Up to a third of people diagnosed with Alzheimer’s disease (AD) may in fact be suffering from a totally separate form of dementia which has only just been identified. Not only does this discovery change our understanding of the causes and nature of dementia, but it could also explain why all attempts to develop a cure for AD have failed.
Alzheimer’s disease, which typically results in memory loss and other signs of cognitive decline, is associated with the build-up of two proteins in the brain, known as amyloid and tau. For years, pharmaceutical companies have been developing drugs designed to remove these proteins from the brain, yet clinical trials have consistently produced disappointing results.
According to a new study in the journal Brain, this may be because a large number of the participants in these trials didn’t actually have amyloid or tau-related pathology to begin with. Instead, they may have been suffering from a condition called limbic-predominant age-related TDP-43 encephalopathy – or LATE for short – which causes symptoms that mimic AD.
The condition is caused by a misfolding of a protein called TDP-43, which regulates gene expression in the brain. After reviewing evidence from thousands of post-mortem examinations, the study authors state that around a quarter of people over the age of 85 have enough misfolded TDP-43 to impair their memory and general cognition.
Affecting the “oldest old” – meaning those older than 80 – LATE is thought to cause a more gradual decline in mental capacities than AD, although when the two conditions are present in combination symptoms tend to develop very quickly.
Nina Silverberg, director of the Alzheimer's Disease Centers Program at the National Institute on Aging, said in a statement that “recent research and clinical trials in Alzheimer's disease have taught us two things: First, not all of the people we thought had Alzheimer's have it; second, it is very important to understand the other contributors to dementia.”
The revelation that many people thought to be suffering from the condition may instead have been afflicted by LATE opens up the possibility of developing new treatments that are more effectively targeted. Study co-author Peter Nelson has already called for more work to be done in this area, stating that “LATE probably responds to different treatments than AD, which might help explain why so many past Alzheimer's drugs have failed in clinical trials.”
However, the study authors lament that at present, a lack of diagnostic tools for LATE represents a major obstacle to clinical progress. In their write-up, they suggest that developing biofluid or neuroimaging biomarkers that could help to diagnose LATE would considerably enhance the chances of finding an effective treatment for several different forms of dementia.
Genetic markers could also be used to help diagnose LATE, and the authors have already identified five separate genes that appear to contribute to the condition – some of which are also involved in causing AD.