17 Jun 2022

The largest study to date on the prevalence of limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) finds that this type of neuropathology is strikingly common among those who survive well into their 80s. Led by Peter Nelson of the University of Kentucky in Lexington and Julie Schneider of Rush University Medical Center in Chicago, the study integrated autopsy and cognitive data across 13 community cohorts that comprised more than 6,000 participants. Roughly half of people with Aβ plaques and tau tangles also had evidence of LATE-NC, whereas a quarter of people with little to no AD pathology had LATE-NC. Either neuropathological scourge alone was tied to cognitive impairment, and the presence of LATE-NC correlated with poorer cognition regardless of the burden of AD pathology.

Alzforum covered the main findings of the study when Nelson presented them at a LATE-NC workshop earlier this year (Feb 2022 conference news).

First discovered as a type of pathology associated with frontotemporal lobar degeneration (FTLD) in 2006, TDP-43 inclusions have since been detected in people without the clinical manifestations of FTLD. Later, researchers attributed this neuropathological entity, particularly within the limbic regions, to an AD-like amnestic syndrome. The term “LATE-NC” was coined three years ago, and researchers proposed a staging scheme in which TDP-43 pathology cropped up in the amygdala in stage 1, moved into the entorhinal cortex and hippocampus in stage 2, and finally into other neocortical regions in stage 3 (May 2019 news).

Since then, researchers have continued to investigate the prevalence of LATE-NC, its relationship to AD pathology, and its influence on cognition (Mar 2022 conference news). However, most of the data on LATE-NC relied upon research-based cohorts, which tend to be heavily skewed toward people with neurodegenerative disease. To get closer to grasping how common LATE-NC is in the broader population, Nelson and colleagues sought out community and population-based studies that included autopsy and cognitive data. The current study, published June 13 in Acta Neuropathologica, included 13 community-based cohorts, with 6,196 participants hailing from the U.S. and U.K., Brazil, Austria, and Finland. They died at an average of 88 years of age.

About 40 percent of participants across the cohorts were cognitively normal at their last clinical visit, and roughly the same proportion had dementia. Fifteen percent reportedly had mild cognitive impairment.

Across all of the cohorts, 39.4 percent of participants had evidence of LATE-NC. For cohorts that staged LATE-NC, about two-thirds had stage 2 or 3 pathology. In other words, about a quarter of all participants had stage 2/3 LATE-NC, which has been tied to cognitive impairment in previous studies (James et al., 2016). 

How did LATE-NC relate to AD pathology? Regardless of how the latter was measured, the main finding was the same: People with more severe AD pathology, such as those with higher CERAD neuritic plaque scores or Braak stages, were more likely to also have LATE-NC. For example, while only a quarter of people with a CERAD score of “none” had LATE-NC, half of people with a CERAD score of “frequent” had this co-pathology. Notably, even among people without Aβ plaques, those with LATE-NC tended to have more extensive primary age-related tauopathy (PART). People who carried an ApoE4 allele were likelier to have LATE-NC, either alone or with Aβ plaques and tau tangles.

How did LATE-NC relate to cognition prior to death? Due to variable cognitive measures collected across the cohorts, the researchers could not generate summary statistics for this relationship. However, a recurrent theme emerged across study groups: Cognitive scores tended to be lower in people with LATE-NC, across the full spectrum of Braak stages.

In all, the findings suggest that LATE-NC is strikingly common in older people, and is more likely to occur in those who also have Aβ plaques and tau tangles. However, it can also occur in the absence of AD pathology. Regardless of how many plaques and tangles crowded a person’s brain at the end of life, the presence of LATE-NC correlated with poorer cognition.—Jessica Shugart

Comments

1. • Peter Nelson
     University of Kentucky
   • Posted: 19 Jun 2022

   Key people for their respective cohorts were Drs. Julie Schneider, Carol Brayne, Maggie Flanagan, Sonal Agrawal, Maria Corrada, Lea Grinberg, Dirk Keene, Gabor Kovacs, Caitlin Latimer, Melissa Murray, Liisa Myllykangas, Claudia Suemoto, Jerry Wang, and Lon White, and others.

   This was a big team effort.

   View all comments by Peter Nelson

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References

News Citations

1. Virtual Workshop Tackles LATE, a Cause of Late-life Dementia 25 Feb 2022
2. Introducing LATE—A Common TDP-43 Proteinopathy that Strikes After 80 1 May 2019
3. Scientists Say LATE Worsens Cognitive Decline 2 Mar 2022

Paper Citations

1. James BD, Wilson RS, Boyle PA, Trojanowski JQ, Bennett DA, Schneider JA. TDP-43 stage, mixed pathologies, and clinical Alzheimer's-type dementia. Brain. 2016 Sep 30; PubMed.

Further Reading

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