Alzheimer’s

Alzheimer’s Drug Targets People With Mild Cognitive Impairment. What Does That Mean?

The approval of a controversial new drug for Alzheimer’s disease, Aduhelm, is shining a spotlight on mild cognitive impairment — 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’s, 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’t 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’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 the Department of Veterans Affairs has declined 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 “becoming a priority,” 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’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 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 — 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% 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’s structure) linked to Alzheimer’s disease. Between 40% and 60% 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 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’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 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 “something isn’t right with my memory or my thinking” — 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 “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-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’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 Dr. 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.

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 — typically, patients with more serious symptoms — the rate was 10%. The American Academy of Neurology’s review found that after two years 15% 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% — 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 Dr. Oscar Lopez, director of the Alzheimer’s Disease Research Center at the University of Pittsburgh.

Specialists versus generalists. Only people with mild cognitive impairment 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 [mild cognitive impairment] 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,” said Petersen of the Mayo Clinic. Arvanitakis of Rush University 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.

We’re eager to hear from readers about questions you’d like answered, problems you’ve been having with your care and advice you need in dealing with the health care system. Visit khn.org/columnists to submit your requests or tips.

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Minister for Seniors at Famed Church Confronts Ageism and the Shame It Brings

Later life is a time of reassessment and reflection. What sense do we make of the lives we have lived? How do we come to terms with illness and death? What do we want to give to others as we grow older?

Lynn Casteel Harper, 41, has thought deeply about these and other spiritual questions. She’s the author of an acclaimed book on dementia and serves as the minister of older adults at Riverside Church in New York City, an interdenominational faith community known for its commitment to social justice. Most of the church’s 1,600 members are 65 and older.

Every Thursday from September to June, Harper runs programs for older adults that include Bible study, lunch, concerts, lectures, educational sessions and workshops or other forms of community-building. She also works with organizations throughout New York committed to dismantling ageism.

I spoke with Harper recently about the spiritual dimension of aging. Our conversation, below, has been edited for length and clarity.

Q: What does a minister of older adults do?

A large part of my job is presence and witness — being with people one-on-one in their homes, at the bedside in hospitals or nursing homes, or on the phone, these days on Zoom, and journeying with them through the critical junctures of their life.

Sometimes if people are going through really difficult experiences, especially medically, it’s easy for the story of the illness and the suffering to take over. Part of my role is to affirm the other dimensions. To say you are valuable despite your sickness and through your sickness. And to affirm that the community, the church is with you, and that doesn’t depend on your capacity or your abilities.

Q: Can you give me an example of someone who reached out to you?

I can think of one today — a congregant in her 70s who’s facing a surgery. She had a lot of fear leading up to the surgery and she felt there could be a possibility she wouldn’t make it through.

So, she invited me to her home, and we were able to spend an afternoon talking about experiences in her life, about the things that were important to her and the ways she’d like the church to be there for her in this time. And then we were able to spend some time in prayer.

Q: What kind of spiritual concerns do you find older congregants bringing to you?

One of the things, undeniably, is death and dying. I see a lot of older adults wanting to express their concerns and desires regarding that.

I can think of one woman who wanted to plan out her memorial service. It was really important for her to think about what would be special for the congregation and her family — a gift she wanted to leave behind.

I rarely encounter a fearfulness about what will happen when someone dies. It’s more about: What kind of care will I receive before I go? Who will care for me? I hear that especially from people who are aging solo. And I think the church has an opportunity to say we are a community that will continue to care for you.

Q: What other spiritual concerns regularly arise?

People are looking back on their lives and asking, “How do I make sense of the things that maybe I regret or maybe am proud or am ambivalent about? What do those experiences mean to me now and how do I want to live the rest of my life?”

We invite story sharing. For instance, we did a program where we asked people to share an important object from their home and talk about how you came to have it and why it’s important to you.

For another program, we asked, “What is a place that’s been important to you and why?” That ended up being a discussion about “thin places” — a Celtic concept — where it feels like the veil between this world and the next is very thin and where you feel a connection with the divine.

Q: Your work revolves around building community. Help me understand what that means.

That’s another theme of spirituality and aging. In middle life and earlier in life, we’re incentivized to be self-sufficient, to focus on what you can accomplish and build up in yourself. In later life, I see some of that shedding away and community becoming a really important value.

There are many types of communities. A faith community isn’t based on shared interests, like a knitting club or a sports team. It’s something deeper and wider. It’s a commitment to being with one another beyond an equal exchange — beyond your ability to pay or repay what I give to you in kind. It’s a commitment to going the extra mile with you, no matter what.

Q: How did the pandemic and spiritual concerns change or influence the nature of spiritual discussions?

Every Sunday, our congregation offers a moment of silence for the victims of covid-19. And every Sunday, we list the names of congregants who are sick and who died, not only of covid. It’s built into our practice to acknowledge sickness and death. And that became something even more needed.

As much as there was a lot of worry about isolation and our older adults, in many ways our ties with one another became stronger. I saw a tremendous amount of compassion — people extending themselves in very gracious ways. People asking, “Can I deliver groceries? Does anyone need a daily phone call? What can I do?”

Q: What about pandemic-related loss?

The grief has been heavy and will live with us for a while. I think that the ongoing work of the church now is to understand what to do in the wake of this pandemic. Because there have been multiple layers of loss — the loss of loved ones, the loss of mobility, the loss of other abilities. There have been significant changes for people, emotionally, mentally, financially or physically. Much of our work will be acknowledging that.

Q: What have you learned about aging through this work?

I’ve learned how real and pervasive ageism is. And I’ve been brought into the world of what ageism does, which is to bring shame in its wake. So that people, instead of moving toward community, if they feel like they’re compromised physically or in some other way, the temptation is to withdraw. I’m pained by that.

Q: What else have you learned?

How wildly creative and liberating aging can be. I’m around people who have all kinds of experience: all these years, all these tragedies and triumphs and everything in between. And I see them every day showing up. There’s this freedom of being without apology.

I’m so appreciative of the creativity. The honesty. And the real radical attention they pay to each other and the world around them. I’m always remarking how many of our older adults pay attention to things that I hadn’t noticed.

Q: It sounds like a form of bravery.

Yes, that’s right. Courage. The courage to almost be countercultural. To say, even if the culture tells me I don’t have a place or I don’t really matter, I’m going to live in a way that pushes back against that. And I’m really going to see myself and others around me. So they’re not invisible, even if they’re invisible in a larger cultural sense.

Those of us who aren’t of advanced age yet, we often think we’re doing a favor by being around older people and listening to their stories. I don’t see it that way at all. It’s not charity to be around older adults. I am a better person, a better minister, our church is a better place because of our older members, not despite them.

It reflects poorly that our imagination is so stunted and limited when it comes to aging — that we can’t see all the gifts that are lost, all the creativity and the care and the relationships that are lost when we don’t interact with older adults. That’s a real spiritual deficit in our society.

We’re eager to hear from readers about questions you’d like answered, problems you’ve been having with your care and advice you need in dealing with the health care system. Visit khn.org/columnists to submit your requests or tips.

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Why We May Never Know Whether the $56,000-a-Year Alzheimer’s Drug Actually Works

The Food and Drug Administration’s approval in June of a drug purporting to slow the progression of Alzheimer’s disease was widely celebrated, but it also touched off alarms. There were worries in the scientific community about the drug’s mixed results in studies — the FDA’s own expert advisory panel was nearly unanimous in opposing its approval. And the annual $56,000 price tag of the infusion drug, Aduhelm, was decried for potentially adding costs in the tens of billions of dollars to Medicare and Medicaid.

But lost in this discussion is the underlying problem with using the FDA’s “accelerated” pathway to approve drugs for conditions such as Alzheimer’s, a slow, degenerative disease. Though patients will start taking it, if the past is any guide, the world may have to wait many years to find out whether Aduhelm is actually effective — and may never know for sure.

The accelerated approval process, begun in 1992, is an outgrowth of the HIV/AIDS crisis. The process was designed to approve for sale — temporarily — drugs that studies had shown might be promising but that had not yet met the agency’s gold standard of “safe and effective,” in situations where the drug offered potential benefit and where there was no other option.

Unfortunately, the process has too often amounted to a commercial end run around the agency.

The FDA explained its controversial decision to greenlight the Biogen pharmaceutical company’s latest product: Families are desperate, and there is no other Alzheimer’s treatment. Also, importantly, when drugs receive this type of fast-track approval, manufacturers are required to do further controlled studies “to verify the drug’s clinical benefit.” If those studies fail “to verify clinical benefit, the FDA may” — may — withdraw them.

But those subsequent studies have often taken years to complete, if they are finished at all. That’s in part because of the FDA’s notoriously lax follow-up and in part because drugmakers tend to drag their feet. When the drug is in use and profits are good, why would a manufacturer want to find out that a lucrative blockbuster is a failure?

Historically, so far, most of the new drugs that have received accelerated approval treat serious malignancies.

And follow-up studies are far easier to complete when the disease is cancer, not a neurodegenerative disease such as Alzheimer’s. In cancer, “no benefit” means tumor progression and death. The mental decline of Alzheimer’s often takes years and is much harder to measure. So years, possibly decades, later, Aduhelm studies might not yield a clear answer, even if Biogen manages to enroll a significant number of patients in follow-up trials.

Now that Aduhelm is shipping into the marketplace, enrollment in the required follow-up trials is likely to be difficult, if not impossible. If your loved one has Alzheimer’s, with its relentless diminution of mental function, you would want the drug treatment to start right now. How likely would you be to enroll and risk placement in a placebo group?

The FDA gave Biogen nine years for follow-up studies but acknowledged that the timeline was “conservative.”

Even when the required additional studies are performed, the FDA historically has been slow to respond to disappointing results.

In a 2015 study of 36 cancer drugs approved by the FDA, only five ultimately showed evidence of extending life. But making that determination took more than four years, and over that time the drugs had been sold, at a handsome profit, to treat countless patients. Few drugs are removed.

It took 17 years after initial approval via the accelerated process for Mylotarg, a drug to treat a form of leukemia, to be removed from the market after subsequent trials failed to show clinical benefit and suggested possible harm. (The FDA permitted the drug to be sold at a lower dose, with less toxicity.)

Avastin received fast-track approval as a breast cancer treatment in 2008, but three years later the FDA revoked the approval after studies showed the drug did more harm than good in that use. (It is still approved for other, generally less common cancers.)

In April, the FDA said it would be a better policeman of cancer drugs that had come to markets via accelerated approval. But time — as in delays — means money to drug manufacturers.

A few years ago, when I was writing a book about the business of U.S. medicine, a consultant who had worked with pharmaceutical companies on marketing drug treatments for hemophilia told me the industry referred to that serious bleeding disorder as a “high-value disease state,” since the medicines to treat it can top $1 million a year for a single patient.

Aduhelm, at $56,000 a year, is a relative bargain — but hemophilia is a rare disease, and Alzheimer’s is terrifyingly common. Drugs to combat it will be sold and taken. The crucial studies that will define their true benefit will take many years or may never be successfully completed. And from a business perspective, that doesn’t really matter.

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