Are Amyloid and Tau Good Biomarkers For Alzheimer’s Disease?

Until relatively recently, physicians were limited in their ability to confirm a case of Alzheimer’s disease until after a patient’s death.

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Today, Alzheimer’s can be more accurately characterized in the living. Positron emission tomography (PET) scans and cerebrospinal fluid (CSF) samples can both reveal two hallmark signatures of the disease: sticky plaques of the amyloid beta protein and twisted tangles of tau protein, which are both implicated in neuron death.

In February, Japanese researchers reported that they had developed a blood test that could accurately measure amyloid beta in the brain. If such a test were to become available to patients and their clinicians, it could potentially offer a less expensive option for measuring the protein than PET scans and a less invasive approach than collecting spinal fluid.

As techniques to assess Alzheimer’s biomarkers advance, researchers are increasingly turning their attention to how best to use these biomarkers. In 2016, for example, a group of neurology experts developed a classification system known as A/T/N, in which seven major Alzheimer’s biomarkers are divided into three binary categories based on the nature of the pathophysiology that each measures. “A” refers to the value of an amyloid biomarker; “T,” the value of a tau biomarker; and “N,” biomarkers of neurodegeneration or neuronal injury.

That same year, the Alzheimer’s Association helped launch the IDEAS study—a longitudinal study exploring the impact of amyloid PET scans on managing patients with dementia. The hope is that IDEAS will show that PET scans are important tools in dementia diagnosis and treatment and should be broadly reimbursed. Currently, cognitive PET scans are reimbursed by Medicare only in rare instances.

Even the Food and Drug Administration (FDA) has taken note of the role amyloid and tau might play in Alzheimer’s. This past February, the FDA developed new draft guidelines for Alzheimer’s clinical trials, which would allow for some Alzheimer’s medications to receive approval if they demonstrate an ability to reduce amyloid and tau buildup in the brain—even in the absence of noticeable cognitive improvements.

Experts Debate Role of Amyloid, Tau

While some researchers favor this movement toward a biomarker-based view of Alzheimer’s, others have cautioned that these two proteins are not adequately linked with Alzheimer’s progression. In a spirited session at the International Neuropsychological Society Annual Meeting held earlier this year, an expert panel debated the role of amyloid and tau as key indicators of Alzheimer’s.

“A biomarker should be sensitive, specific, and predictive of meaningful clinical outcomes,” said Adam Brickman, Ph.D., an associate professor of neuropsychology at Columbia University’s Taub Institute for Research on Alzheimer’s Disease and the Aging Brain. While PET and CSF assays can accurately capture the levels of amyloid and tau in the brain, Brickman said the ability of these measures to predict clinical outcomes is lacking.

“About one-third of older adults with noticeable amyloid plaques have no Alzheimer’s symptoms, while about one-third of people with symptoms have no plaques,” Brickman said. That results in only about a 45 percent accuracy when using these biomarkers to diagnose Alzheimer’s.

More importantly from a clinical perspective, modifying an Alzheimer’s biomarker should influence short- and/or long-term health outcomes. To date, every experimental Alzheimer’s medication that targets amyloid has failed to reduce disease progression, despite patients often showing noticeable reductions in their amyloid levels. The same has been true of medications that reduce tau levels.

Clifford Jack, M.D., a professor of radiology at the Mayo Clinic (and chair of the A/T/N working group) believes in the value of these biomarkers. “Cognitive problems and other Alzheimer’s symptoms are a consequence of this disease, not the definition,” he said. “Only recognizing Alzheimer’s as a distinct [biological] entity can we identify disease risk factors and treatments.”

Many Questions Remain Unanswered

Even if amyloid- and tau-targeting drugs were not such clinical disappointments, using protein biomarkers as a basis for Alzheimer’s diagnosis is complicated by the fact that much of what is known is based on research of predominantly white adults, noted Jennifer Manly, Ph.D., also an associate professor at the Taub Institute.

Available evidence suggests that Alzheimer’s varies among different racial and ethnic populations. Manly highlighted one study that found black decedents with diagnosed Alzheimer’s have a higher prevalence of mixed pathologies in their brains (that is, more than one neurological problem). “Not much is known about the role of these biomarkers in diverse populations,” she said.

Another thorny topic is what kind of societal impact a biomarker-based classification might have. As noted, about one-third of adults have significant buildup of amyloid and tau even though they appear cognitively normal. “What happens if 30 percent more people are now classified as having a disease?” Manly asked. “What kind of resources are needed to handle that? What impact will it have on affected people?”

Despite all of the unanswered questions, Manly and Brickman do not think that all efforts into targeting amyloid and tau should be stopped. Rather than seeing amyloid and tau as biomarkers for Alzheimer’s, Brickman posits that the proteins might be risk factors just as high blood pressure is a risk factor for strokes. Therefore, lowering amyloid buildup could help reduce the risk of Alzheimer’s in people who do not yet have the disease.

Many pharmaceutical companies have shifted their strategies for Alzheimer’s medications to a more preventive approach, enrolling people at the earliest stages of the disease to test if amyloid or tau drugs delay the onset of symptoms. The problem Brickman sees is that the new FDA guidance could allow some of these drugs to gain approval solely based on showing a biological improvement, and not whether they can delay the onset of dementia. ■