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Alzheimer's or LATE? An Emerging Clinical Conundrum

— TDP-43 brain pathology gets a name; may account for many dementia cases now attributed to AD

Last Updated May 1, 2019
MedpageToday
A grid of MRI images of the human brain.

A brain disorder that mimics clinical features of Alzheimer's dementia has been named and defined by an international consensus working group.

The newly-named pathology is called LATE (Limbic-predominant Age-related TDP-43 Encephalopathy), and was described in a consensus report by Peter Nelson, MD, PhD, of the Sanders-Brown Center on Aging at the University of Kentucky in Lexington, and colleagues, writing in .

"LATE is a really important cause of dementia that has been understudied and underappreciated," Nelson said.

"It's been known for a while in the clinical pathology literature that as people get really old, there seems to be a dissociation between what we see -- in terms of the neuropathology of Alzheimer's -- and cognitive impairments," he noted in an interview with 鶹ý. "It turns out that there is not really a dissociation. There are a lot of people who don't have Alzheimer's but have impairments, and it turns out that many of these people have LATE."

LATE is a TDP-43 (transactive response DNA binding protein of 43 kDa) proteinopathy that is associated with an amnestic dementia syndrome. It affects people at the very latest stage of the aging spectrum and has a relatively restricted anatomical distribution of misfolded TDP-43. People with LATE can have comorbid brain pathologies, including amyloid-beta plaques and tauopathy. Hippocampal sclerosis also can be present.

Community-based autopsy cohorts have reported that over 20% -- and up to 50% -- of brains of people older than age 80 had LATE neuropathological change.

"In our autopsy cohort, for example, about a third of our patients -- whether or not they had Alzheimer's disease -- also had TDP-43 proteinopathy," Nelson said. "That means that a third of our patients had a substantial pathology for which there was no name."

In Alzheimer's clinical trials, many people also have LATE, he added. "If you treat them for Alzheimer's disease and they don't get better, does that mean the Alzheimer's drug is not working? Not necessarily. We need to be able to remove these individuals from Alzheimer's clinical trials, or we will never be able to get Alzheimer's clinical trials to work," Nelson said.

LATE affects the "oldest of the old" patients, which is one way it is distinguished from frontotemporal dementia. No biofluid or PET biomarker shows TDP-43 specifically, so LATE can be identified only at autopsy at this point.

"That's a huge knowledge gap," Nelson noted. "But we do have biomarkers for Alzheimer's disease: if you have someone with memory impairment and advanced age -- a patient who is negative for Alzheimer's amyloid and doesn't have parkinsonisms -- the chances of them having LATE are quite high."

Developing LATE-specific biomarkers should be a high scientific priority, the consensus group said. And until there are biomarkers for LATE, clinical trials need to be powered to account for TDP-43 proteinopathy, they added.

At autopsy, LATE can be staged by a hierarchical pattern of TDP-43 pathology -- first, in the amygdala, then in the hippocampus, and finally in the middle frontal gyrus. Genetic risk factors for LATE have some overlap with frontotemporal lobar degeneration and with Alzheimer's disease.

LATE carries a very large burden on public health, at least as large as that of Alzheimer's disease, the consensus group noted. While LATE may progress more gradually than Alzheimer's, when the two diseases are combined -- which is common -- cognitive decline appears to be more rapid than in either disease alone. LATE is also not a new brain disorder, they added.

"Every pathologist wants to discover a new disease," Nelson said. "In this case, we did not. We are naming a disease that people have known about for a while. We're getting everyone on the same page."

Disclosures

This work was supported by the National Institute on Aging and other NIH institutions, the National Health and Medical Research Council of Australia, the National Institute for Health Research in the U.K., Addenbrooke's Charitable Trust, the Paul G. Allen Family Foundation, and Alzheimer's Research UK.

The authors reported no competing interests.

Primary Source

Brain

Nelson PT, et al "Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report" Brain 2019 DOI: 10.1093/brain/awz099.