LATE: A New Term for Another Type of Dementia

The term "Alzheimer's disease" may have multiple meanings depending on the context in which it is used [1]. In most non-scientific articles, "Alzheimer's disease" usually means "Alzheimer's dementia." Dementia is a doctor's diagnosis of a condition characterized by cognitive problems that are severe enough to affect day-to-day activities. Alzheimer's disease is the presence of a specific type of brain pathology, namely the presence of amyloid plaques and neurofibrillary tangles, that may lead to dementia. However, not everyone with amyloid plaques has dementia, and not everyone with dementia has Alzheimer's disease. Other forms of dementia include vascular dementia, Lewy body dementia, and frontotemporal dementia. Recently, a consensus working group described a new type of pathology often found in patients with dementia, limbic-predominant age-related TDP-43 encephalopathy (LATE) [2].

WHAT IS LATE?

LATE is characterized by the aggregation of a protein, TDP-43, which can lead to the death of brain cells. Aggregates of TDP-43 were initially identified in two other neurodegenerative diseases, amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease) and frontotemporal lobar degeneration (FTLD-TDP). In LATE, TDP-43 aggregates initially appear in the amygdala, the part of the brain important for emotions, then in the hippocampus, the part of the brain important for memory, and then in other brain regions. Some patients with LATE also have shrinkage of the hippocampus known as hippocampal sclerosis.

LATE usually affects the oldest old individuals (those over 80). In fact, more than 20% of individuals over the age of 80 have evidence of LATE pathology, though not all have dementia. It can affect memory function, and its clinical symptoms often mimic Alzheimer's. The authors of the paper estimate that about 15-20% of patients in advanced age diagnosed with Alzheimer's disease might actually have LATE.

LATE and Alzheimer's disease are not mutually exclusive. Individuals with Alzheimer's disease may also have TDP-43 aggregates. Likewise, those with LATE may also have amyloid plaques. However, the authors identified a few differences between Alzheimer's and LATE. Individuals with "pure" LATE pathology had slower cognitive decline than those with "pure" Alzheimer's pathology. However, those with both decline faster. Additionally, individuals with preserved verbal fluency (i.e. the ability to come up with words in a certain category), despite verbal memory defects, were at risk for LATE, while Alzheimer's tends to affect both.

WHAT ARE THE IMPLICATIONS?

LATE typically occurs in the oldest old, has subtly different clinical presentations than Alzheimer's, and may be associated with more hippocampal shrinkage. However, there is currently no way to unambiguously identify LATE in living patients. The author stress that the development of LATE biomarkers should be a high scientific priority. In addition, although we know many ways to reduce the risk of Alzheimer's, there is still a lack of understanding of the risk factors for LATE. Finally, since LATE pathology can co-occur with Alzheimer's pathology, many of the patients in Alzheimer's clinical trials may also have LATE pathology. This could potentially obscure the results in clinical trials, and the authors suggest that clinical trials should be large enough to account for those with LATE pathology.

Dementia is a very heterogeneous syndrome [3]. Alzheimer's patients have amyloid plaques and neurofibrillary tangles. However, they could have other brain pathologies as well, such as other aggregated proteins or vascular problems. To successfully develop treatments for dementia, we will have to appreciate its complexity.

1. Knopman DS, Petersen RC, Jack CR, Jr. (2019) A brief history of "Alzheimer disease": Multiple meanings separated by a common name. Neurology.
2. Nelson PT, Dickson DW, Trojanowski JQ et al. (2019) Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain.
3. Kapasi A, DeCarli C, Schneider JA (2017) Impact of multiple pathologies on the threshold for clinically overt dementia. Acta Neuropathol 134, 171-186.