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Medical News & Perspectives
August 21, 2019

Debate Sparks Over LATE, a Recently Recognized Dementia

JAMA. 2019;322(10):914-916. doi:10.1001/jama.2019.12232

This spring, a group of 35 experts introduced what they say is a recently recognized form of dementia: limbic-predominant age-related TDP-43 encephalopathy, or LATE. Aptly named, LATE strikes “the oldest old”—usually those in their 80s and 90s—causing progressive memory loss.

According to the group’s report, which appeared in the journal Brain, the condition has largely flown under the radar in part because its symptoms mimic those of Alzheimer disease. The key difference shows up on autopsies. Some people with clinically diagnosed dementia have a buildup of misfolded TAR DNA-binding protein 43 (TDP-43) primarily in limbic brain regions, the areas involved in learning and memory, among other functions. These TDP-43 deposits are the hallmark that sets LATE apart from Alzheimer disease, according to Peter Nelson, MD, PhD, the report’s lead author and a neuropathologist at the University of Kentucky in Lexington.

Nelson said that LATE helps to explain why many people with Alzheimer-type dementia don’t have its characteristic cerebrospinal fluid or brain imaging biomarkers. Some of them could have LATE, according to his group. More frequently, however, TDP-43 inclusions coexist with β-amyloid plaques and tau tangles on autopsies, indicating that LATE and Alzheimer disease often go hand in hand.

The new classification is part of a larger evolution in how experts think about dementia. “It’s becoming more and more clear that the initial thoughts that we had about the disease or diseases that underlie dementia were hopelessly inadequate in terms of encompassing the complexity and the heterogeneity of the actual conditions,” Nelson said.

However, some say the field is moving too fast by defining late-onset dementia with TDP-43 as its own disease, before a true consensus exists.

A Strong Association

The report was the product of a 2-day workshop last October funded by the National Institute on Aging (NIA). International experts in brain imaging, clinical diagnosis, genetics, neuropathology, and neuropsychology met in Atlanta to name and define the disease and set research priorities.

According to Nelson, who co-chaired the meeting, about a third to half of the oldest old have LATE pathology, and about a fifth have changes severe enough to be associated with discernible cognitive impairment. The disease appears to start in the amygdala before spreading to the hippocampus, followed by the middle frontal gyrus—a progression that marks the stages of disease. Many patients with later-stage LATE also have hippocampal sclerosis, a condition in which the hippocampus shrinks as its cells die off. Although LATE on its own is associated with gradual memory loss, it appears to hasten the effects of Alzheimer disease in patients with both pathologies.

The meeting’s attendees agreed that a strong association between cognitive impairment and TDP-43 “proteinopathy” in older brains, demonstrated in autopsy studies, justified classifying LATE as a distinct disease. Using a statistical analysis, the report’s authors estimated that LATE’s brain changes were associated with more than 17% of Alzheimer-type dementias in advanced age in 2 studies from Rush University in Chicago. Brain changes associated with Alzheimer disease, vascular disease, and Lewy body dementia accounted for about 39%, 25%, and 12% of dementia cases, respectively, in this group of people, who on average were around 90 years old at their time of death.

For now, there’s no clinical biomarker or treatment for LATE, and the report aims to raise awareness and stimulate research to advance these goals. The article offers guidelines for how neuropathologists can diagnose and stage LATE’s brain changes and highlights critical knowledge gaps relevant to clinicians and researchers.

Nina Silverberg, PhD, director of the NIA’s Alzheimer’s Disease Research Centers Program and Nelson’s meeting co-chair, said that physicians should suspect LATE when older patients with Alzheimer disease symptoms test negative for biomarkers.

That idea, however, is controversial. Not everyone agrees that LATE is a distinct condition. In addition to Alzheimer disease, TDP-43 inclusions have also been observed in people with Lewy body dementia, Huntington disease, and chronic traumatic encephalopathy, among other neurological conditions. Abnormal TDP-43 inclusions are implicated in amyotrophic lateral sclerosis (ALS) and approximately half of frontotemporal lobar degeneration (FTLD) cases, a cause of dementia in people younger than 60 years. And LATE shares some genetic risk factors with both FTLD and Alzheimer disease.

“Our understanding of the role of TDP-43 in neurodegenerative diseases is still evolving—and it deserves further study. However, there is currently no consensus on the clinical relevance of the LATE concept,” cautioned Susan L-J Dickinson, chief executive officer of the Association for Frontotemporal Degeneration, in a statement to JAMA.

Ready for Prime Time?

In 2008, William Hu, MD, PhD, published a study reporting the amygdala-first deposition of TDP-43 in people with Alzheimer disease. Hu, who is a neurologist at Emory University in Atlanta, said the majority of LATE cases have the clinical presentation and pathological indicators of Alzheimer disease, with the predominant finding being the latter condition. These cases are “essentially an Alzheimer’s-plus type of situation,” he said. “It’s Alzheimer’s disease plus something else, but we can’t ignore the elephant in the room.”

Hu believes the minority of cases that aren’t accompanied by Alzheimer brain plaques and tangles could be a late-onset version of FTLD with TDP-43 pathology, which occasionally arises in old age. Although TDP-43 deposits in FTLD and LATE are typically found in different brain regions, their locations sometimes overlap, he said. And both conditions can include hippocampal sclerosis.

Hu and others say that what’s being called LATE may not be its own condition. Instead, it could represent a previously unnamed variant or later stage of more than one already established neurodegenerative disease. Yet, thanks to news coverage, Hu said patients are confused. Some with a diagnosis of Alzheimer disease supported by biomarker testing have begun asking him if they instead might have LATE. For these patients, the question restarts the painful process of mourning and accepting their diagnosis.

Hu also said he worries that efforts directed at raising awareness and standardizing terminology before the evidence supports it could divert dollars away from already underfunded lines of TDP-related dementia research. “I do not believe that broad usage of this term is ready for prime time, nor should we have a systemic effort to align the centers across the country to adapt the terminology,” he said. In a letter to Brain, he and 21 international coauthors urged researchers to “defer broad usage of LATE until (and only if) the science is mature.”

For Nelson’s group—which he said represents most of the scientists who first uncovered TDP-43 and, later, its association with dementia—there’s ample proof of a disease that affects millions. He called the efforts around LATE “massively overdue.”

“There has been evidence of [LATE] for the past 25 years, and there’s been no progress and almost nobody knows about it,” he said. “We have to begin to make some degree of advance in this area, and that will be greatly facilitated by some degree of common parlance.”

In their report, his group addressed questions about the diagnostic “boundary zones” between brain changes seen in LATE, Alzheimer disease, and FTLD. They argued that TDP-43 proteinopathy increases in old age while severe Alzheimer neuropathological changes decrease. And end-stage Alzheimer disease often doesn’t present with TDP-43 proteinopathy.

Nelson called the idea that LATE could be a form of FTLD a “nonstarter.” He pointed out that FTLD is usually associated with language and behavioral changes, not memory loss. Additionally, “whereas there appear to be important areas of overlap with FTLD, LATE is approximately 100 times more prevalent and affects persons at a later stage of the human aging spectrum,” he said.

Whether or not they’re all willing to call it “LATE,” researchers on both sides of the debate agree that much more work is needed to increase understanding of TDP-43 pathology in dementia. Silverberg encouraged patients with cognitive impairment to participate in research that tracks clinical symptoms and collects biosamples over time. She said she also hopes more patients agree to be autopsied: “It’s going to take years of looking at what the clinical symptoms are and then looking at people’s brains when they pass to get a better understanding.”

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