What is it like to have asymptomatic Alzheimer’s disease?
The answer’s obvious, isn’t it? It is like nothing. It’s a silly question, really. How could living without symptoms — the vexing troubles with concentration, word finding, recalling new facts, the loss of a mental map — be an experience of something?
Like most short and simple answers, particularly when the subject is Alzheimer’s, the obvious answer’s wrong.
For several years I’ve studied the experiences of people living with what someday may be called asymptomatic or cognitively unimpaired Alzheimer’s disease. Much of this work involves talking to people who have neither dementia nor mild cognitive impairment (MCI), but they do have evidence of Alzheimer’s disease pathology. I focused on people who learned their amyloid PET scan shows “elevated amyloid.” My research colleagues call them “biomarker positive” and categorize them as having “pre-clinical Alzheimer’s disease.”
I’m not ready to diagnose and label them as patients. Not quite because I’m waiting on the results of my colleagues’ studies, whose results could both validate this new stage of Alzheimer’s disease and discover a treatment for it. (I’ll say more about these studies later.)
The key discovery my colleagues and I have made is that though these people may be asymptomatic, they do have a disease experience. Though they aren’t ill, compared to before they learned their amyloid biomarker result, they feel different. These feelings are animated by changes in how they interpret memory lapses, ponder present and future options, and relate to other people, especially family, friends, and co-workers.
As one woman who learned she had elevated amyloid explained to me, “It’s less about medical than about my personality. A colonoscopy isn’t going to change who I am. This is my brain involved.”
This is the first of two essays on what life is like living at biomarker-defined risk of dementia. First, permit me to set the stage.
From the bedside to the desktop
In the late 20th century, we saw the rise of what I call desktop medicine. The desktop, with its fast networked computer, is where researchers discover these diseases and where physicians and patients go to find information to diagnose and treat them. Some examples of desktop diseases are hypertension, diabetes, hypercholesterolemia, and osteoporosis.
This is very different from my practice at the Penn Memory Center, which follows a “bedside medicine” model. The foundation of bedside medicine is talking. I begin with a patient’s chief complaint — My memory is failing — and then take a history of their illness experience, followed by an exam and cognitive testing. I then transform this information into a personalized case of the natural history of disease — for example, a diagnosis of dementia caused by Alzheimer’s disease. This practice is essentially the same as what physician Alois Alzheimer was doing at the beginning of the 20th century.
Unlike bedside diseases, desktop diseases are not defined by a person’s signs and symptoms. (Hypertension has been called “the silent killer.”) Instead, they’re defined by numbers. Their treatments don’t relieve present disability — instead, they reduce the risk of those events happening in the future. Finally, whereas bedside diseases are discovered by the joint work of clinicians and pathologists, desktop diseases are discovered and diagnosed through the joint work of clinical trialists and actuaries.
The trialist designs controlled, randomized, blinded experiments to test a drug in people with pathophysiological risk factors, such as elevated low-density lipoprotein, or LDL. If the trial shows the drug performs better than control (for example, fewer heart attacks) then the risk factor becomes a marker of disease and the actuaries step in. They tease apart the data to determine what cutoffs on the markers determine a person is at sufficient risk to take the drug. I call this clinical-actuarial correlation.
In clinical practice, my colleagues call clinical-actuarial correlation “running the numbers,” and when a desktop disease is discovered, actuaries and web designers are eager to provide us with numbers. Cardiac disease, for example, has been an actuarial delight (see here and here and here).
Possibly quite soon, depending on the results of ongoing clinical trials in cognitively unimpaired people, dementia care will go desktop.
Waiting on the studies
There are, at present, three ongoing trials testing anti-amyloid drugs in cognitively unimpaired “biomarker positive” people. Notably, in the coming months, one of these trials — Lilly’s Trailblazer 3 testing donanemab — will conclude. Like the other trials (Eisai’s AHEAD testing lecanemab, and Roche’s PREVENtron testing trontinemab), the therapeutic goal is to discover whether lowering amyloid will slow the transition from being a person who is cognitively unimpaired to a person living with dementia. Simply put, a positive trial will achieve two interrelated goals: validate a stage of disease before dementia or MCI, and discover treatment for that same stage.
When that happens, I’ll start running the numbers on my patients’ brains.
Much of what I’ve learned about what this will be like comes from people who participated in one of the earliest of these preclinical anti-amyloid trials. The A4 study tested Lilly’s solanezumab against a placebo. Although solanezumab was unsuccessful, A4 established a foundation for the three ongoing trials. My colleagues and I interviewed 50 people who learned they had elevated amyloid and, for comparison, 30 who learned a “not elevated” result and therefore could not enroll in A4.
We called our study SOKRATES, for the Study of Knowledge and Reactions to Amyloid Testing — a fitting acronym, I think, as it gestures to the philosopher who declared that, despite the threat of death, the unexamined life is not worth living. To protect confidentiality, the quotes you’ll read are stripped of identifying information except for basic descriptive information on age and gender and bits of biography.
Nine or 9,000 amyloids
Among the people who learned an elevated amyloid result, the feeling of some degree of elevated risk of developing dementia was nearly uniform. A 78-year-old man explained, “I’ve a higher risk than most people to get Alzheimer’s, but it doesn’t mean I will get it.” In contrast, people who received a “not elevated result” demonstrated varying understandings of what that meant.
In both groups, however, two notable but potentially correctable misunderstandings emerged.
First, some people’s risk assessments were arguably off, especially the people with a not elevated result who concluded they would never get Alzheimer’s or had altogether eliminated the possibility of dementia from their future, neglecting that other diseases such as Lewy Body disease and LATE. The correction here, of course, is education about probability and the other diseases that cause dementia.
The second problem was seen in both groups, and it amplified a common challenge with diagnosing desktop diseases. Patients and doctors alike struggle with ambiguity and uncertainty. Remember, in A4, their amyloid PET result wasn’t a number but instead one of two categories: “elevated” or “not elevated.”
This categorical, qualitative information was frustrating, as this 68-year-old woman explained: “I asked the doctor, I said, ‘OK, how many amyloids? Are we talking nine amyloids or 9,000 amyloids?” People wanted the norm for amyloid and whether their result showed twice as many or three times as many. Others wondered if they were low, medium, or high. These sentiments from people whose health is typically writ by numbers — blood pressure, PSA, A1c, calcium scores, etc. — are understandable.
The point is, as pathology is to bedside medicine, numbers are to desktop medicine. People want three metric measures: what’s my number, how does my number fit along the range of possible results, and how does it translate into my personal risk. A desktop diagnosis that falls short on any one of these three features may still be fit for practice, but it will likely cause patients frustration (“Do I have nine or 9,000 amyloids?”).
For Alzheimer’s disease, the answer to “what’s my number?” is doubly challenging. Challenging because the field is working through which biomarker test or tests, what cutoffs, and what risk calculators will define cognitively unimpaired Alzheimer’s disease. Doubly because the tests and calculators are all intellectual property.
There’s money to be made. Or not.
‘I worry a little bit more’
A feeling of being at risk can change a person.
People who learned of an elevated amyloid result remained cognitively unimpaired, but for some, the knowledge changed how they felt about their memory. A 67-year-old man explained that before the test he worried when he forgot things, but after, he worried more. “You think, ‘OK, is this the beginning of Alzheimer’s?’” He, like others, noted, “To know [the amyloid is] up there maybe just kind of reinforces a little bit the possibility that it could be Alzheimer’s related.”
Knowledge of elevated amyloid was an impactful event. We measured this with the Impact of Events Scale, which asks questions such as “I had waves of strong feelings about it” and “I thought about it when I didn’t mean to.” Two to three days after learning an amyloid PET result, the elevated amyloid group showed notable increases in scores compared with the not-elevated group. As a clinician, I’m attentive to the fact that scores were particularly elevated in younger people, women, or those reporting memory problems, suggesting patients who need particular attention to their well-being.
Notably, these feelings didn’t translate into symptoms of catastrophic mental illness, such as depression, unremitting anxiety, or suicide. This at least in part reflects the meticulous process of education and assessments of mood and well-being that preceded the PET scan. People who failed to understand the test, or who reported signs of significant depression, anxiety, or plans of self-harm weren’t tested. Instead, they were offered treatment for their mood disorder.
For people who learned a not elevated result, one word summed up how they felt about the knowledge of reduced risk: relief.
We saw that word repeatedly in their interviews. A 70-year-old man with a notable family history of Alzheimer’s who learned a not elevated result said, “I’m always living under this cloud that someday I may get it [Alzheimer’s]. Having the test and having the results negative at least took a lot off my mind for the foreseeable future.”
Can medicine do this?
Lilly’s Trailblazer3 is designed to ease the drug’s translation into practice. Subjects were enrolled if they had a positive blood test for amyloid, not a resource- and time-intensive PET scan (as was the design of A4). The ease of such a test — it’s just a tube of blood — tempts a self-directed, DIY home diagnosis of cognitively unimpaired Alzheimer’s, as is the case with HIV and diabetes, for example. Self-diagnosis might begin with a prompt from an ad on the internet, and then home-administered biomarker and cognitive tests.
In these early days, when we’re still figuring out what it is like to be a person with cognitively unimpaired Alzheimer’s disease, I’m not so enthusiastic about this practice. There’s a need for a human in the loop, a clinician to educate a person about the test and its possible results and to assess mental readiness to receive it and reflect on how they will live with the result and treatment.
This isn’t an unusual demand for clinicians. Education and assessment of mood are core aspects of medical practice — whether bedside or desktop — and advances in online education and telemedicine could ease bottlenecks of access to tests and treatment.
Medicine can do this.
What concerns me is that doctors aren’t so skilled at helping people reflect on how to live with cognitively unimpaired Alzheimer’s disease, on being present in the weeks to follow the result, as they and their families learn to live with their result and take on weighty matters about time, relationships and decisions about how to live and work, and, for a few, how to end their lives.
Remember, cognitively unimpaired Alzheimer’s disease isn’t just a medical matter. It’s more about personality. Because — unlike a positive colonoscopy result or reduced bone mineral density — living at biomarker risk of Alzheimer’s dementia can change who you are. As a interviewee explained, “You can’t unlearn this information.”
Next week, Part 2 takes on what they do with what they’ve learned.
Jason Karlawish is a professor of medicine, medical ethics, health policy, and neurology at the University of Pennsylvania’s Perelman School of Medicine, co-director of the Penn Memory Center, and executive producer of the “Age of Aging” podcast.
Source: www.statnews.com
