LATE Dementia: New Diagnosis Changes Understanding of Cognitive Decline

A newly recognized form of dementia is changing how doctors understand cognitive decline, improving diagnosis, and highlighting the need for a wider range of treatments.

Increasingly diagnosed, the condition – known as age-related TDP-43 limbic-predominant encephalopathy (LATE) – recently received official diagnostic guidelines. Research suggests LATE currently affects approximately one-third of people over 85 and 10% of those over 65. Experts in dementia believe some patients previously diagnosed with Alzheimer’s disease may actually have LATE.

“In about one in five patients we see, what was initially thought to be Alzheimer’s appears to be LATE,” said Greg Jicha, a neurologist and associate director of the Sanders-Brown Center on Aging at the University of Kentucky. This distinction is important because accurate diagnosis is the first step toward better care and potential treatment strategies.

“Clinically, it can look like Alzheimer’s – they have memory problems,” Jicha added. “It walks like a duck, talks like a duck, but then it doesn’t quack, it honks.”

Generally, LATE progresses more slowly and is less severe than Alzheimer’s disease on its own, explained Pete Nelson, associate director of the Sanders-Brown Center, who helped lead efforts to identify the disorder. This can be reassuring for patients and their families, though it doesn’t mean the condition is without impact.

However, there is currently no specific treatment for LATE. Moreover, many older adults have more than one type of dementia pathology, and when LATE occurs alongside Alzheimer’s, it can worsen symptoms and accelerate cognitive decline, Nelson noted. “Pure Alzheimer’s disease is worse than pure LATE. But Alzheimer’s plus LATE is worse than either one alone – faster, more severe, a more brutal end,” he said.

Around half of individuals aged 85 with severe Alzheimer’s also have LATE, Nelson stated, adding that this combination tends to increase the likelihood of experiencing more distressing symptoms like psychosis and urinary incontinence. Understanding these co-occurring conditions is crucial for comprehensive patient care.

LATE typically emerges later in life than Alzheimer’s. Its symptoms generally involve memory impairment and, sometimes, difficulty finding words or naming objects, according to David Wolk, a neurologist who leads the Alzheimer’s Disease Research Center at the University of Pennsylvania. Alzheimer’s disease often affects the ability to plan, organize, and complete tasks, and can also cause mood and behavioral changes.

Ray Hester, 79, initially received a diagnosis of early-stage Alzheimer’s disease, experiencing difficulty recalling words and a decline in decision-making. A blood plasma analysis suggested amyloid buildup in his brain, a protein associated with Alzheimer’s plaques, said Danica Coy, clinical research coordinator at the Sanders-Brown Center.

However, further evaluation for an Alzheimer’s clinical trial at the center revealed no amyloid accumulation on a brain scan, Coy recalled. He didn’t have Alzheimer’s; he had LATE.

“There’s a certain relief in knowing it’s not Alzheimer’s,” said his wife, Sandy Hester, at their home in Versailles, Kentucky. Her mother and aunt both had Alzheimer’s, and she feared her husband’s cognitive decline would follow a similar trajectory: “It would progress very, very quickly.”

But her husband’s decline doesn’t appear to be as rapid. “I’m very grateful for that,” she said.

Neil Carey, 87, a retired social worker from Lexington, Kentucky, who was previously told Alzheimer’s disease was the cause of his mild cognitive impairment, later discovered through a PET scan that he did not have the disease. He and his wife, Lora Lee Clark, felt some relief, but also uncertainty about what LATE meant for the future.

“I don’t care what you call it,” Carey said. “Putting a name to it isn’t going to change anything.”

He used to have a “wonderful vocabulary,” he noted, “but now my word field is greatly reduced.” He continues to read books, exercise at the gym, and socialize with friends, but increasingly forgets names and details. He was particularly distressed when he immediately forgot the sermon he had listened to at church one Sunday, despite paying attention. “That’s very frightening,” he said.

Recognition of LATE began in 2018 when Nelson convened approximately 35 researchers worldwide to explore designating a new diagnosis unrelated to Alzheimer’s, evaluating data from brain autopsies and other research. “What drove me was the fact that there was no diagnosis for 30% of dementia cases,” he explained.

In 2019, the group published a report naming a disease that researchers had long struggled to classify based on its biology and effects on the brain. Alzheimer’s disease involves the formation of amyloid plaques, followed by another protein, tau, forming tangles. LATE involves abnormal accumulations of a different protein, called TDP-43.

This protein was identified in 2006 by other researchers who observed its presence in distinct neurological disorders, such as amyotrophic lateral sclerosis (ALS). It’s found in the nucleus of nearly all body cells and participates in regulating RNA and DNA genetics, Wolk said. But in ALS and other neurodegenerative disorders, it explained, the protein leaks out of the nucleus and forms clumps in the rest of the cell.

In LATE, the hippocampus, a brain region involved in memory formation and learning, tends to shrink more than in Alzheimer’s disease, said Reisa Sperling, a neurologist at Harvard, who proposed the disorder’s name. Therefore, diagnosis often involves brain imaging of the hippocampus, tests to detect Alzheimer’s pathology, and assessing whether cognitive symptoms resemble LATE more than Alzheimer’s.

Patients with pure LATE would not be eligible for recently approved Alzheimer’s drugs, because they don’t have the amyloid the medications target. Nupur Ghoshal, a professor of neurology and psychiatry at Washington University School of Medicine in St. Louis, noted the issue is more complex for people with both Alzheimer’s and LATE.

She said that in some patients with both dementias, assessments indicate LATE is the more influential factor in their condition. If “amyloid isn’t the driving factor, is it prudent to include those patients in amyloid treatments?” she asked. She added she would likely offer the drugs to these patients, but inform them that “they may get modest benefit, but they’ll get all the risks.”

Sperling said she “would treat the amyloid if they have it,” but emphasized the importance of finding therapies for LATE.

Dementia experts said that because trials with anti-amyloid drugs occurred before widespread recognition of LATE, some participants may have had both Alzheimer’s and LATE and benefited less from the drugs. This could have contributed to the overall relatively modest success of drugs in slowing cognitive decline in people with mild Alzheimer’s, according to specialists.

“Maybe the people who have pure Alzheimer’s really respond well to these drugs, and the effectiveness was actually diluted in cases that have a lot more of these other concurrent pathologies,” Wolk said.

The first clinical trial testing a treatment for LATE is underway at the University of Kentucky, with Hester and Carey participating. It involves nicorandil, a drug approved in Europe and Asia to treat angina, chest pain caused by reduced blood flow to the heart.

“It’s a heart pill, but it appears to act on the genetic anomalies that were linked to LATE,” Jicha, who leads the trial, explained. Because nicorandil increases circulation in small blood vessels, the hope is it can help prevent the hippocampus from shrinking and protect brain tissue.

The trial, expected to conclude next year and lasting two years, involves 64 people with relatively mild memory problems, who take daily either two heart-shaped pills—a placebo or nicorandil.

“It became very important to me,” said Laurel Scott, 72, a participant from Louisville. Her issues are so mild she hasn’t been officially diagnosed with cognitive impairment, but her memory test scores have slightly declined since her initial assessment last year, Coy, the clinical research coordinator, said.

Scott, a retired emergency medical technician, recalled her brother dying with dementia and her two sisters battling Alzheimer’s. “I wanted to get involved in something right away so I could find out for myself if this was going to happen to me or to help someone else by participating in a trial,” she said.

The cause of LATE remains unknown, but a genetic variant that increases the risk of Alzheimer’s and vascular conditions, APOE4, also elevates the risk of LATE.

Several neurologists said they now plan to re-evaluate some patients for LATE. “What we’re learning about LATE is that it’s much more common than we thought,” said Ghoshal, adding that she will examine cases where “I would have bet my money and said this person has Alzheimer’s, but they have no amyloid pathology.”

For Hester, a retired hospital biomedical equipment technician and Air Force veteran accustomed to an active, travel-filled life, the goal is “to get up tomorrow and keep going.”

He began having trouble with complex home repair projects he once easily tackled. But he volunteered to change the 473 light bulbs at his church, he said. His wife sometimes accompanies him to hold the ladder steady so he doesn’t fall.

She also helps him with his difficulty recalling words, a symptom exacerbated by another diagnosis: progressive primary aphasia. During lunch at their home, he was stumped trying to remember the word for a church room, calling it “the area where we have a lot of people.” His wife guided him to the correct word: “auditorium.”

When trying to remember when an event occurred, he said, “starts with s.”

“September?” she asked. He shook his head: “No, it’s a day.”

“Sunday? Or Saturday?” she asked, suggesting the two days of the week that start with S. “Saturday,” he replied.

He undertakes projects, like organizing photos into albums, and methodically typing his medical history on the back of hymn sheets.

Knowing he has LATE instead of Alzheimer’s matters, he said. “But I still have problems, don’t I?” he concluded.