Scientists have been puzzled by patients with signs of dementia, but whose brains don't show the aberrant proteins that are typical biomarkers of Alzheimer’s disease. Now researchers say they have an explanation: a newly defined neurodegenerative disease whose symptoms are similar to Alzheimer’s but is caused by a different misbehaving protein.
The disease, called LATE, seems to develop more slowly than Alzheimer’s and to appear later in life, when people are in their 80s and 90s, an international team of researchers reported Tuesday in the journal Brain. The brains of people who develop the disease don't contain the protein amyloid beta, which causes plaques to develop between nerve cells, or tau, which grows tangles that clog the interiors of cells, eventually killing them.
“All over the world we saw very old people who had deterioration of their faculties and dementia, but no plaques and tangles,” said the report’s lead author, Dr. Peter Nelson, a professor of pathology at the Sanders-Brown Center on Aging at the University of Kentucky. “This explains a lot of that.”
LATE affects more than 1 million Americans, according to Nelson. “If you go to any nursing home, you’ll see evidence of it,” he said.
About 75 percent of people get Alzheimer’s disease, and some develop both Alzheimer’s and LATE, in combination, hastening the descent into dementia.
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Knowing which protein is affecting the brains of seniors is significant since therapies being developed to treat Alzheimer’s disease target amyloid beta and tau. Medications designed to knock out those proteins won’t make a dent in a disease caused by the LATE protein, TDP-43.
That may explain the failures of some very promising Alzheimer’s drugs. The new report “won’t advance treatment today or tomorrow but it will help us understand why some of the treatments in the past failed,” said Dr. Richard Isaacson, director of the Alzheimer’s Prevention Clinic at NewYork-Presbyterian and Weill Cornell Medicine.
If 40 percent of the people in a clinical trial testing a drug that targets amyloid beta “didn’t even have amyloid in their brains, the study failed because it enrolled the wrong patients,” said Isaacson, who was not involved in the new report.
There are some similarities between the two proteins that cause Alzheimer’s and the one implicated in LATE. All three, in their normal states, perform necessary functions in the brain. In people who develop either disease the proteins start to fold in pathological ways, leading them to gunk up nerve cells and the spaces in between them.
“Proteins always get folded, but when they misfold, it causes a lot of problems,” Nelson said. “It produces toxic effects because the protein is impaired from its normal activities.”
Currently there is no blood test that can detect the presence of LATE.
Without a biomarker for TDP-43, a brain autopsy after a patient dies is the only way doctors know for sure what was the underlying cause of dementia. Without a biomarker, it will not be possible to screen patients to make sure that only those with true Alzheimer’s are entered into clinical trials to test new therapies for the disease, said Dr. Julia Kofler, an associate professor of pathology at the University of Pittsburgh Medical Center.
For now, researchers will have to depend on less reliable methods to distinguish between the two diseases. MRIs offer some hints because the pattern of nerve damage seen with LATE is slightly different from that seen in Alzheimer’s.
The search for a biomarker becomes more urgent as people live longer, said Sandra Weintraub, a professor of psychiatry and behavioral sciences and a member of the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease at Northwestern University. According to a 2018 report from the Centers for Disease Control and Prevention, by 2060, the number of Americans with Alzheimer's will hit nearly 14 million, or about 3.3 percent of the projected population.
“This is a really important step carrying this field forward,” Weintraub said of the report. “People are living longer. And the more you prolong someone’s life, the more you increase their risk of getting this.”