It’s never too LATE to learn more about dementia

By Richard Merrick

In 2019 news headlines announced a “dementia breakthrough as new disease type identified” in response to the paper introducing ‘LATE’ (1), a newly defined pathology in the brain linked to dementia. Last month a follow up study found that roughly 40% of older adults show brain changes due to LATE (2), suggesting that this previously unknown condition is remarkably common. So what is LATE, and how might it change our understanding of dementia?

What is LATE?

LATE stands for Limbic-predominant Age-related TDP-43 Encephalopathy. In a nutshell, TDP-43 is another kind of abnormal protein aggregate found in old age which can damage brain cells in key memory circuits in the brain. This damage can lead to dementia, with symptoms of a decline in memory and thinking skills, and the ability to do day-to-day tasks.

TDP-43 was on the radar as a cause of rarer younger onset dementias such as ALS (Amyotropic Lateral Sclerosis). However, pathologists were not looking for it in the brains of older people, as it was not considered to be a routine cause of dementia in old age. In contrast to the abnormal proteins that define Alzheimer’s disease, which have been measured and studied for decades (even first identified 100 years ago), LATE only recently emerged on the radar. So dementia researchers are still playing catch up to learn how common it is, and what impact it has.

What did the new study find?

In addition to finding that around 40% (or 2 in 5) of older people show any brain changes due to LATE, it found that 25% (1 in 4) have LATE stage 2 or above, which is linked to cognitive impairment (2).

A key strength of this study is that it summarises data from 13 cohort studies from different parts of the world. Unlike clinic-based cohorts which combine patients with clinical diagnoses and healthy volunteers, this study used population-based or community-based cohorts, which are more likely to give findings representative of the full range of brain changes seen in the population. Despite this, there was still a wide range of estimates from these cohorts. Although this can partly be explained by differences such as age, other factors such as variation in the methods used to detect TDP-43 are harder to unpick.

The study was a large international collaboration and many of the cohort studies have been running for decades. It has taken several years for scientists to go back through brain tissue collected over that time to look for evidence of TDP-43 in these key brain circuits. None of which would have been possible without the original study participants (over 6000 people) who were interviewed over many years, and who donated their brains for examination after death.

Another piece of the puzzle

Many assume that the causes of dementia fit neatly into the clinical diagnoses that we are used to hearing, like Alzheimer’s disease or Vascular dementia. Although this can be the case in younger, often more genetically-driven forms of dementia - the kind more commonly seen in memory clinics (and therefore in clinic-based cohorts) - this is not the norm in older age groups, where dementia is most common. Population-based studies in these older age groups show that two or more pathologies is common (called ‘mixed pathology’). And although dementia becomes more likely as the severity or number of pathologies increases, there remains a proportion of people who do not experience dementia.

So the relationship between any type of pathology and dementia is not as straightforward as we may expect; for example the association between Alzheimer’s brain changes and dementia gets less strong with increasing age (3). The same population-based study estimated the contribution of different brain pathologies to dementia, finding a roughly 20% contribution each for age, Alzheimer’s, vascular and other types of pathology (4). The new evidence that LATE is both common and impactful makes it another piece of the puzzle of mixed pathology in old age.

A new perspective on the puzzle

As well as reminding us to think more holistically about brain changes in old age, and their relationship to dementia, this evidence further puts into perspective the relative contribution of these commonly co-occurring pathologies. Alzheimer’s disease has dominated research efforts for decades, but despite many clinical trials and even the recent controversial approval of a drug in the USA, an effective treatment remains elusive. Some may argue that the unknown presence of LATE has hampered these efforts, confounding clinical trial results, and that future trials should only include those with Alzheimer’s brain changes and exclude anything else - despite this not reflecting the majority of people with dementia.

Uncomfortable though it may be to accept, putting all our eggs in one basket to pursue a treatment for Alzheimer’s may not have the hoped-for benefit in the oldest age groups used to justify the investment. Although the prevention agenda is gaining traction both with researchers and policymakers, there remains reluctance to re-evaluate how we commit societal resources proportionately (and sustainably) to better address the needs of older populations. Hopefully this new evidence on LATE may help to shift our perspective and prompt a re-appraisal.