Remember these words: Rose, Chair, Hand, Blue, Spoon. Draw a clock. Name as many animals as you can in one minute. What’s the date today? List words that start with the letter F. Recall the first five words.
Since the 1980s, memory tests like these, often taken with a paper and pencil and scored by clinicians trained to read the results, have been the mainstay of the diagnosis of Alzheimer’s disease, a brain disorder which erodes memory and thinking, eventually leaving a person unable to perform basic tasks. The condition affects an estimated 6.7 million Americans over age 65, according to the Alzheimer’s Association.
While these symptom-based tests are very good at determining when a person’s memory and thinking aren’t normal, they’re not great at helping doctors suss out the cause of those impairments—which can include everything from vitamin and hormone deficiencies to small strokes, to tumors, to infections, to related disorders like Parkinson’s and Lewy body disease.
Symptom based tests are cited as one reason for the failures of early amyloid clearing drugs for Alzheimer’s. Reviews of patient data following the clinical trials for two drugs—bapineuzumab and solanezumab–found as many as one-third of patients who were enrolled didn’t have the disease they were being treated for—the buildup of a sticky pieces of beta amyloid and tau proteins in the brain, which is the hallmark of Alzheimer’s disease.
But doctors’ reliance on symptom-based testing could soon change. Under new draft guidelines for the diagnosis of Alzheimer’s disease, unveiled on Sunday at a large international gathering of physicians and researchers, these memory tests would take a backseat to biomarkers—proteins and other signals that can be detected in blood, spinal fluid, and on brain scans—that are telltale signs of the disease process unfolding in the brain.
Such tests have been available to doctors and clinical trial participants but have not been widely applied to patients in clinical practice. Now, with expensive and risky new drugs coming to market that promise to slow the progression of the disease, there’s new urgency for improved diagnosis.
Getting the diagnosis right
“Getting the diagnosis right is absolutely critical to be able to provide these new therapies to the right patients,” said Dr. Gil Rabinovici, who directs the Alzheimer’s Disease Research Center at the University of California at San Francisco.
Dr. Rabinovici led a large study, published in 2019 in the journal JAMA, that showed just how impactful these biomarkers can be.
Over two years, researchers gave brain imaging positron emission tomography, or PET, scans that use radioactive tracers to light up deposits of beta amyloid in the brain to more than 11,000 patients diagnosed with early memory and thinking changes with an uncertain cause.
PET imaging of the brain changed the diagnosis for 35% of patients in the study—ruling out Alzheimer’s for 25% who were initially thought to have it and determining that Alzheimer’s was the cause for 10% of people whose deficits had initially been ascribed to a different cause.
“And this was in specialty memory clinics,” Rabinovici said.
The scans changed how doctors managed patients a whopping 60% of the time—typically prompting them to prescribe or discontinue memory enhancing drugs such as donepezil, or Aricept, and memantine.
Beyond drug treamtents, a biomarker-based diagnosis can also improve a patient’s quality of life, says Dr. Charlotte Teunissen, a professor of neurochemistry at Amsterdam University Medical Center.
Teunessin says emerging research shows that precise diagnosis by biomarkers leads to lower health care costs and less institutionalization. It keeps people at home in normal care for longer. “So it leads to less burden and also less healthcare costs,” said Teunissen, who is a co-author of the new guidelines.
Rabinovici cheered the move to a biological basis for diagnosis.
“This is a long-awaited advance for our field, where we are elevating care to start to apply some of these biomarkers that had been in the pipeline and have been in research and start to apply them to the care of patients in the real world. And I think that’s just that’s great progress,” said Rabinovici, who was not involved in the development of the new guidelines.
The amyloid PET scans Rabinovici used in his trial have been FDA approved for more than 10 years, but while Medicare covered the cost of these scans for patients enrolled in research studies, the agency declined to cover the cost of the scans for most routine clinical evaluations.
Now, with the first FDA approved medication—Leqembi—on the market, which requires evidence of beta amyloid build-up in the brain, Medicare is reportedly set to expand coverage for the amyloid PET scans that are required to see those deposits.
New blood tests to diagnose Alzheimer’s
Testing all patients suspected of having Alzheimer’s with invasive spinal taps and expensive brain scans made sense for research, but “it’s just no way to solve a mass public health problem,” said Dr. Clifford Jack, a neuroradiologist at the Mayo Clinic in Rochester, Minnesota, who studies the use of brain imaging for the diagnosis of memory disorders.
Jack is also a co-author of the new guidelines which are being developed on behalf of the Alzheimer’s Association and the National Institute on Aging. They were presented Sunday at the Alzheimer’s Association International Conference 2023, which is being held in Amsterdam.
They build on 2018 guidelines for diagnosing Alzheimer’s in patients participating in clinical trials. They mark the first updates to the type of diagnosis used in clinical care since 2011.
After the proposed guidelines are presented, they will be posted on the Alzheimer’s Association website for public comment for 30 days. After the public comment period, the study authors will revise them again and resubmit them for approval, which could come by the end of the year, Jack said.
“We’re updating these criteria to modernize them to the modern era, where it is completely feasible to diagnose the disease biologically at a mass scale,” Jack said, “And two, there’s something you can actually do about the disease.”
For the first time, the guidelines will direct doctors to use blood tests to detect signs of Alzheimer’s in the brain. Research shows these blood tests which have been developed alongside powerful new amyloid and tau-clearing therapies, are now nearly as accurate gold-standard tests for measuring Alzheimer’s proteins in spinal fluid.
“In head-to-head comparisons, they’re basically equivalent,” Jack said.
While some of these blood tests are available to doctors now through specialized labs that analyze them, none of them has yet received FDA approval, though Dr. Constantine Lyketsos, director of the Memory and Alzheimer’s Treatment Center at Johns Hopkins, expects some will clear that hurdle within the next year.
“It’s a huge advance,” Rabinovici said, “It’s something that five years ago I would have thought was science fiction that we can measure these brain proteins in the blood.”
Blood tests will do several important things, Jack said, they will make the cost of diagnosis less expensive and more easily accessible to patients who can’t easily get to specialized memory centers and specialists.
They will also allow doctors to better stage the disease, Jack said, since markers for Alzheimer’s disease show up in the blood before there’s evidence of disease on brain scans—something that will help doctors determine where a patient is in the progression of the disease.
A diagnosis of Alzheimer’s before symptoms?
The new guidelines propose a 6-stage classification where people are diagnosed first on the basis of biomarkers and later on the basis of symptoms.
If the new guidelines are adopted as proposed, a person could soon be diagnosed with Alzheimer’s Disease on the basis of abnormal blood testing alone, even without any noticeable memory loss. That would be Alzheimer’s disease, stage 1.
Jack said he knows that idea will not sit well with all of his colleagues.
“This is a big controversy in the field,” Jack said.
Right now, in order to start taking the new amyloid-clearing monoclonal antibodies, patients have to have evidence of beta amyloid buildup in their brains, through tests of spinal fluid and on brain scans. They also have to have symptoms of impaired memory and thinking that’s judged to be in an early and treatable stage.
There are clinical trials now underway testing whether these drugs can stop or significantly delay the development of memory loss in people who have evidence of amyloid in their brains, but who do not yet have symptoms. The results of those trials are still a few years away.
“So in our new criteria, when we say, ‘Can Alzheimer’s disease be diagnosed in someone who is asymptomatic?’ The answer is an emphatic yes, from us,” Jack said. “Symptoms are the consequence of the disease. They’re not the definition of the disease.
Jack points to the example of type 2 diabetes. The vast majority of people who are diagnosed with diabetes on screening blood tests for fasting blood sugars don’t have any symptoms.
“Does that mean they don’t have diabetes? Because they’re not yet blind or they don’t have kidney failure? No, of course not. They have the disease,” Jack said.
Making decisions about treatment
Evidence from autopsies shows that some people with normal thinking and memory die with loads of beta amyloid in their brains.
Jack believes eventually, everyone with beta amyloid buildup in their brains will have impaired cognition, as long as they don’t die of something else—a broken hip followed by pneumonia; a heart attack, cancer—first.
“In older people, you can name any disease that can be diagnosed in asymptomatic people, and there will be some people who will die of other causes,” Jack said.
He says that doesn’t mean that people with Alzheimer’s disease don’t deserve good diagnosis and good care.
For some people, going through all the steps to find out if they qualify to take the new drugs may not be worth it for the estimated benefit, which can be difficult for patients and caregivers to see or measure, said Lyketsos, at Johns Hopkins. Lyketsos noted he’s having about a dozen of these conversations each week with his patients right now, driven by curiosity about the new drugs.
He says right now, after patients demonstrate some early difficulty in thinking and memory on those paper and pencil tests, he might order some simple tests to rule out other things like vitamin deficiencies and low thyroid hormone.
If he still suspects Alzheimer’s, he talks to them about getting a spinal tap or brain scan to get a better understanding of what’s causing their symptoms.
If those tests suggest beta amyloid may be driving their problems, he next looks at genetics—people who have a gene called APOE4, can be more vulnerable to dangerous brain swelling while taking monoclonal antibodies to clear amyloid.
Doctors also have to see if patients need other medications—such as blood thinners for atrial fibrillation—that might further complicate the use of amyloid clearing drugs.
Finally, while people may have biomarkers for Alzheimer’s disease, it may not be the only condition causing their dementia. A brain MRI scan would be needed, Jack said, to rule out other problems like bleeding in the small blood vessels of the brain or other types of memory stealing disorders.
“And the patient would then be presented with a choice,” Jack said. “You know, we could do all this screening assessment. And if everything looks good, you can go on treatment. Or maybe you’re just not interested in the screening assessment, and we’ll skip the whole thing. So that’s how that’s how it’s going to have to work for patients right now,” he said.
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Rabinovici said there is increased interest in from patients in getting a diagnosis and doing it earlier than they might have before.
“I think for many years, people had a bit of a nihilistic approach, including doctors about diagnosing Alzheimer’s because they felt like there was little that we could offer patients and families,” he said, noting that he didn’t agree with that. He thinks any information that can help patients plan and guide their care is valuable.
“But now that we actually have therapies… I think that will really catalyze the field and elevate care,” Rabinovici said.
Meg Tirrell contributed reporting