Presenting Researchers with a New Way to Define Alzheimer’s Disease

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It’s been a game changer, experts say: Advances in brain imaging have empowered scientists to safely measure deposits of the proteins beta-amyloid and tau in the brains of people while they are alive—not just during an autopsy after death. This leap forward in imaging means clinical researchers—though not yet doctors—now have biomarkers to search for and measure to determine if Alzheimer’s disease (AD) is present.

A biomarker is valuable in diagnosing AD the way that high cholesterol can signal that a person is at increased risk for coronary artery disease, or that persistently high blood glucose levels enable an endocrinologist to diagnose diabetes—even if there is no evidence of high blood sugar–related nerve damage, vision loss, or other common complications.

The new approach to AD was developed in 2018, when an international panel of experts appointed by the National Institute on Aging and the Alzheimer’s Association (NIA-AA) published the “research framework” that spelled it out. With this definition, a person is said to have AD if he or she has both beta-amyloid and tau in the brain— even if the individual has only mild symptoms, or no symptoms at all.

Although this biomarker-based definition of AD has stirred up a bit of controversy, with some people in the medical community questioning whether it makes sense to label someone with no symptoms as having a disease, many scientists around the globe are relieved to have a common understanding of the illness.

Emerging from an imperfect definition

The diagnosis of AD has been based on two elements: clinical findings and autopsy results. Clinical findings were based on signs and symptoms of the disease described by patients, along with a doctor’s observations during an examination. Is your memory gradually or quickly getting worse? Are you confused a lot? Do you have difficulty with language or expressing yourself verbally? Those were the types of questions a doctor asked to figure out if AD might be part of the equation.

The second critical piece was the autopsy done when someone died. Powerful scientific evidence indicates that in people with AD, deposits of beta-amyloid first develop in brain tissue, triggering the formation of tau tangles. The illness was confirmed if these were found on autopsy.

The evolution of sophisticated positron-emission tomography (PET) imaging techniques has changed all of this, enabling doctors and researchers to safely peer into the brain while a person is alive. In addition to imaging, betaamyloid can be measured in a person’s cerebrospinal fluid, a sample of which is taken via a lumbar puncture.

Once common: Misdiagnoses

Not surprisingly, individuals often are mistakenly diagnosed with AD. Autopsies reveal that 10 to 30 percent of people diagnosed with the illness didn’t actually have it; examiners don’t find beta-amyloid or tau deposits in brain tissue. Put another way, physician accuracy in diagnosing AD has been somewhere between 70 percent and 90 percent. This is acceptable by some standards—most people misdiagnosed with AD have another form of dementia that’s incurable—but it still leaves plenty of room for improvement.

That said, the volume of misdiagnoses has been very much an issue for scientists designing clinical trials to test new AD drugs. If roughly 1 in 5 people believed to have AD didn’t in fact have the illness, trials including these individuals were generating corrupted results. Tests of potentially beneficial medications for lowering beta-amyloid or tau levels in the brain, for example, are thereby rendered useless.

Critical change: A new staging system

As part of its new proposed definition, the NIA-AA panel has revised the former method for identifying the stages of AD. Previously, AD was recognized as an illness with three distinct stages: preclinical disease, in which brain changes have occurred but aren’t causing symptoms; mild cognitive impairment, in which brain changes have occurred and are associated with slight, but noticeable cognitive decline; and, finally, dementia.

Since that definition was written in 2011, however, a great deal of research has shown that AD progresses slowly and continuously over time. Instead of three distinct stages of the illness, the new definition explains the condition as occurring on a continuum, using biomarkers and cognitive symptoms to describe its severity. This more nuanced system for staging Alzheimer’s disease will benefit the development of medications aimed at stopping symptoms before they arise. A disease defined for research only—for now. Authors of the new research framework (one of whom is the author of Memory Disorders White Paper) stress that the new definition is supposed to be used only in clinical research, and not yet by doctors caring for patients with this illness. That said, biomarkers such as beta-amyloid, tau, and others that may surface over time could someday be valuable in diagnosing the disease, as well as in making decisions about treatment—if an effective therapy is found.

People who volunteer for clinical trials can help deepen our understanding of AD.

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