When Daniel Gibbs, M.D., enrolled in an Alzheimer’s study at UC San Francisco almost a decade ago, researchers needed access to a secure government facility just to confirm that he had the disease. They summoned Gibbs to the Lawrence Berkeley National Laboratory, hooked him up to an IV, and wheeled him into a donut-shaped machine called a PET (positron emission tomography) scanner. Then they waited.
In a building next door, radiochemists fired up a cyclotron, a huge contraption equipped with powerful magnets. The magnets spun tiny particles faster and faster, ultimately creating a nuclear reaction that produced radioactive molecules known as tracers. The tracers were designed to safely detect markers of Alzheimer’s in the brain. But soon after they were created, the molecules would begin to decay. So they had to be transported to Gibbs immediately.
The radiochemists placed the time-sensitive cargo in a plastic cylinder the size of a large soda bottle and sent it hurtling through a network of pneumatic tubes. The cylinder arrived in Gibbs’ room with a loud “woosh” and a “thud.” The UCSF researchers quickly extracted the tracers and transferred them into his IV tube. “It was timed down to the second,” recalls Gibbs, a retired neurologist who, ironically, had spent his career caring for patients with Alzheimer’s. “They had stopwatches running.”
The tracers traveled through Gibbs’ bloodstream into his brain, where they latched onto abnormal proteins that are characteristic of Alzheimer’s disease. Only then, using the PET scanner, could the researchers peer inside the black box of his brain. On the scans, clusters of the tracers lit up like constellations.
At the time, the test Gibbs received was cutting edge — and heralded by many in the field as a tantalizing glimpse of the future of Alzheimer’s diagnostics. For decades, the only way for a family to know for sure if their loved one had the disease was by having their brain autopsied after they died. PET scans allowed physicians to bring certainty to patients during their lives.
But even today, few people suspected of having Alzheimer’s ever receive such testing. Although longer-lasting and more convenient tracers exist today, PET scans still come with financial and logistical hurdles. Neither Medicare nor Medicaid will pay for Alzheimer’s scans, which cost upward of $5,000 a pop. And patients often must travel to major cities to get them. (Biomarkers of Alzheimer’s can also be detected in spinal fluid — a less expensive test but one that requires a lumbar puncture, which is uncomfortable and invasive, so many patients choose not to get one.)
Scientists may have finally found a way to overcome these limitations. In 2020, researchers at UCSF and elsewhere unveiled several groundbreaking studies of a new, highly sensitive blood test developed in the labs of the pharmaceutical company Eli Lilly. The studies demonstrated that the test could detect tiny concentrations of Alzheimer’s-associated proteins in patients’ blood with remarkable accuracy, even before the onset of cognitive symptoms. Since then, other research groups have announced additional promising blood tests for the disease. Experts say the U.S. Food and Drug Administration (FDA) could approve the first of these tests by the end of the year.
Blood tests are less expensive than PET, less invasive than a lumbar puncture, and easy to use, which means they likely will become far more widely used than the other diagnostic options. The early versions now go for around $1,200 to $1,500, about a quarter the price of a PET scan, and the cost should fall as the market expands. Many experts are optimistic that a boom in accessible Alzheimer’s tests could enable new insights into the disease, speed the development of new treatments, and radically improve patient care. More patients could learn — as Gibbs did — that their brains harbor signs of Alzheimer’s disease as early as 20 years before cognitive troubles start.
But these advances also raise vexing questions. What does it mean if you test positive for Alzheimer’s biomarkers but have no symptoms? How certain is it that you will develop the disease? Should you try new medications that could slow its progression but might also cause serious side effects? Would you want to know that you could one day face a devastating illness for which there is currently no cure?
Worth a thousand words
In 1901, a 51-year-old woman named Auguste Deter walked into a German asylum with a variety of strange symptoms, including memory loss, paranoid delusions, agitation, problems with sleep, and mental confusion. “I’ve lost myself,” she remarked before she died four years later, according to the records of her doctor, Alois Alzheimer, M.D.
After Deter’s death, Alzheimer autopsied her brain. He noticed that the thin outer layer, or cortex, was shrunken. And when he examined slices of it under a microscope, he saw dark clumps of sticky “plaques” and stringy “tangles” in and among the nerve cells. These plaques and tangles would come to be recognized as the hallmarks of Alzheimer’s disease.
But the problem of how to spot them in living patients stymied the field for almost a century. Without definitive diagnostic tests, the elderly were condemned to maddening uncertainty: Were flashes of forgetfulness or confusion just “senior moments” or signs of impending precipitous decline?
Even patients clearly suffering from dementia were often misdiagnosed. Clinicians had trouble distinguishing between Alzheimer’s and other brain disorders with similar cognitive symptoms, such as frontotemporal dementia and atypical parkinsonism. This made it difficult for doctors to adequately advise families and likely confounded the results of many early drug trials. (Between 1998 and 2017, pharmaceutical companies made 146 unsuccessful attempts to develop Alzheimer’s medicines.)
In the early 1980s, scientists identified the key proteins comprising plaques and tangles: amyloid beta and tau, respectively. By the next decade, they had shown that these compounds were detectable in spinal fluid using a lumbar puncture, also known as a spinal tap. And in 2004, radioactive tracers like those used on Gibbs, which made it possible to see Alzheimer’s proteins on a PET scan, made their debut.
Gil Rabinovici, M.D., who began a fellowship in memory disorders at UCSF’s Memory and Aging Center a year later, recalls how exciting it was to observe the brain “at a molecular level” in order to diagnose a disease that, according to what he’d learned in medical school, could only be revealed after death. The Memory and Aging Center, which was then emerging as a national leader in research and care of Alzheimer’s disease and other causes of dementia, was one of the first places in the country to adopt PET technologies. In the clinic, Rabinovici saw how valuable these tests could be for patients.