What is LATE dementia?

When we talk about dementia, Alzheimer’s disease is often the first condition that comes to mind. However, cognitive decline in later life can have different underlying causes. One of the less recognised is LATE dementia, short for Limbic-predominant Age-related TDP-43 Encephalopathy.

LATE is a relatively recently characterised brain disorder associated with the accumulation of abnormal forms of a protein called TDP-43 in specific areas of the brain, particularly regions of the limbic system involved in memory. It tends to affect people at advanced ages, especially those over 80, and can cause memory and thinking difficulties that resemble those seen in Alzheimer’s disease.

Understanding LATE dementia is increasingly important as populations age and research shows that dementia can result from several different, and sometimes overlapping, biological processes.

LATE dementia and TDP-43: what is the connection?

TDP-43 is a protein that normally plays an important role in regulating gene expression within cells. In LATE, researchers have identified abnormal accumulations of this protein in areas of the brain associated with memory and cognition.

The presence of TDP-43 pathology is not exclusive to LATE. It has also been associated with other neurodegenerative conditions. What makes LATE distinctive is its characteristic distribution in the brain, its association with advanced age and its relationship with memory impairment.

Research suggests that LATE may be relatively common among older adults. A 2022 study combining neuropathological, genetic and clinical data from 13 community- and population-based studies found autopsy-confirmed LATE neuropathologic change (LATE-NC) in around 40% of the participants with available amyloid plaque data. The study was supported in part by grants from the U.S. National Institutes of Health (NIH), including the National Institute on Aging (NIA).

Is LATE dementia the same as Alzheimer’s disease?

No. LATE dementia and Alzheimer’s disease are different conditions, although their clinical manifestations can be difficult to distinguish.

Both can involve:

• Progressive memory problems.
• Difficulties with thinking and decision-making.
• Problems finding words.
• Changes in everyday cognitive functioning.

One of the main differences lies in the underlying brain pathology. Alzheimer’s disease is primarily associated with abnormal accumulation of amyloid-beta and tau proteins, whereas LATE is associated with TDP-43 pathology.

However, the distinction is not always straightforward. LATE can occur alongside Alzheimer’s disease and other forms of brain pathology. This is particularly relevant because the combination of different pathologies may contribute to a more pronounced cognitive decline. Research has found that more than half of people with signs of LATE in some autopsy studies also showed Alzheimer’s-related pathology.

This reinforces an increasingly important idea in dementia research, cognitive decline in older age is often more complex than a single diagnosis might suggest.

What are the symptoms of LATE?

The symptoms associated with LATE dementia can resemble those of Alzheimer’s disease. Memory impairment is particularly relevant, but people may also experience difficulties with thinking, decision-making and language.

According to the National Institute on Aging, symptoms can include:

• Memory problems.
• Difficulty thinking or making decisions.
• Trouble finding the right words.
• Getting lost or wandering.

Research published in recent years has also suggested that LATE may have a distinctive relationship with memory decline and certain aspects of cognitive functioning. Importantly, researchers are still working to understand how the progression of LATE differs from other causes of dementia.

How is LATE dementia diagnosed?

This is one of the major challenges surrounding LATE. At present, LATE cannot be definitively diagnosed during life through a validated routine clinical test. Its definitive identification has traditionally relied on neuropathological examination of brain tissue after death.

This situation is changing as research focuses on identifying biomarkers and clinical profiles that could help recognise LATE while a person is alive.

Researchers are investigating whether patterns involving memory decline, brain changes, genetic factors and biological markers could help distinguish LATE from Alzheimer’s disease and other dementias. The development of reliable biomarkers could be particularly important for research and, in the future, for more personalised approaches to diagnosis and care.

Why does LATE matter for dementia research?

The growing recognition of LATE highlights the complexity of dementia and the importance of looking beyond a single disease model.

As people live longer, understanding the different biological pathways associated with cognitive decline becomes increasingly relevant. Identifying these pathways could help researchers develop better diagnostic tools, improve the classification of dementia and design interventions that are better adapted to the characteristics of each person.

LATE also illustrates why early detection and the integration of multiple types of health data are becoming increasingly important in ageing research. Biological, clinical, behavioural and other real-world information can contribute to a more complete understanding of cognitive health.

This perspective is closely aligned with the objectives of COMFORTage, a European project focused on developing innovative approaches to the prevention of dementia and frailty. The project brings together artificial intelligence, medical innovation, digital technologies and different sources of health-related data to support more integrated and person-centred approaches to healthy ageing.

Looking beyond a single cause of dementia

LATE dementia reminds us that cognitive decline in later life can have multiple biological causes. Alzheimer’s disease remains an important cause of dementia, but it is not the only pathway involved.

Understanding conditions such as LATE can therefore contribute to a more nuanced approach to dementia research—one that recognises different forms of pathology, the possibility of coexisting conditions and the diversity of ageing trajectories.

References

National Institute on Aging (NIA). What Is Limbic-Predominant Age-Related TDP-43 Encephalopathy (LATE)?. https://www.nia.nih.gov/health/alzheimers-and-dementia/what-limbic-predominant-age-related-tdp-43-encephalopathy-late

Nelson, P. T. et al. (2019). Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain. https://pubmed.ncbi.nlm.nih.gov/31039256/

Nag, S. & Schneider, J. A. (2023). Limbic-predominant age-related TDP43 encephalopathy (LATE) neuropathological change in neurodegenerative diseases. Nature Reviews Neurology. https://pubmed.ncbi.nlm.nih.gov/37563264/

National Institute on Aging. TDP-43 in AD/ADRD: Establish biomarkers and dementia risk profiles (Milestone 9.T). https://www.nia.nih.gov/research/milestones/diagnosis-assessment-and-disease-monitoring/tdp-43-ad-adrd-establish-biomarkers

**Article written by Ana Vizcaíno from Fundación Intras, a key partner in the COMFORTage project.