Science ALZ Copathology
About 20 years ago, neuropathologists began to report an inconvenient finding in the autopsied brains of people with dementia: Most have evidence of more than one disease. Studies since have shown the brains of up to half of people diagnosed with Alzheimer’s disease also have a key feature of Parkinson’s disease—deposits of the protein alpha synuclein. At the same time, up to half of Parkinson’s patients who develop dementia have elevated levels of beta amyloid and tau proteins, hallmarks of Alzheimer’s.
Researchers studying neurodegenerative diseases are catching on to the importance of this phenomenon, often called copathology. It complicates current disease classifications, which are tightly linked to their signature proteins. But it also offers clues as to why some dementia patients show faster cognitive decline, and some people on antiamyloid drugs for Alzheimer’s seem to fare worse than others. Copathology “helps explain why symptoms don’t match biomarkers, why trajectories vary so much, and why treatment results are not necessarily what we expect them to be,” neuropathologist Lea Grinberg of the Mayo Clinic told researchers at the Alzheimer’s and Parkinson’s Diseases Conference (AD/PD) in March.
Why the diseases overlap so often remains a mystery, but it’s not a coincidence. “It seems that they stimulate each other,” Grinberg says. Tests now being developed to pick up multiple biomarkers should give a clearer picture of these mixed pathologies in living patients. And an upcoming clinical trial will be the first to take aim at a common dementia copathology, testing the amyloid-clearing Alzheimer’s drug donanemab in people who have both amyloid in their brains and dementia with Lewy bodies—abnormal clumps of alpha synuclein.
“The ultimate goal is to define these diseases based on the biology, and understand the occurrence of these pathologies across the spectrum of diseases,” says Mark Frasier, chief scientist at the Michael J. Fox Foundation for Parkinson’s Research, which is running large studies to track and characterize copathologies. “I do think this is where the field is headed.”
Copathologies increase with advancing age. “Almost no one has only one pathology in the brain when they get to be 80,” says neurologist David Wolk of the University of Pennsylvania. Last year, he and colleagues published clinical criteria for another neurodegenerative disease that often occurs with Alzheimer’s in people over age 85: limbic-predominant age-related TDP-43 encephalopathy (LATE). It is marked by the buildup of TDP-43, a protein also seen in some types of frontotemporal dementia.
But copathologies aren’t limited to the old. One study of familial Alzheimer’s patients who developed dementia in their 40s found that half died with Lewy bodies as well as Alzheimer’s pathology in their brains. And in research presented at this year’s AD/PD meeting, neurologist Tom Tropea of the Institute for Neurodegenerative Disorders showed that people in the early stages of Parkinson’s, who represent a younger patient group, had elevated levels of p-tau217, a blood-based marker of Alzheimer’s pathology. Higher p-tau217 was associated with faster rates of cognitive decline and steeper drops in day-to-day functioning.
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Most cases of copathology are discovered at autopsy or in academic centers that conduct specialized testing, often for research. For example, a spinal fluid test developed by Amprion Diagnostics can detect Parkinson’s, dementia with Lewy bodies, and related diseases. Hopefully, wider use of such testing will lead more people with copathologies to trials of experimental agents, says Amprion’s chief executive, Russ Lebovitz.
Some blood tests in development could give patients a broad snapshot of mixed pathologies. Richard Mayeux, a neurologist at Columbia University, is working on one using extracellular vesicles—protein-laden particles that cells, including neurons, release into the blood. Measuring the payloads of neuron-derived vesicles can reveal the presence of proteins associated with LATE, Alzheimer’s, Parkinson’s, and diseases of the brain’s blood vessels, another important type of copathology.
Last month, Carlos Cruchaga, a human genomicist at Washington University in St. Louis, unveiled an experimental blood test using 15 protein markers that, together, can distinguish among the major dementia brain pathologies and quantify them. To develop the test, Cruchaga used artificial intelligence to analyze blood data from thousands of patients. The panel still needs to be validated in real-world clinical settings, and isn’t able to predict disease in asymptomatic people. But for a person with dementia, “It can tell you, you have 75% Alzheimer’s pathology and 20% Parkinson’s pathology and 5% frontotemporal dementia,” Cruchaga says.
Unfortunately, Wolk says, “We have a pretty limited armamentarium” to treat any single neurodegenerative disease—let alone multiple overlapping diseases. Currently only the antibody drugs for Alzheimer’s can clear a disease protein. It’s uncertain whether giving them to people who may also have dementia with Lewy bodies will be useful, but some patients will opt for them anyway, he says. “Can we really say that it’s not going to help them to at least remove the thing that you can remove?”
The upcoming trial, slated to launch later this year, will recruit people in the early stages of dementia with Lewy bodies—but who also have high amyloid—to see whether donanemab tempers their symptoms. Neurologist Sharon Sha of Stanford University, a lead investigator on the trial, thinks an “interactive effect” between beta amyloid and alpha synuclein speeds patients’ damage and decline. She hopes the trial not only shows benefit, but “helps the field to recognize the importance of being inclusive of copathology in clinical trials.”
Treatment for mixed pathology could one day mean combining drugs—administering treatments developed for Alzheimer’s alongside those for Parkinson’s or frontotemporal dementia, for example. Or, some predict, it could aim at a yet-to-be-discovered common source or pathway in neurons that drives multiple pathologies—making today’s rigid disease categories even less relevant.
“In the future we will not talk about ‘Alzheimer’s disease,’” says Johannes Attems, a neuropathologist at the University of Innsbruck. Rather, “You see a patient and in his brain is so much amyloid beta and so much tau, so much alpha synuclein, so much TDP-43. That’s it,” he says. “And you have something to give him.”
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