Scientists Suspect Many Alzheimer's Diagnoses Wrong

LATE, formally known as limbic-predominant age-related TDP-43 encephalopathy, a recently recognized brain disorder that mimics the clinical features of Alzheimer's disease, could be more common than Alzheimer's, according to a report published on April 30 in the journal Brain. The report suggests that many patients diagnosed with Alzheimer's might instead be suffering from this newly discovered disease.

"While we've certainly been making advances in Alzheimer's disease research – such as new biomarker and genetic discoveries – we are still at times asking, 'When is Alzheimer's disease not Alzheimer's disease in older adults?'" said Richard J. Hodes, M.D., director of the National Institute on Aging (NIA), part of the National Institutes of Health, the nation's medical research agency. "The guidance provided in this report, including the definition of LATE, is a crucial step toward increasing awareness and advancing research for both this disease and Alzheimer's as well."

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 increasing understanding that a variety of diseases and disease processes contribute to dementia. Each of these diseases appears 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 is a protein that normally helps to regulate gene expression (the process of taking the genetic information in DNA and translating it into biological functions) in the brain and other tissues. Prior studies found that unusually misfolded TDP-43 has a role in causing 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% 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," said Nina Silverberg, Ph.D., director of the Alzheimer's Disease Centers Program at NIA. "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."

Supported by NIA, a workshop was held last October in Atlanta, co-chaired by Dr. Silverberg and Peter Nelson, M.D., Ph.D., from the University of Kentucky, Lexington, the lead author on the paper. 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.

The authors wrote that LATE is an under-recognized condition with a very large impact on public health. They 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.

"It is important to note that the disease itself is not new," said Dr. Silverberg. "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."