Toxic clumps of two proteins, beta-amyloid and tau, are the well-known hallmarks of Alzheimer’s disease, the most common cause of dementia. But another protein, TDP-43, has gained increasing recognition in recent years as another bad actor on this list. It contributes to a form of cognitive impairment that is surprisingly common among older people and has even received its own designation as a separate condition from other dementias such as Alzheimer’s. Like amyloid and tau, TDP-43 aggregates into clumps that wreak havoc on the brain, leading to cognitive impairment in a condition known as limbic-predominant age-related TDP-43 encephalopathy, or LATE. A recent study has found that LATE may be both highly prevalent in the older general population and in individuals with Alzheimer’s disease, leading to worsening cognition in the latter group.

“LATE is not only an important, separate cause of Alzheimer’s-type dementia,” says Julie Schneider, a neurologist and neuropathologist at Rush University in Chicago. “It seems to also be important within a large subset of people with Alzheimer’s disease pathology.”

TDP-43 was first identified in 2006, when researchers discovered contorted versions of the protein in the brains of patients who had passed away with amyotrophic lateral sclerosis (ALS) and patients with a common form of frontotemporal dementia known as frontotemporal lobar degeneration (FTLD). A year later, scientists reported that pathological TDP-43 was also present in the brains of people with Alzheimer’s disease and hippocampal sclerosis, a disease associated with pathological changes in the hippocampus. In this latter group, TDP-43 aggregates typically appeared in the limbic regions, such as the hippocampus and amygdala, areas also affected by Alzheimer’s disease.

Once the scientific community became aware of TDP-43, “people from all over the world were seeing manifestations of it,” says Peter Nelson, a neuropathologist at the University of Kentucky. At the time, however, there was no common terminology for the condition. So in 2018 researchers gathered in Atlanta for a workshop to discuss the nature of TDP-43 pathology in the brain. From that gathering came a consensus paper, published in 2019, in which LATE was first introduced as a term to describe what many viewed to be a unique brain disorder. At the time, the “LATE” label had its critics, however—and there are still some in the research community who question whether the moniker is necessary.

Nelson, an author of the consensus paper, says that LATE provided a description for a third of cases where previously there was no standardized diagnosis—and helped catalyze new research in the field. “One of the very satisfying things about that 2019 paper is that it coincided with a great leap in the number of people studying this,” he adds. “It turns out that this disease is way more common than people think—and it’s way more impactful than is frequently appreciated.”

A Common Condition

Studies to date suggest that LATE—as the name implies—tends to occur later in life, in people who are in their 80s or older.

Clinically, LATE looks very much like Alzheimer’s, Nelson says. Memory loss is one of the earliest and most prominent signs of the disorder, but at later stages, other domains of cognition also become impaired. Nelson adds that, symptom-wise, “pure” LATE tends to be associated with more gradual decline than “pure“ Alzheimer’s—but that the combination of Alzheimer’s and LATE appears to lead to more swift and severe symptoms than either alone.

In this most recent study, published last month in Acta Neuropathologica, Nelson, Schneider and their colleagues from several different research institutions examined data collected from more than 6,000 deceased individuals (62 percent women) who had donated their brain for research. These participants passed away at an average age of 88 and belonged to 13 community groups in the U.S, the U.K., Brazil, Austria and Finland. Prior to death, 42 percent had dementia, 15 percent had mild cognitive impairment, and 43 percent were cognitively normal.

After examining both brain tissues and characteristics such as cognitive status prior to death, the research team found that approximately 40 percent of participants had pathological changes associated with LATE. Among participants with amyloid plaques—a telltale sign of Alzheimer’s disease—in their brain, the proportion of LATE was approximately 50 percent. “This paper really helped solidify the idea that LATE is much more common than we might have previously thought,” says Nina Silverberg, director of the Alzheimer’s Disease Centers Program at the National Institute on Aging, who was not involved in the study. (Silverberg helped organize the 2018 workshop that led to the naming of LATE.)

The researchers also found evidence that, among participants with Alzheimer’s, those who also had LATE tended to exhibit greater cognitive impairments than those who did not have LATE. Why this happens is an open question, Schneider says. Part of the explanation may be that damage from more than one pathological process may simply lead to more damage. Whether they feed on each other to make things worse is not yet clear, she adds.

Currently, a definitive LATE diagnosis can only be made during an autopsy, unlike Alzheimer’s, where the pathological hallmarks such as amyloid plaques can be identified by imaging the brain with positron-emission tomography or by assessing the cerebrospinal fluid, the liquid surrounding the brain and spinal cord.

The search for a biomarker that detects TDP-43 is currently underway—but in the meantime, clinicians are nearing development of a means to diagnose this disease while patients are still alive, according to Schneider. Because biomarkers for Alzheimer’s are available, if a patient comes to the clinic with a pattern of memory loss indicative of Alzheimer’s and appear to have a shrunken hippocampus—but without any signs of amyloid—it may be a telling sign. “I put my bets on the person having LATE,” Schneider says. “And I think a lot of the other clinicians are surmising the same thing now.”

A New Condition?

When LATE was first introduced to the scientific community, not everyone was onboard in accepting it. In response to the consensus paper, a group of researchers—including some that were involved in the initial discovery of TDP-43—wrote an opinion piece that questioned whether the new term was needed. “The term LATE is proposed as a catchy acronym to describe the presence of TDP-immunoreactive lesions in Alzheimer’s disease, as well as in older adults,” the authors wrote. “However, we question the term’s novelty and nosology, the framework that seemingly separates LATE from FTLD-TDP and other diseases.”

William Hu, a neurologist at Rutgers University and one of the authors of that opinion article, still questions whether LATE should be labeled a distinct disorder. In Hu’s view, TDP-43 aggregates are a pathological feature of the various diseases in which they have been found—and they should not be lumped together as a single entity. Before treating LATE as a confirmed entity, Hu says, researchers need to look more closely at the molecular characteristics of the TDP-43 clumps found in these different disease subtypes to determine whether they can truly fall under a single diagnostic umbrella.

Hu adds that in conditions like ALS and FTLD, the evidence to date points to TDP-43 pathology as a primary cause of the disease. But when it comes to Alzheimer’s, there are still important questions about TDP-43 that need to be tackled. For example, are the TDP-43 aggregates simply a side effect of degenerating brain cells, or are they contributing to pathology in some way? Is TDP-43 linked with amyloid buildup, or is it an independent process?

The controversy around the LATE label has helped raise important questions—and sparked efforts to address them, Silverberg says. Many unknowns about LATE remain, and better understanding of this condition may not only help find therapeutics for individuals with TDP-43 pathology but also pave the way to better clinical trials for Alzheimer’s disease.

“Maybe part of the reason we have had so many failed trials is that some people who looked like they had Alzheimer’s disease—before we had biomarkers we could use during life—may have had something else,” Silverberg says. “At least with the new trials, we’ll know that the target is amyloid. They are including amyloid—and hopefully, in the future, we’ll be able to do the same with TDP-43.”

Ultimately, Schneider says, “I think what’s not important so much as the name is the message. I think the motivation for all of us is to get out the word of how important it is to study LATE and TDP-43.”