Researchers Uncover Distinct Patterns of a Common Pathology in Dementia

Known as LATE, a very common form of brain pathology affects ~40% of elderly patients. Researchers at Houston Methodist have unraveled several patterns of LATE in the brains of aging and demented patients. These patterns have distinct clinical, pathologic, and genetic associations.

In a study published in the journal Acta Neuropathologica, Houston Methodist researchers have delineated the brain expression pattern of a protein called TDP-43 whose pathological form is implicated in several forms of dementia. Previously, studies had found that a pathological form of the protein TDP-43 was expressed in the brains for two less common neurological disorders, Lou Gehrig’s disease (or amyotrophic lateral sclerosis), and frontotemporal lobar degeneration (FTLD). TDP-43 pathology was subsequently recognized to be an important contributor to common forms of dementia in human aging. In 2019, a consensus working group suggested the term “limbic-predominant age-related TDP-43 encephalopathy”, or “LATE”, for this common form of TDP-43 in older patients. However, it remained unclear whether distinct subtypes of LATE were present in the aging and diseased brain. Using molecular labeling techniques on autopsied human brains, Houston Methodist researchers found that LATE has distinct spatial and morphologic TDP-43 expression profiles. Moreover, using an unbiased hierarchical clustering approach, they demonstrated that these patterns corresponded to clinical findings, as well as to other common age-related pathologies (Alzheimer’s disease, Lewy body disease) and to specific genetic risk factors for dementia.

“By examining which groups of cells and structures in the amygdala region are affected at the beginning of dementia, we can begin to understand why LATE pathology happens and how it progresses,” said Matt Cykowski, MD, assistant professor of pathology and genomic medicine. “Further, studies like this can help to refine how we classify different types of dementia so that we can give the most accurate diagnosis to the patient’s family.” While Alzheimer’s disease remains the most common form of dementia in the elderly population, other pathologies have long been known to cause dementia, including “hippocampal sclerosis of aging” (now included in the new term LATE), and Lewy body dementia. In fact, Alzheimer’s disease and LATE neuropathologies may be closely linked, with recent studies showing LATE neuropathology as a co-morbid condition in up to 50% of patients with Alzheimer’s disease.

Matthew D. Cykowski, MD Assistant Professor of Pathology and Genomic Medicine

The links between Alzheimer’s disease and LATE do not end there, however. At autopsy, some elderly patients with clinically designated “Alzheimer’s disease” during life can have LATE pathology, with TDP-43 inclusion pathology and hippocampal sclerosis, rather than pathologic Alzheimer’s disease. The true incidence of these “Alzheimer mimic” cases in the elderly population is not possible to accurately estimate given the lack of biomarkers for LATE pathology in living patients. However, Cykowski mentioned the Houston Methodist autopsy service commonly sees examples of this, often in patients over the age of 85 who were diagnosed with a slowly progressive form of late-onset “Alzheimer’s” during life. In fact, Cykowski’s experience suggests that brain autopsy is very useful in this “oldest old” cohort (those over 85 years), as many patients in this cohort are diagnosed with “Alzheimer’s disease” during life, but at autopsy have multiple neuropathologies, including LATE. More recent evidence shows that LATE pathology originates in the immediate region surrounding the amygdala, a heterogeneous structure that is known for emotion processing, among other functions. To investigate how TDP-43 expression progresses in the brain from the early stages of LATE, Cykowski and his team performed immunohistochemical studies of human brain tissue. These brains were autopsied from a patient pool with a continuum of cognitive symptoms ranging from normal to severe amnestic dementia. The researchers were blinded to the clinical diagnosis of each patient, their other whole brain pathologies, and their genetic risk factors. Their goal was to first determine whether patterns of pathological TDP-43 expression could be identified in the amygdala region, and then investigate if these patterns corresponded to unique clinical, pathologic, and genetic features using unbiased hierarchical clustering. Upon analyzing brain tissue stained for both physiological and pathological TDP-43, four distinct patterns of the protein’s expression in the amygdala region began to emerge. One pattern was associated with advanced LATE disease, and closely resembled pathology seen in FTLD with TDP-43 pathology. These brains frequently had hippocampal sclerosis. Notably, the patients with this pattern of LATE were much older than is typically seen in FTLD, and none of them was diagnosed with frontotemporal dementia during life. This confirmed this was indeed a subtype of LATE, and not a type of FTLD. The second pattern of TDP-43 pathology was reminiscent of the neurofibrillary tangles observed in Alzheimer’s disease, and co-localized to the tau pathology of tangles. This second pattern of pathology was strongly associated with a well-known genetic risk factor for dementia, APOE ε4. The third TDP-43 expression pattern was manifest as neuronal inclusions and thick neurites in the amygdala. This third TDP-43 pattern of LATE was significantly associated with Lewy body disease and lower age at death. And finally, the fourth and most common pattern of LATE pathology was associated with a higher likelihood of normal cognition. An additional significant finding was that the TMEM106B genetic risk factor was strongly associated with LATE, no matter the pattern of TDP-43 pathology observed. As the next step in their research, the team plans to search for proteins other than TDP-43 that could be associated with different forms of LATE. Another avenue of research is also to look at the amygdala itself much more closely. Since the structure is composed of different subtypes of neurons, Cykowski hypothesizes there are specific groups of neurons more susceptible to developing TDP-43 pathology seen in LATE. This will likely involve single-cell sequencing and spectroscopy studies in the future. “We have a large segment of the US population that is aging. This group, often called the “Baby Boomers”, are just now entering into the age range that is most vulnerable to dementia,” said Cykowski. “As a result, over the next 20 years, we will be seeing even more LATE pathology in this aging segment of the population. So, there is an urgent need to study the pathology of dementia, including LATE.”

Cykowski, M.D., Arumanayagam, A.S., Powell, S.Z. et al. Patterns of amygdala region pathology in LATE-NC: subtypes that differ with regard to TDP-43 histopathology, genetic risk factors, and comorbid pathologies. Acta Neuropathol 143, 531–545 (2022). https://doi.org/10.1007/s00401-022-02416-5

September 2022

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