A recently recognised form of dementia is changing the understanding of cognitive decline, improving the ability to diagnose patients and underscoring the need for a wider array of treatments, reports The New York Times.
Patients are increasingly being diagnosed with the condition, known as LATE, and guidelines advising doctors how to identify it were published this year.
LATE is now estimated to affect about a third of people aged 85 and older, and 10% of those 65 and older, according to those guidelines. Some patients who have been told they have Alzheimer’s may actually have LATE, dementia experts say.
“In about one out of every five people that come into our clinic, what previously was thought to maybe be Alzheimer’s disease actually appears to be LATE,” said Dr Greg Jicha, a neurologist and an associate director of the University of Kentucky’s Sanders-Brown Centre on Ageing.
“It can look like Alzheimer’s clinically – they have a memory problem,” Jicha said. “It looks like a duck, walks like a duck, but then it doesn’t quack, it snorts instead.”
On its own, LATE, shorthand for Limbic-predominant age-related TDP-43 encephalopathy, is usually less severe than Alzheimer’s and unfolds more slowly, said Dr Pete Nelson, an associate director of the Sanders-Brown Centre, who helped galvanise efforts to identify the disorder.
That can be reassuring to patients and their families. But there is no specific treatment for LATE.
Also, many older people have more than one type of dementia pathology, and when LATE occurs in conjunction with Alzheimer’s, it exacerbates symptoms and speeds decline, he said.
“Pure Alzheimer’s disease is worse than pure LATE,” he said. “However, Alzheimer’s disease plus LATE is worse than either alone – swifter, more severe, a more brutal endpoint.”
About half of 85-year-olds with severe Alzheimer’s also have LATE, said Nelson, adding that with the combination, “you also tend to be more likely to have some of the hair-raising, horrible symptoms such as psychosis and urinary incontinence and other things”.
LATE usually emerges at an older age than Alzheimer’s, with symptoms generally limited to impaired memory and, sometimes, difficulty finding words or naming objects, said Dr David Wolk, a neurologist who directs the Alzheimer’s Disease Research Centre at the University of Pennsylvania.
Alzheimer’s often also affects the ability to plan, organise and perform tasks, and it can cause mood and behaviour changes, he said.
LATE began to be recognised after Nelson convened about 35 Alzheimer’s researchers from around the world in 2018 to explore designating a new non-Alzheimer’s diagnosis, evaluating data from brain autopsies and other research.
“What sparked it for me was the fact that I didn’t have a diagnosis for 30% of my cases of dementia,” he said. “It means we’re missing something.”
In 2019, the group published a report naming a condition that researchers had long tried to categorise based on its biology and effects on the brain.
Biologically, Alzheimer’s involves plaques formed by amyloid, followed by another protein, tau, forming tangles. LATE involves abnormal accumulations of another protein, called TDP-43.
The protein was identified in 2006 by other researchers, who noted its presence in other neurological disorders, including amyotrophic lateral sclerosis (ALS). It is in the nucleus of almost every type of cell in the body and is involved in genetic regulation of RNA and DNA, Wolk said.
But in LATE and other neurodegenerative disorders, he said, the protein seeps out of the nucleus and forms clumps in the rest of the cell.
In LATE, the hippocampus, a brain area involved in memory formation and learning, often shrinks more than it does in Alzheimer’s, said Dr Reisa Sperling, a neurologist at Harvard, who proposed the disorder’s name. So, diagnosis typically involves brain imaging of the hippocampus, testing for Alzheimer’s pathology and evaluating whether cognitive symptoms seem more like those of LATE than Alzheimer’s.
Patients with pure LATE would be ineligible for the recently approved Alzheimer’s drugs because they don’t have the amyloid those drugs target.
For people with both Alzheimer’s and LATE, the question is more complex, said Dr Nupur Ghoshal, a Professor of Neurology and Psychiatry at Washington University School of Medicine.
She said that for some patients with both dementias, evaluations indicate that LATE is the strongest factor in their condition. “If amyloid’s not driving the show, is it prudent to include those patients in amyloid treatments?” she asked. She said she would probably offer the drugs to such patients, but would tell them that they may have a modest benefit, but “will have all the risks”.
Sperling said she would “treat for amyloid if they had it”, but emphasised the importance of finding therapies for LATE.
Dementia experts said that since anti-amyloid drug trials occurred before widespread recognition of LATE, it’s possible that some participants had both Alzheimer’s and LATE and may have benefited less from the drugs. That could have contributed to the relatively modest overall success of the drugs in slowing cognitive decline in people with mild Alzheimer’s.
“Maybe people who are just pure Alzheimer’s actually really respond well to these drugs, and it’s been brought down by cases that have a lot more of these other co-pathologies,” Wolk said.
The first clinical trial testing a treatment for LATE is under way at the University of Kentucky. It involves nicorandil, a drug approved in Europe and Asia to treat angina, chest pain caused by reduced blood flow to the heart.
“It is a heart pill, but it seems to work on the genetic abnormalities that have been linked to LATE,” said Jicha, who leads the trial. Because nicorandil increases circulation in small blood vessels, he said, the hope is that it might help keep the hippocampus from shrinking and protect brain tissue.
The two-year trial, expected to end next year, involves 64 people with relatively mild memory problems, who take two heart-shaped pills daily, either a placebo or nicorandil.
What causes LATE is still unknown, but a genetic variant that increases risk for Alzheimer’s and vascular conditions, APOE4, also elevates risk for LATE.
Several neurologists said they now plan to re-evaluate some patients for LATE. “What we’re learning about LATE is it’s much more common than we thought,” said Ghoshal, adding that she will examine cases in which “Gosh, I would have bet this person had Alzheimer’s disease, but lo and behold, they don’t have any amyloid pathology”.
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