Understanding and Detecting LATE, a Common Form of Dementia

Alzheimer’s isn’t the only neurodegenerative disease that causes progressive memory loss. In the last two decades, researchers have characterized another condition called Limbic-Predominant Age-Related TDP-43 Encephalopathy, or LATE for short. While Alzheimer’s involves the buildup of beta-amyloid plaques and tau tangles, LATE involves the aggregation of the TDP-43 protein in the brain’s memory hub, the hippocampus. 

LATE is common in older individuals, appearing in nearly one-third of people over 85. It also often overlaps with other dementias, especially Alzheimer’s, and people with both diseases decline faster. 

Some researchers believe that grouping together people with both dementias may contribute to the failure of Alzheimer’s medications in some clinical trials. Unlike Alzheimer’s, however, there are no biomarkers for LATE, meaning that clinicians can only confirm it upon autopsy. 

On Sunday, researchers at the Alzheimer’s Association International Conference (AAIC) in London presented new studies that further our understanding of what’s happening in the brain and the development of biomarkers that could help detect the disease.

LATE under the microscope

What makes pure LATE different, and slower progressing, than the combination of Alzheimer’s and LATE? 

Sandra Tomé, a researcher at KU Leuven in Belgium, looked at brain tissue from over 100 post-mortem donors under the microscope to look for any differences. Those who had LATE but no Alzheimer’s plaques and tangles, as expected, declined slower and died later in life. They were also more likely to carry the ApoE2 gene, which is protective against Alzheimer’s. 

Under the microscope, people with pure LATE had a distinct distribution pattern of various forms of TDP-43 aggregates throughout the brain. In the hippocampus, for example, it led to more “swollen” nerve cells. Figuring out these differences and what they mean could provide “clues that might help with stratifying pure LATE cases,” said Tomé. 

Alifiya Kapasi, a researcher at Rush University Medical Center, was interested in understanding whether the microglia, the brain’s immune cells, were behaving differently in LATE compared to Alzheimer’s. Under the microscope, she saw that when there were signs of LATE in the brain, she saw more microglia, and more shrinkage of the brain’s memory hub, indicating faster decline. 

“We think that neuroinflammation may represent a promising strategy,” for treating LATE, said Kapasi. 

What can biomarkers teach us about LATE?

Philip Wong, a professor at Johns Hopkins Medicine, spoke about his model of LATE and how a cerebrospinal fluid biomarker might help detect the disease before symptoms start. 

TDP-43 helps control which genes are activated and what proteins are formed by the cell. Wong believes that before TDP-43 builds up in the brain in LATE, the protein stops working optimally. 

In the cerebrospinal fluid, Wong and colleagues detected a small peptide — molecules made from the same building blocks as proteins but much smaller — called cryptic HDGFL2, which is formed when TDP-43 loses its ability to do its job. As a result, levels of this peptide rise in one’s 50s, a decade before TDP-43 starts building up in the brain, making it a potential biomarker. 

His work in mice and humans shows LATE may be a two-pronged problem: Healthy TDP-43 stops working first and then later on, it starts to form toxic aggregates that kill brain cells. Since the loss of proper TDP-43 function also leads to tau aggregation in the brain, this model might explain why people with both Alzheimer’s and TDP-43 decline faster. 

”Restoring TDP-43 may be an attractive therapeutic strategy,” concluded Wong, adding that detecting cryptic HDGFL2 may help stratify prospective participants for clinical trials. 

Konstantinos Arfanakis, a professor at Rush University Medical Center, presented his work developing an imaging-based biomarker for LATE, called MARBLE. He used a common type of brain scan, an MRI, which is already used as part of a workup when doctors suspect there may be a neurodegenerative disease.

Jessica Langbaum, senior director of Alzheimer’s Prevention & Research, at Banner Health, told Being Patient that this approach of using these common scans is “interesting” because it “doesn’t require extra patient burden.” 

The researchers developed an algorithm using brain scans from more than 1,000 people with and without cognitive impairment and dementia, and used their post-mortem brain tissue to confirm a LATE diagnosis. Then, they tested how well it worked on a group of 103 older individuals. MARBLE could spot LATE 76 percent of the time.  

Both MARBLE and cryptic HDGFL2 biomarkers are still very early in the research process but “represent the progress” in the field, Langbaum said. If these are validated in larger studies, she said, these biomarkers “could be helpful in the early detection of TDP-43 dysfunction to help diagnose and treat or prevent LATE.”