Who should take new drug for Alzheimer's?
The approval of a controversial new drug for Alzheimer's disease, Aduhelm, is shining a spotlight on mild cognitive impairment (MCI) - problems with memory, attention, language or other cognitive tasks that exceed changes expected with normal aging.
After initially indicating that Aduhelm could be prescribed to anyone with dementia, the Food and Drug Administration now specifies that the prescription drug be given to individuals with MCI or early-stage Alzheimer's, the groups in which the medication was studied.
Yet this narrower recommendation raises questions. What does a diagnosis of MCI mean? Is Aduhelm appropriate for all people with MCI, or only some? And who should decide which patients qualify for treatment: dementia specialists or primary care physicians?
Related video: Biden receives coronavirus booster shot
Debate surrounds Aduhelm because its effectiveness has not been proved, its cost is high (an estimated $56,000 a year, not including expenses for imaging and monthly infusions), and its potential side effects are significant (41 percent of patients in the drug's clinical trials experienced brain swelling and bleeding).
Furthermore, an FDA advisory committee strongly recommended against Aduhelm's approval, and Congress is investigating the process leading to the FDA's decision. Medicare is studying whether it should cover the medication, and Veterans Affairs has declined to do so under most circumstances.
Clinical trials for Aduhelm, developed by Biogen, based in Cambridge, Mass., excluded adults over 85, people taking blood thinners, people who had experienced a stroke, and those with cardiovascular disease or impaired kidney or liver function, among other conditions. If those criteria were broadly applied, 85 percent of people with MCI would not qualify for the drug, according to a research letter in the Journal of the American Medical Association.
Given these considerations, carefully selecting patients with mild cognitive impairment who might respond to Aduhelm is "becoming a priority," said Kenneth Langa, a professor of medicine, health management and policy at the University of Michigan.
Ronald Petersen, who directs the Mayo Clinic's Alzheimer's Disease Research Center, said, "One of the biggest issues we're dealing with since Aduhelm's approval is, 'Are appropriate patients going to be given this drug?' "
Here's what people should know about MCI based on a review of research studies and conversations with leading experts.
- Basics
Mild cognitive impairment is often referred to as a borderline state between normal cognition and dementia. But this can be misleading. Although a significant number of people with mild cognitive impairment eventually develop dementia - usually Alzheimer's disease - many do not.
Cognitive symptoms - for instance, difficulties with short-term memory or planning - are often subtle but they persist and represent a decline from previous functioning. Yet a person with the condition may still be working or driving and appear entirely normal. By definition, mild cognitive impairment leaves intact a person's ability to perform daily activities independently.
According to an American Academy of Neurology review of dozens of studies, published in 2018, mild cognitive impairment affects nearly 7 percent of people 60 to 64, 10 percent of those 70 to 74 and 25 percent of those 80 to 84.
- Causes
Mild cognitive impairment can be caused by biological processes (the accumulation of amyloid beta and tau proteins and changes in the brain's structure) linked to Alzheimer's disease. Between 40 percent and 60 percent of people with mild cognitive impairment have evidence of Alzheimer's-related brain pathology, according to a 2019 review.
But cognitive symptoms can also be caused by other factors, including small strokes; poorly managed illnesses such as diabetes, depression and sleep apnea; responses to medications; thyroid disease; and unrecognized hearing loss. When these issues are treated, normal cognition may be restored or further decline forestalled.
-Subtypes
In the past decade, experts have identified four subtypes of mild cognitive impairment. Each appears to carry a different risk of progressing to Alzheimer's disease, but precise estimates haven't been established.
People with memory problems and multiple medical issues who are found to have changes in their brain through imaging tests are thought to be at greatest risk. "If biomarker tests converge and show abnormalities in amyloid, tau and neurodegeneration, you can be pretty certain a person with MCI has the beginnings of Alzheimer's in their brain and that disease will continue to evolve," said Howard Chertkow, chairin cognitive neurology and innovation at Baycrest, an academic health sciences center in Toronto that specializes in care for older adults.
- Diagnosis
Usually, this process begins when older adults tell their doctors that "something isn't right with my memory or my thinking" - a "subjective cognitive complaint."
Short cognitive tests can confirm whether objective evidence of impairment exists. Other tests can determine whether a person is still able to perform daily activities successfully.
More sophisticated neuropsychological tests can be helpful if there is uncertainty about findings or a need to better assess the extent of impairment. But "there is a shortage of physicians with expertise in dementia - neurologists, geriatricians, geriatric psychiatrists" - who can undertake comprehensive evaluations, said Kathryn Phillips, director of health services research and health economics at the University of California at San Francisco's School of Pharmacy.
The most important step is taking a careful medical history that documents whether a decline in functioning from an individual's baseline has occurred and investigating possible causes such as sleep patterns, mental health concerns and inadequate management of chronic conditions that need attention.
Mild cognitive impairment "isn't necessarily straightforward to recognize, because people's thinking and memory changes over time [with advancing age] and the question becomes 'Is this something more than that?' " said Zoe Arvanitakis, a neurologist and director of Rush University's Rush Memory Clinic in Chicago.
More than one set of tests is needed to rule out the possibility that someone performed poorly because they were nervous or sleep-deprived or had a bad day.
"Administering tests to people over time can do a pretty good job of identifying who's actually declining and who's not," Langa said.
- Progression
Mild cognitive impairment doesn't always progress to dementia, nor does it usually do so quickly. But this isn't well understood. And estimates of progression vary, based on whether patients are seen in specialty dementia clinics or in community medical clinics and how long patients are followed.
One review of 41 studies found that 5 percent of patients treated in community settings each year went on to develop dementia. For those seen in dementia clinics - typically, patients with more serious symptoms - the rate was 10 percent. The American Academy of Neurology's review found that, after two years, 15 percent of patients were observed to have dementia.
Progression to dementia isn't the only path people follow.
A sizable portion of patients with mild cognitive impairment - from 14 to 38 percent - are discovered to have normal cognition upon further testing. Another portion remains stable over time. (In both cases, this may be because underlying risk factors - poor sleep, for instance, or poorly controlled diabetes or thyroid disease - have been addressed.) Still another group of patients fluctuate, sometimes improving and sometimes declining, with periods of stability in between.
"You really need to follow people over time - for up to 10 years - to have an idea of what is going on with them," said Oscar Lopez, director of the Alzheimer's Disease Research Center at the University of Pittsburgh.
- Specialists vs. generalists
Only people with MCI associated with Alzheimer's should be considered for treatment with Aduhelm, experts agreed.
"The question you want to ask your doctor is, 'Do I have MCI due to Alzheimer's disease?'" Chertkow said.
Because this medication targets amyloid, a sticky protein that is a hallmark of Alzheimer's, confirmation of amyloid accumulation through a PET scan or spinal tap should be a prerequisite. But the presence of amyloid isn't determinative: One-third of older adults with normal cognition have been found to have amyloid deposits in their brains.
Because of these complexities, "I think, for the early rollout of a complex drug like this, treatment should be overseen by specialists, at least initially," Petersen said.
Arvanitakis agreed. "If someone is really and truly interested in trying this medication, at this point I would recommend it be done under the care of a psychiatrist or neurologist or someone who really specializes in cognition," she said.
- - -
This report is a product of Kaiser Health News, a nonprofit news service covering health issues. It is not affiliated with Kaiser Permanente.
Related Content
'Covid hit us like a cyclone': An Aboriginal town in the Australian Outback is overwhelmed
Two kids, a loaded gun and the man who left a 4-year-old to die
