The approval of a controversial new drug for Alzheimer鈥檚 disease, Aduhelm, is shining a spotlight on mild cognitive impairment 鈥� 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 mild cognitive impairment or early-stage Alzheimer鈥檚, the groups in which the medication was studied.
Yet this narrower recommendation raises questions. What does a diagnosis of mild cognitive impairment mean? Is Aduhelm appropriate for all people with mild cognitive impairment, or only some? And who should decide which patients qualify for treatment: dementia specialists or primary care physicians?
Controversy surrounds Aduhelm because its effectiveness hasn鈥檛 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% of patients in the drug鈥檚 clinical trials experienced brain swelling and bleeding).
Furthermore, an FDA advisory committee Aduhelm鈥檚 approval, and the process leading to the FDA鈥檚 decision. Medicare whether it should cover the medication, and the Department of Veterans Affairs to do so under most circumstances.
Clinical trials for Aduhelm excluded people over age 85; those taking blood thinners; those 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% of people with mild cognitive impairment would not qualify to take the medication, according to a new 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 鈥渂ecoming a priority,鈥� said Dr. Kenneth Langa, a professor of medicine, health management and policy at the University of Michigan.
Dr. Ronald Petersen, who directs the Mayo Clinic鈥檚 Alzheimer鈥檚 Disease Research Center, said, 鈥淥ne of the biggest issues we鈥檙e dealing with since Aduhelm鈥檚 approval is, 鈥楢re appropriate patients going to be given this drug?鈥欌��
Here鈥檚 what people should know about mild cognitive impairment 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 鈥� usually Alzheimer鈥檚 disease 鈥� many do not.
Cognitive symptoms 鈥� for instance, difficulties with short-term memory or planning 鈥� 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鈥檚 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% of people ages 60 to 64, 10% of those 70 to 74 and 25% of 80- to 84-year-olds.
Causes. Mild cognitive impairment can be caused by biological processes (the accumulation of amyloid beta and tau proteins and changes in the brain鈥檚 structure) linked to Alzheimer鈥檚 disease. Between 40% and 60% of people with mild cognitive impairment have evidence of Alzheimer鈥檚-related brain pathology, according to a .
But cognitive symptoms can also be caused by other factors, including small strokes; poorly managed conditions 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. During the past decade, experts have identified four subtypes of mild cognitive impairment. Each subtype appears to carry a different risk of progressing to Alzheimer鈥檚 disease, but precise estimates haven鈥檛 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. 鈥淚f 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鈥檚 in their brain and that disease will continue to evolve,鈥� said Dr. Howard Chertkow, chairperson for 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 鈥渟omething isn鈥檛 right with my memory or my thinking鈥� 鈥� a so-called 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 鈥渢here is a shortage of physicians with expertise in dementia 鈥� neurologists, geriatricians, geriatric psychiatrists鈥� 鈥� who can undertake comprehensive evaluations, said Kathryn Phillips, director of health services research and health economics at the University of California-San Francisco School of Pharmacy.
The most important step is taking a careful medical history that documents whether a decline in functioning from an individual鈥檚 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 鈥渋sn鈥檛 necessarily straightforward to recognize, because people鈥檚 thinking and memory changes over time [with advancing age] and the question becomes 鈥業s this something more than that?鈥欌�� said Dr. Zoe Arvanitakis, a neurologist and director of Rush University鈥檚 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. 鈥淎dministering tests to people over time can do a pretty good job of identifying who鈥檚 actually declining and who鈥檚 not,鈥� Langa said.
Progression. Mild cognitive impairment doesn鈥檛 always progress to dementia, nor does it usually do so quickly. But this isn鈥檛 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.
A review of 41 studies found that 5% of patients treated in community settings each year went on to develop dementia. For those seen in dementia clinics 鈥� typically, patients with more serious symptoms 鈥� the rate was 10%. The American Academy of Neurology鈥檚 review found that after two years 15% of patients were observed to have dementia.
Progression to dementia isn鈥檛 the only path people follow. A sizable portion of patients with mild cognitive impairment 鈥� from 14% to 38% 鈥� 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 鈥� poor sleep, for instance, or poorly controlled diabetes or thyroid disease 鈥� have been addressed.) Still another group of patients fluctuate, sometimes improving and sometimes declining, with periods of stability in between.
鈥淵ou really need to follow people over time 鈥� for up to 10 years 鈥� to have an idea of what is going on with them,鈥� said Dr. Oscar Lopez, director of the Alzheimer鈥檚 Disease Research Center at the University of Pittsburgh.
Specialists versus generalists. Only people with mild cognitive impairment associated with Alzheimer鈥檚 should be considered for treatment with Aduhelm, experts agreed. 鈥淭he question you want to ask your doctor is, 鈥楧o I have MCI [mild cognitive impairment] due to Alzheimer鈥檚 disease?鈥欌�� Chertkow said.
Because this medication targets amyloid, a sticky protein that is a hallmark of Alzheimer鈥檚, confirmation of amyloid accumulation through a PET scan or spinal tap should be a prerequisite. But the presence of amyloid isn鈥檛 determinative: One-third of older adults with normal cognition have been found to have amyloid deposits in their brains.
Because of these complexities, 鈥淚 think, for the early rollout of a complex drug like this, treatment should be overseen by specialists, at least initially,鈥� said Petersen of the Mayo Clinic. Arvanitakis of Rush University agreed. 鈥淚f 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,鈥� she said.
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