Much of the spectrum of age-related neurodegenerative conditions is associated with, and at least partly caused by, the accumulation of abnormal proteins or protein aggregates in the brain. These include the α-synuclein associated with Parkinson’s disease, the amyloid-β and tau of Alzheimer’s disease, and so forth. This sort of condition, in which malformed proteins are a contributing cause, is termed a proteopathy. A more recently recognized neurodegenerative proteopathy involves the TDP-43 protein, and the evidence for its relevance to age-related dementia has reached the point at which researchers and administrators now feel that they can advocate for greater recognition and funding for research and development in this part of the field.
Alzheimer’s is the most common form of dementia, which is the loss of cognitive functions – thinking, remembering, and reasoning – and everyday behavioral abilities. In the past, Alzheimer’s and dementia were often considered to be the same. Now there is rising appreciation that a variety of diseases and disease processes contribute to dementia. Each of these diseases appear differently when a brain sample is examined at autopsy. However, it has been increasingly clear that in advanced age, a large number of people had symptoms of dementia without the telltale signs in their brain at autopsy. Emerging research seems to indicate that the protein TDP-43 – though not a stand-alone explanation – contributes to that phenomenon.
TDP-43 (transactive response DNA binding protein of 43 kDa) is a protein that normally helps to regulate gene expression in the brain and other tissues. Prior studies found that unusually misfolded TDP-43 has a causative role in most cases of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. However, these are relatively uncommon diseases. A significant new development seen in recent research is that misfolded TDP-43 protein is very common in older adults. Roughly 25 percent of individuals over 85 years of age have enough misfolded TDP-43 protein to affect their memory and/or thinking abilities.
TDP-43 pathology is also commonly associated with hippocampal sclerosis, the severe shrinkage of the hippocampal region of the brain – the part of the brain that deals with learning and memory. Hippocampal sclerosis and its clinical symptoms of cognitive impairment can be very similar to the effects of Alzheimer’s. “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.” Scientists have now described the newly-named pathway to dementia as Limbic-predominant Age-related TDP-43 Encephalopathy, or LATE.
LATE is an under-recognized condition with a very large impact on public health. Researchers emphasized that the “oldest-old” are at greatest risk and, importantly, they believe that the public health impact of LATE is at least as large as Alzheimer’s in this group. The clinical and neurocognitive features of LATE affect multiple areas of cognition, ultimately impairing activities of daily life. Additionally, based on existing research, the authors suggested that LATE progresses more gradually than Alzheimer’s. However, LATE combined with Alzheimer’s – which is common for these two highly prevalent brain diseases – appears to cause a more rapid decline than either would alone.