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Courtesy of Rob Dobi
At first, it may look like Alzheimer’s disease — but it isn’t.
When adults older than 80 start to forget things, so much so that it becomes worrisome, they could be suffering from a recently identified, slowly progressing form of dementia called Limbic-predominant age-related TDP-43 encephalopathy, or LATE.
It’s a type of dementia that many people have never heard of, and that clinicians are only just beginning to recognize.
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“The condition has gotten a lot more attention over the last year, but there is still somewhat limited knowledge about it,” even among neurologists, says Dr. David Wolk, professor of neurology at the University of Pennsylvania Perelman School of Medicine and director of the Penn Alzheimer’s Disease Research Center.
LATE — an appropriate acronym for a disease whose symptoms don’t appear until a person reaches their 80s or 90s — primarily involves memory loss. At least in its early phase, it does not prompt other symptoms characteristic of Alzheimer’s disease, such as getting lost in familiar settings, finding words or trouble reading, experts say.
With LATE, “you have a slowly percolating memory loss,” says Dr. Julie A. Schneider, director of the Alzheimer’s Disease Research Center at Rush University Medical Center. “It ultimately can become severe, but it takes time for it to occur and doesn’t involve cognitive function. It’s mostly centered around memory loss.”
Wolk agrees. People with LATE “experience forgetfulness,” he says. “They forget plans they’ve made and conversations, and cuing doesn’t seem to help. Outside of memory, they tend to function fairly well day to day.”
People with LATE eventually may develop functional problems similar to Alzheimer’s, but because LATE begins at an older age and progresses very slowly, many patients don’t live long enough for those problems to arise, Wolk says. “Many may pass away before it reaches that point,” he says.
How common is LATE?
It’s unclear how many people have LATE, although some estimates put the number at up to 20 percent of all dementias. “Millions,” says Dr. Pete Nelson, professor of pathology at the University of Kentucky College of Medicine, who studies the disorder. “One-third of those over the age of 80 have this pathology.”
What causes LATE?
Changes in the brains of people with LATE differ from those with Alzheimer’s, according to experts.
Alzheimer’s is driven by an abnormal buildup of two proteins in the brain that form amyloid plaques and tau tangles. The brains of people with LATE show atypical amounts of a different protein, TDP-43.
TDP-43 was first linked with other neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia and Lewy body dementia.
The cause of TDP-43 buildup is unknown. Scientists have identified several genetic links associated with the risk of LATE, and research is looking for ways to identify diagnostic biomarkers and drug targets.
“We’ve known for a long time that some people look like they have Alzheimer’s disease, but there is no amyloid plaque, so there is another reason they have memory loss,” Schneider says. “[Earlier], we would say, ‘Oh they probably had some strokes in the past, or they have Lewy body.’ ”
How is LATE diagnosed?
Biomarker tests using brain imaging, and now blood tests, can reveal abnormal plaque and tau, providing a specific diagnosis of Alzheimer’s disease. But biomarker tests have not been developed for TDP-43 , making a LATE diagnosis challenging.
The only way to definitively diagnose it “is from an autopsy,” Nelson says. “There is a huge unmet need to find a specific biomarker.” Biomarkers are identifiable characteristics, such as the presence of specific molecules in blood or other bodily fluid, or specific genes, that can help nail down a diagnosis.
Researchers, however, have found one striking anomaly associated with LATE that offers an important clue. The hippocampus — the brain’s memory center — often appears severely “shrunken” on an MRI scan in people with LATE, researchers say. So the absence of plaque coupled with atrophy, or shrinking, of the hippocampus often can point to a LATE diagnosis.
But it gets complicated. It’s possible to have Alzheimer’s and LATE. Nelson estimates that about half of those with Alzheimer’s also have evidence of LATE.
Thus, a positive diagnosis of Alzheimer’s — as determined by plaque-detecting scans or biomarker blood tests — doesn’t always rule out LATE, he says.
The presence of the two diseases in the same person has important implications for prognosis. “LATE itself is relatively slow. Alzheimer’s by itself is worse. But when they occur together, it’s swifter and more severe than Alzheimer’s by itself,” he says.
In 2019, a working group of several dozen scientists published a consensus statement describing criteria that could help clinicians diagnose the condition. “One of the reasons we put this committee together was to bring [LATE] out to the community,” Schneider says. “A lot of clinicians are not aware of it.”
What are the treatments for LATE?
While several drugs are available to treat the symptoms of Alzheimer’s and a couple slow its progression in its mild cognitive impairment and mild dementia stages, there is no treatment for LATE, researchers say.
The medications for Alzheimer’s don’t appear to help LATE symptoms, experts say.
“Most of us don’t think that the drugs will do much for you if your memory loss is mostly due to LATE,” Schneider says.
The University of Kentucky currently has a drug trial underway studying the effects of nicorandil, a drug licensed in Europe and Asia for angina, which is chest pain that occurs as a result of reduced blood flow to the heart. The drug increases circulation in small blood vessels, and the scientists hope this will reduce the risk of hippocampus shrinkage, Nelson says.
The more scientists can learn about Alzheimer’s and other dementias, the more likely such knowledge will speed the discovery of new therapeutic and diagnostic approaches to LATE, researchers say.
Although “it’s such a newly recognized condition, my hope is that our growth in understanding and better treating it will be rapid,” Wolk says.
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