new criteria are drug or diagnostic company employees or board members, one-third reported significant conflicts of interest, and more than one-quarter were representatives for the Alzheimer’s Association, which also has pharmaceutical ties, Widera noted. The criteria broaden the number of people who meet diagnostic criteria for Alzheimer’s from today’s 6.25 million adults to about 40 million, based on current estimates, most of whom are cognitively normal.

“Most of these people will never progress to mild cognitive impairment or dementia in their lifetimes….,” Widera said. “The idea that these drugs will not be prescribed to asymptomatic amyloid-positive individuals is a farce, based on the history of pharmaceutical marketing in the United States.

“Amyloid seems to be playing a role in Alzheimer’s: Clearing it yields a measurable difference in that it slightly slows disease progression,” Widera said. “Yet even when most of the amyloid is cleared from the brain, the disease still progresses. ... This should give us pause when we’re redefining a disease purely based on the presence of amyloid.” ■