New Dementia Subtype That Mimics Alzheimer’s Identified
Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a specific type of dementia that mimics Alzheimer disease (AD) but is caused by TDP-43 protein deposits in the brain rather than beta-amyloid accumulation and mostly affects people older than 80 years, says a consensus working group convened by the US National Institute on Aging.
LATE has “an expanding but under-recognized impact on public health,” given that the “oldest old” — a rapidly growing demographic group — are at greatest risk, the authors note.
Autopsy data indicate that about 1 in 4 people older than 85 demonstrated LATE neuropathologic change (LATE-NC) to a degree sufficient to be associated with discernible cognitive impairment, they say.
The conclusions of the working group were published online April 30 in the journal Brain.
Important Step Forward
The need to accurately define the LATE subtype of dementia has been building.
“People from all over the world were seeing evidence of a neurodegenerative disease that was not Alzheimer’s disease but which was being confused with Alzheimer’s disease because the cognitive symptoms are quite overlapping,” first author Peter Nelson, MD, PhD, of the Sanders-Brown Center on Aging, University of Kentucky, Lexington, told Medscape Medical News.
“We got together a large, international, multidisciplinary group of experts to discuss the topic and arrived at new nomenclature and ways of classifying the disease. This is an important step forward because it will provide a much better basis for studying the diseases that cause the dementia syndrome,” said Nelson.
The working group’s recommendations include guidelines for the diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, the group proposes a preliminary anatomically based staging system that reflects a hierarchical pattern of brain involvement:
- Stage 1: amygdala only
- Stage 2: amygdala and hippocampus
- Stage 3: amygdala, hippocampus and middle frontal gyrus
LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas are also affected, the group says. Neuroimaging studies demonstrate that for patients with LATE-NC, there is also atrophy in the medial temporal lobes, the frontal cortex, and other brain regions.
Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. “The discovery of these genetic risk variants indicates that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer’s disease, but also suggests disease-specific underlying mechanisms,” the group says.
A key goal of the working group is to catalyze future research on LATE. There are “large gaps in our understanding of LATE,” and there is “an urgent need for research focused on LATE,” the authors write.
In particular, the identification of LATE-specific biomarkers “should be a high scientific priority,” they say. Until there are biomarkers for LATE, clinical trials should be powered to account for TDP-43 proteinopathy, they suggest. They note that the coexistence of LATE neuropathology and AD neuropathology could obscure the effects of a potential disease-modifying agent.
“In the near term, it’s important for everyone to know that there is more than one disease that causes dementia. It’s unfortunate in a sense that more than one disease can affect the brain. Nonetheless, it also provides good opportunities to start developing treatments, one disease at a time,” Nelson told Medscape Medical News.
Tip of the Iceberg?
Commenting on the report in a statement, Maria Carrillo, PhD, chief science officer at the Alzheimer’s Association, said it “reinforces that Alzheimer’s and related dementias are incredibly complex diseases. We must learn more about each contributing cause of dementia so we can understand how these changes begin and interact and co-occur, and how to best diagnose, treat, and prevent them.
“This is an important area of research but is not likely to affect clinical practice until more research is completed. We need to learn more about LATE’s cause, progression, and risk factors and be able to measure it in living individuals (ie, a biomarker) so that it can we can properly understand its contribution — on its own and when it appears with Alzheimer’s,” said Carrillo.
Howard Fillit, MD, founding executive director and chief science officer of the Alzheimer’s Drug Discovery Foundation in New York City, told Medscape Medical News that this work “builds on a lot of the knowledge that we’ve had for a number of years now and kind of frames that knowledge into this new entity.
“In medicine, we have slicers and dicers,” he added, “and from a research point of view, it is useful to define these subtypes of clinical, pathological groups of people with dementia. But the aging brain has many misfolded proteins, and I think this is just the tip of the iceberg. It certainly makes TDP-43 one of the misfolded proteins that could be a target for therapeutic trials.
“But it’s very likely that none of these misfolded proteins are pure, and most people will have multicomorbid pathology. Trying to eliminate one misfolded protein in the aging brain, like beta-amyloid, is probably not going to work. That is increasingly being recognized,” Fillit said.
Major support for the working group was provided by the National Institute on Aging. The authors, Carrillo, and Fillit have disclosed no relevant financial relationships.
Brain. Published online April 30, 2019. Full text