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Research Highlights

Nearly 40% of older adult brains studied showed signs of LATE pathology

Nearly 40% of older adults may experience brain damage caused by Limbic-predominant Age-related TDP-43 Encephalopathy (LATE), a form of dementia that is often mistaken for Alzheimer’s disease, according to an NIA-supported study recently published in Acta Neuropathologica. This research — which examined autopsy, genetic, and clinical data — provide further support for the recognition of LATE as a separate-from-Alzheimer’s, commonly occurring dementia.

Microscope image of brain with LATE dementia
NIA-funded researchers found that nearly 40% of older adult brains had TDP-43 clusters, a hallmark of LATE dementia. Image courtesy of Nelson lab, University of Kentucky, Lexington.

At first glance, LATE looks a lot like Alzheimer’s. It mainly affects older adults and initially causes problems with thinking, learning, and remembering. However, in recent years, when scientists have examined the autopsied brains of dementia patients, they have noticed that some have a hallmark of damage that is different from the ones typically seen in Alzheimer’s.

Specifically, they found that the brains of people who experience LATE can be distinguished by clusters of TDP-43, a protein that normally may play several roles in gene activity. These abnormal clusters were first noted in frontotemporal dementia and amyotrophic lateral sclerosis, which are rare neurodegenerative disorders.

In this study, a team of researchers from around the world tried to estimate how many older adults may experience LATE. Led by scientists at the University of Kentucky and Rush Medical College in Chicago, the team analyzed the data of 6,196 subjects who participated in 13 community- or population-based aging studies conducted in a total of five countries. Similar to public opinion polls, community- or population-based studies attempt to sample a representative swath of a given population.

In alignment with previous studies, initial results showed that dementia is common in older adults. The data showed that 42% of the participants had been diagnosed with dementia and about 14% with mild cognitive impairment, a condition that causes memory and thinking problems that may lead to dementia. In contrast, 43% showed no signs of dementia.

An analysis of the brain autopsy data found that almost 40% of all the participants had hallmark TDP-43 clusters, indicating they may have had LATE regardless of whether they were diagnosed with dementia. The results also suggest that the damage that occurs during LATE may be even more common in people who also have Alzheimer’s. About 55% of the participants who had high levels of amyloid plaques, a hallmark of Alzheimer’s, also had TDP-43 clusters. In contrast, only 27% of participants who had no or low levels of plaques also had the clusters.

Much of the data from the U.S. subjects was collected at 10 Alzheimer’s Disease Research Centers (ADRCs), an NIA-funded nationwide network of researchers that works to translate research advances into improved diagnosis and care for people with Alzheimer’s.

Overall, the results support the idea that recognizing LATE as a common and distinct disorder may ultimately help researchers better understand and develop precise treatments for those who experience dementia. The results also highlight the value of participation in brain donation studies, such as those conducted by the NIA ADRCs.

This research was supported in part by NIH grants P30AG072958, P30AG072977, K08AG065463, RF1AG072080, K08AG065426, R01AG038651, UF1AG057707, R01AG021055, P30AG066519, R01AG061111, R01AG057187, P30AG072946, RF1NS118584, R01AG054449, RF1AG069052, P30AG072972, R01AG062517, U19AG069701, K24AG053435, R01AG067482, R01AG064233, R01AG022018, P30AG010161/P30AG072975, P30AG062677, UF1NS125417, U01AG006786, R01AG034676, P30AG66509, U19AG066567, U24AG021886.

These activities relate to:

NIA’s AD+ADRD Research Implementation Milestone 2.P, “Determine the mechanism of TDP-43 and FUS pathogenesis and toxicity.”

NIA’s AD+ADRD Research Implementation Milestone 2.U, “Determine underlying pathobiologic and molecular mechanisms of cellular TDP-43 displacement, post-translational modifications such as phosphorylation, and pathology in pre-symptomatic and manifest common dementias.”

Reference: Nelson P, et al. Frequency of LATE neuropathologic change across the spectrum of Alzheimer’s disease neuropathology: Combined data from 13 community-based or population-based autopsy cohorts. Acta Neuropathol. 2022. Epub June 13. doi: 10.1007/s00401-022-02444-1.

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