Awareness around the existence of multiple neurological diseases affecting the aged population and contributing to dementia is growing. New research has resulted in a “call to action” from a group of researchers to declare that a recently recognized disease entity, named limbic-predominant age-related TDP-43 encephalopathy (LATE), is a degenerative brain disease that mimics features of Alzheimer’s disease, but is a distinct disease.

“It’s time to stop thinking of dementia as a “one-size-fits-all” disease,” noted Peter Nelson, MD, PhD, professor at the Sanders-Brown Center on Aging at the University of Kentucky and first author on the study.

“LATE is a prevalent but underrecognized condition in the elderly,” said Dennis Dickson, MD, a neuropathologist at the Mayo Clinic. “We have been studying this protein for many years, but now we have a common goal to target, which is something we want to make clinicians aware of. LATE needs to be recognized and differentiated from Alzheimer’s disease.” The working group describes LATE as an underrecognized risk for public health and calls for an urgent focus on research to improve prevention, diagnosis, and treatment of the disease.

Their report, published in Brain, is titled “Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report.

The first pathological manifestation of LATE was identified in 13 elderly patients with dementia and brain changes in 1994. Since then, other groups have built and expanded on this work, culminating in the formation of this working group to “develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia.” The consensus paper is “an accumulation of research from multiple groups that have spent the past decade working on this,” noted Melissa Murray, PhD, a molecular neuroscientist at the Mayo Clinic and an author on the paper.

What makes LATE different from Alzheimer’s disease? 

The authors define LATE neuropathological change (LATE-NC) by “a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology.”

TDP-43 (transactive response DNA binding protein of 43 kDa) regulates gene expression in the brain and other tissues. 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% of individuals over 85 years of age have enough misfolded TDP-43 protein to affect their memory and/or thinking abilities.

LATE is distinguished from other diseases with TDP-43 pathology in large part because it affects older subjects (over 80 years old) and because the TDP-43 proteinopathy has a relatively restricted neuroanatomical distribution.

LATE affects multiple areas of cognition, ultimately impairing activities of daily life, but it appears that LATE progresses more gradually than Alzheimer’s. However, LATE combined with Alzheimer’s—a common combination—appears to cause a more rapid decline than either would alone.

“Given that persons of advanced age (past 80 years) are at greatest risk for LATE and constitute a rapidly growing demographic group in many countries, LATE has an expanding but underrecognized impact on public health,” the report said.

Among the goals of the working group was to agree to a name and common nomenclature for the disease. Age-related TDP-43 proteinopathy has been known to clinicians for about a decade, but a common terminology was lacking. Identifying the disease is an important step in catalyzing future research, the report says.

The working group recommends that TDP-43 testing be performed as part of routine autopsy evaluation in all older patients. Also, more investigation is needed to test for memory and nonmemory symptoms that distinguish LATE from other degenerative disorders.

Additional recommendations include highlighting the need for the development of biomarkers, further pathological studies, and the generation of new animal models. Suggestions were provided for possible strategies to help guide future therapeutic interventions, including the importance of removing subjects with LATE from other clinical trials, which could significantly improve the chances of successful Alzheimer’s breakthroughs. The researchers also discussed the importance of more epidemiological, clinical, neuroimaging, and genetic studies to better characterize LATE, and the need for research in diverse populations.

This work is a collaboration between researchers at the Mayo Clinic, University of Kentucky, the University of Texas Southwest Medical Center, Rush University Medical Center, the University of Cambridge in the U.K., and other institutions.


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