If we talk about dementias, a lot of names may come to mind, but there is certainly one name that stands out from all the others: Alzheimer’s.

The deficits that this disease generates, highlighting the effect it has on memory, and its typical evolution is something generally well documented and known not only by the scientific community but also by the general population.

However, Alzheimer’s is not the only existing dementia, and we can also find some with similar symptoms and presentation styles. One of them, which in fact in the past was considered a subtype of Alzheimer’s, has recently received the consideration of an independent clinical entity: we are talking about the age-related limbic-predominant encephalopathy TDO-43 or LATE , which we will talk about throughout this article.

Limbic-predominant age-related encephalopathy (LATE): what is it?

Limbic-predominant age-related encephalopathy or LATE is a proteinopathy type disease that generates a dementia highly similar to Alzheimer’s disease , in which alterations in the TDP-43 protein are present. It is a disease that generates neurodegeneration, and which is characterized by a progressive loss of cognitive abilities as the brain cells degenerate and die.

Despite the fact that this dementia has been recently identified, the truth is that it is estimated that in fact around 20 to 50% of subjects over 80 years of age could suffer from it. It is more frequent in women, although it should also be taken into account that life expectancy above 80 years of age is much lower in men. It has often been confused with Alzheimer’s, and in fact although early research identified it as a subtype of Alzheimer’s. However, it is a different condition.

Dementia due to LATE is especially known to cause severe affectation at the level of the hippocampus , despite the fact that the first manifestations usually affect the limbic pathways. The dementia that it generates is characterized by being affected at an amnesiac level, and little by little as the disease progresses, other areas of the brain and other cognitive functions are affected.

The progression of this dementia is much slower than in other neurodegenerative pathologies , but it can be associated with others and in this case it worsens the picture.

Progression in 3 phases

Although more research is needed, studies so far seem to indicate the existence of three major stages through which the disease is evolving and generating increasing affectation. In fact, there are several proposed classifications, but generally the following consensus classification is taken as a reference.

Phase 1: Tonsil involvement

Unlike other dementias, one of the first areas affected by dementia caused by LATE is the amygdala. Initially, this is an affectation that occurs specifically in this brain region. This affectation can generate alterations at the level of mood , and according to studies it causes a tendency towards agitation and even aggression in patients at this stage.

Phase 2: Hippocampal involvement

In a second phase, the hippocampus begins to be affected by encephalopathy. In this phase memory is more compromised, and although it is not usually the first affected area, it is the alteration that is usually most recognized.

Gliosis and neuronal loss occur, and it is possible that sclerosis appears in a comorbid way at the hippocampal level and even an asymmetry between both hemispheres can be seen. Astrocytosis and entorhinal cortex affectations with hypertrophied microglia can also be seen. In addition, the dentate gyrus, occipitotemporal, insula and lower olive also degenerate at this stage.

Phase 3: Affectation in frontal medial rotation

In this third stage, behavioural alterations are manifested, also provoking a severe affectation of daily life activities that can even be more severe than in other dementias. In addition to this region , the frontal and temporal areas are also affected , which leads to the appearance of symptoms similar to those of advanced Alzheimer’s. It is also common for subcortical degeneration to begin, especially at the level of the basal ganglia.


The causes of LATE, as with most other dementias, are not entirely known and understood. However, it has been observed that the presence of accumulations of TDP-43 protein in different points of the brain is linked to its appearance.

This protein is part of our organism and is of great help when it comes to expressing the genes linked to the development and functioning of the brain correctly, but nevertheless when unfolded and in excess this protein can be neurotoxic and generate neurodegeneration and the decrease of different cognitive abilities (among them memory).

This factor also appears in other pathologies, but it is a quite relevant differential factor with respect to Alzheimer’s disease. Moreover, in age-related limbic-predominant TDP-43 encephalopathy there are no visible alterations of the TAU protein, which in Alzheimer’s disease is abundant in the form of the generation of neurofibrillary tangles that hinder synaptic transmission.

Another risk factor, as indicated by its full name, is age : this problem has been observed in people whose age was between seventy and eighty years old, and its probability of occurrence increases as the years go by. Several analyses have also been carried out at the genetic level and the presence of mutations in genes such as GRN, APOE, and TMEM106B also appear to be risk factors.

Alzheimer’s and LATE: two easily confused diagnoses

In terms of symptoms, dementia caused by the encephalopathy known as LATE is apparently very similar to Alzheimer’s , which is why until now it had not been identified as a separate entity of its own. In fact, the discovery of this pathology leads us to believe that many of the cases diagnosed with Alzheimer’s actually suffered from this recently discovered problem.

One of the main differences can be found at the neurobiological level, as we commented in the previous section: while in Alzheimer’s disease accumulations of TAU protein are observed in LATE, there are no major alterations in this protein, while there are in the TDP-43 protein (something which in turn is not common in Alzheimer’s disease).

Likewise, although both pathologies affect brain regions such as the amygdala, the hippocampus and the midfrontal gyrus, the order of presentation is different: in LATE the beginning of degeneration is seen at the amygdala level, while in Alzheimer’s it is the temporal lobe and the hippocampus that begin to degenerate.

But although they are different entities, it is also true that PDD-43 encephalopathy can appear associated with other disorders, including Alzheimer’s (also amyotrophic lateral sclerosis and frontal dementias). In this sense, although the neurodegeneration caused by LATE is much more gradual than in Alzheimer’s when it occurs by itself , when both pathologies appear together the neurodegeneration process is much faster than in either condition separately.

  • You may be interested in: “Alzheimer’s: causes, symptoms, treatment and prevention

Looking for a treatment

At present there is no well-established treatment for this dementia, but the fact that it works differently from Alzheimer’s disease makes it possible to explain why many of the drug treatments for what were thought to be cases of this disease are not successful.

Mechanisms and techniques to combat this disease should be explored , probably focusing on combating excessive accumulation of TDP-43 protein. Likewise, once the existence of differences at a symptomatic level with Alzheimer’s has been analyzed to a greater extent, more specific training and cognitive stimulation programs could be developed, although on the other hand the programs already developed are not specifically focused on Alzheimer’s but rather on the fight against the symptoms it generates, which in this sense are largely shared.

Bibliographic references

  • Nelson, P.T., Dickson, D.W., Trojanowski, J.Q., Jack, C.R., Boyle, P.A., Arfanakis, K., Rademakers, R., Alafuzoff, I., Attems, J., Brayne, C., Coyle-Gilchrist, I.T.S., Chui, H.C., Fardo, D.W., Flanagan, M.E., Halliday, G., Hokkanen, S.R.K., Hunter, S., Jicha, G.A., Katsumata, Y., Kawas, C.H., Keene, C.D., Kovacs, G.G., Kukull, W.A., Levey, A.I., Makkinejad, N., Montine, T.J., Murayama, S., Murray, M.E., Nag, S., Rissman, R.A., Seeley, W.W., Sperling, R.A., White III, C.L., Yu, L. & Schneider, J.A. (2019). Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain, awz99.