A brain disorder that mimics Alzheimer’s disease has for the first time been defined: Limbic-predominant Age-related TDP-43 Encephalopathy, or LATE.
Alzheimer’s disease is characterized by beta-amyloid, a protein that forms into hardened plaques in the brain and causes neuron death. The main symptom of Alzheimer’s is dementia, which is loss of cognitive functions—thinking, remembering, and reasoning—and every-day behavioral abilities. It is difficult to obtain an official diagnosis. For most people, Alzheimer’s can only confirmed after death, with a brain autopsy.
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, in advanced age, a large number of people have 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 the presence of TDP-43 in most cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, which 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 is also commonly associated with severe shrinkage of the hippocampal region of the brain—the part of the brain that deals with learning and memory. Hippocampal shrinkage causes cognitive impairment that can be very similar to the effects of Alzheimer’s.
The problem for researchers is that many people with characteristics of LATE disease—memory loss and confusion—are involved in clinical trials for Alzheimer’s that target beta-amyloid. When these trials fail, it may be because they do nothing to address TDP-43.
“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,” said Nina Silverberg, Ph.D., director of the Alzheimer’s Disease Centers Program at NIA. In the past many people who enrolled in clinical trials were not positive for amyloid.
“Noting the trend in research implicating TDP-43 as a possible Alzheimer’s mimic, a group of experts convened a workshop to provide a starting point for further research that will advance our understanding of another contributor to late life brain changes,” Silverberg explained. In addition to U.S. scientists, experts included researchers from Australia, Austria, Sweden, Japan, and the United Kingdom with expertise in clinical diagnosis, neuropathology, genetics, neuropsychology and brain imaging.
As it turns out, LATE is an under-recognized condition with a very large impact on public health. It is estimated that nearly one million people diagnosed with Alzheimer’s are actually affected with LATE. Older adults (85-95) are at greatest risk for LATE and the public health impact of the disease is believed to be at least as large as Alzheimer’s in this group. LATE affects multiple areas of cognition, ultimately impairing activities of daily life. Additionally, based on existing research, 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.
“It is important to note that the disease itself is not new. LATE has been there all along, but we hope this report will enable more rapid advancement in research to help us better understand the causes and open new opportunities for treatment,” said Dr. Silverberg.
For more information about participating in Alzheimer’s disease and related dementias clinical research, visit the NIA website.