On April 17, 2026, Erin Connolly, research analyst for the Duke-UNC Alzheimer’s Disease Research Center (ADRC) Bryan Brain Bank, gave a presentation for the National Alzheimer's Coordinating Center (NACC) webinar series on limbic-predominant age-related TDP-43 encephalopathy (LATE).
In her talk, titled "LATE-NC subtyping by Unbiased Hierarchical Clustering of Morphological and Regional Patterns of TDP-43 Lesions in the Amygdala," she explored a new way of classifying a brain condition called LATE neuropathological change (LATE-NC), a form of age‑related dementia that can look like Alzheimer’s disease. She explained a study on tiny abnormal protein deposits called TDP‑43 lesions in the amygdala, a brain region involved in memory and emotion.
Using an unbiased computational method called hierarchical clustering, Erin and other members of the team led by Shih-Hsiu “Jerry” Wang, MD, PhD, analyzed the shape, appearance, and location of these lesions to identify patterns. These patterns may represent different subtypes of LATE‑NC, helping scientists to better understand how the disease develops and why it affects people differently.
About LATE-NC
LATE-NC affects about a third of individuals over age 80. In LATE, a protein called TDP-43 is excluded from the nucleus, where it normally regulates RNA-processing. Instead of staying in the nucleus, it moves into the cell’s outer compartment and begins to clump together into abnormal protein deposits.
This leads to a loss of normal TDP-43 function, which causes the cell to lose the normal, healthy functions of TDP‑43 and start producing faulty RNA and proteins. At the same time, the buildup of these protein clumps can become toxic to brain cells.
The symptoms of LATE are very similar to Alzheimer's disease, often leading to misdiagnosis, making it very important for scientists to be able to distinguish between the two conditions.
Advances in Research
Research in LATE-NC has thus far focused on the distribution of TDP-43 aggregates across brain regions, advancing from the amygdala (stage 1) to the hippocampus (stage 2), to the frontal cortex (stage 3). However, TDP-43 aggregates come in different sizes and shapes and can be found both in the cell body and cell processes, with some brains showing predominantly cytoplasmic inclusions, others showing predominantly thick and thin neuronal processes, and some showing a combination of both.
In this study, Erin and her colleagues analyzed the appearance and distribution of TDP‑43 protein clumps in about 100 brain samples donated from individuals with LATE‑NC, using tissue from the Duke‑UNC ADRC Bryan Brain Bank. When they used an unbiased computational clustering approach to sort the cases, four recurring patterns of TDP‑43 buildup emerged:
- Broad mixed pattern: a combination of several lesion types
- Thick neurite‑predominant pattern: marked by thicker, abnormal fibers
- Tangle‑like inclusion‑predominant pattern: resembling the tangles seen in other neurodegenerative diseases
- Subpial neurite‑predominant pattern: with lesions concentrated near the brain’s surface
The team is now investigating whether these distinct patterns are linked to specific symptoms, clinical histories, or genetic backgrounds. Understanding these connections could help clarify how LATE‑NC develops and why it affects individuals differently, ultimately improving diagnosis and guiding future research into targeted treatments.
NACC was established in 1999 by the National Institute on Aging (NIA) and serves as a centralized data repository for the ADRC's. The LATE webinar series was a joint effort between the Clinical, Biomarker, Imaging, and Neuropathology Cores of the ADRCs and was attended by over 150 individuals nationwide.