By the time a person starts exhibiting the memory problems and other symptoms of Alzheimer's disease, a catastrophic cascade of cellular events has been playing out inside their brain for years or even decades. Misfolded proteins and fragments of protein have been ever so slowly clumping together, forming microscopic plaques and tangles that interfere with the function of neurons. Eventually, these brain cells die and this neurodegeneration takes its toll on memory and cognition.

The slow-burning fuse of Alzheimer's creates a terrible predicament for doctors, patients, and the scientists seeking therapies: Once symptoms appear, so much damage has already been done that it may be impossible to fix it. This might explain why clinical trials of drugs intended to slow or reverse the cellular damage caused by Alzheimer's disease have so far yielded one demoralizing failure after another. (Several drugs have been approved to treat the symptoms, but none target the underlying cause.)

Many researchers now believe that those clinical trials may have failed because the drugs were given too late. Some of the same drugs — or new ones — might have a better chance if administered earlier. It's a hypothesis with logical appeal, but it's unproven. And it depends on detecting signs of Alzheimer's in people who aren't yet experiencing symptoms.

In recent years, scientists have developed several methods for doing just that. The best-established biological markers are based on brain scans and tests of cerebrospinal fluid. More recently, researchers have made breakthroughs in their decades-long pursuit of a simple blood test for Alzheimer's proteins.

Biomarker tests have clarified how the disease progresses, and some are now widely used in Alzheimer's clinical trials, though not yet commonplace in clinical practice.

"There's evidence that biomarkers start to show changes 20 years before onset of dementia," says Andrew Saykin, director of the Alzheimer's Disease Research Center at the Indiana University School of Medicine. That presents a huge window for early intervention. "It's very tough to reverse neurodegeneration once it's happened, but if we could prevent it from happening there's really an opportunity to have a major impact on the disease," Saykin says.

Visualizing the problem

Alzheimer's disease is the most common cause of dementia, affecting an estimated 5.8 million Americans. Memory problems are often the first sign, but confusion and other cognitive difficulties appear later, along with changes in mood, behavior, and personality. To make a diagnosis, doctors typically interview the patient and a family member, and conduct cognitive assessments.

A definitive diagnosis, however, can come only after death, by examining slices of brain tissue under a microscope. The pathological signature of Alzheimer's has two components: plaques, which are clumps of a protein fragment called beta-amyloid, found in the spaces between cells, and tangles, twisted strands of a protein called tau that form inside cells. Scientists don't understand how amyloid and tau cause neurodegeneration, but most believe these compounds are key links in the disease mechanism. (A minority of researchers, however, argue that more investigation of alternative mechanisms is needed.)

Pathology studies, mouse experiments, and other research have long implicated amyloid as a culprit in Alzheimer's. But there was no way to see amyloid buildup in the living brain until 2002, when researchers developed a compound that incorporates a radioactive isotope of carbon (carbon-11) and binds to amyloid, making it visible on a positron emission tomography (PET) brain scan.

"Amyloid PET scanning was really just transformative," says William Jagust, a neuroscientist the University of California, Berkeley. Many candidate therapies are designed to clear amyloid from the brain. As researchers began using amyloid-targeted PET, they realized that a significant proportion of the patients enrolled in these trials didn't actually have elevated amyloid.

"About a third of the people who were enrolled in these clinical trials for 'Alzheimer's disease' actually turned out not to have Alzheimer's disease," says Clifford Jack, a brain imaging researcher at the Mayo Clinic in Rochester, Minnesota. "That's a really huge problem."

PET scans reveal typical patterns of amyloid and tau accumulation in the brain of an Alzheimer's patient. Amyloid appears throughout the brain, whereas tau is more concentrated in certain regions. (CREDIT: WILLIAM JAGUST / UC BERKELEY)

Now virtually all clinical trials of anti-amyloid therapies use amyloid PET to screen patients for enrollment. Newer compounds based on a different radioactive isotope, fluorine-18, have expanded their use even more, says Richard Carson, a PET imaging researcher at Yale University, and coauthor of a 2019 paper on the method in the Annual Review of Biomedical Engineering.

Amyloid PET has also made it possible to test experimental therapies in people who show signs of amyloid accumulation but aren't yet experiencing memory problems. The largest such effort to date is called the A4 study, which began enrolling patients in 2014. It has experienced delays due to the pandemic, says Reisa Sperling of Harvard Medical School, one of the study's leaders. The trial will be an important test of the early-is-better treatment strategy. Sperling expects to have results by early 2023.

Biomarker diversity

In addition to changing clinical trials, amyloid PET and other biomarkers have changed the way researchers conceptualize Alzheimer's, says neurologist Michael Weiner of the University of California, San Francisco, who leads the Alzheimer's Disease Neuroimaging Initiative. "We don't think of the diagnosis being made by symptoms [anymore], we think of identifying pathology using biomarkers."

That shift is spelled out in recommendations published in 2018 by the National Institute on Aging and the nonprofit Alzheimer's Association that urge researchers — though not yet clinicians — to define Alzheimer's using biomarkers. "In that paper we basically say that someone has Alzheimer's disease if they have positive amyloid and positive tau biomarkers," says Jagust, one of the authors.

Emerging research suggests that the newer tau PET scans may match up better with a person's cognitive status than amyloid PET scans do, Jagust says. "If you have a whole lot of tau in your brain, it's very improbable that you're going to be cognitively normal, whereas you can have a whole lot of amyloid in your brain and still be cognitively normal."

That fits with the overall picture from Alzheimer's biomarker research showing that different biomarkers track different stages of the disease process. The earliest indicator that trouble is brewing appears to amyloid fragments circulating in cerebrospinal fluid (CSF) bathing the brain and spinal cord. Tau appears to begin accumulating later, overlapping considerably with neurodegeneration and memory problems but preceding the severe cognitive decline that robs people of their independence in later stages of the disease.

Clues in the blood

One of the fastest-developing areas of Alzheimer's biomarker research is on tests that can be done with an ordinary blood sample. It's a difficult goal because the blood-brain barrier prevents potential biomarker molecules from getting into the bloodstream in significant amounts. And blood contains many additional proteins that can foul up the analysis. "You have something like 50,000 times less signal to noise in the blood," says Randall Bateman, a neurologist at Washington University in St. Louis. Bateman's group is one of several that have recently begun to overcome these obstacles with new, super-sensitive assays that can detect minuscule amounts of amyloid or tau in blood samples.

One of the most promising methods involves immunoprecipitation, which uses immune system proteins called antibodies to concentrate a particular protein in a sample. In 2017, Bateman and colleagues reported that a blood test based on this approach matched amyloid PET scan results in 41 adults age 60 or older. All study subjects who had positive PET scans had amyloid blood levels below a certain threshold, indicative of a higher risk of Alzheimer's. However, several subjects with negative PET scans also had amyloid blood levels below this threshold, suggesting that improvements may be needed to avoid false positives.

In 2018, researchers in Japan and Australia reported a similar blood test that matched amyloid PET results with about 90 percent accuracy in a larger sample of 254 older adults. Preliminary findings reported earlier this year suggest that these blood tests have promise for predicting the onset of Alzheimer's disease in people who don't yet have symptoms or are experiencing only mild cognitive impairment.

Researchers have also made recent progress on a blood test for tau. In a paper published July 28 in the Journal of the American Medical Association, an international team of researchers reported that a blood test for a specific subtype of tau accurately distinguished Alzheimer's disease from other neurodegenerative diseases in 1,402 study subjects from Colombia, Sweden, and the United States.

If blood tests for amyloid and tau prove to be reliable for diagnosing and predicting the course of Alzheimer's disease, the impacts could be huge. "By having a blood test, the numbers of people we can screen for Alzheimer's and enroll in clinical trials grows by orders of magnitude," says Bateman.

A blood test could also help remove some of the uncertainty around the clinical diagnosis of Alzheimer's disease in routine practice, Bateman says. Memory problems have many potential causes, so doctors can't always confidently diagnose patients. Not knowing can be stressful for patients and their families, Bateman says. "It helps a lot when people know what they're dealing with and what they can expect, and we come up with a plan for what to do about it."

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