Diagnostic Guidelines Developed for LATE, New Alzheimer-Like Brain Disorder

Peter T. Nelson, MD, PhD, professor, University of Kentucky Sanders-Brown Center on Aging

Peter T. Nelson, MD, PhD

An international working group has released new consensus-based recommendations for the diagnosis and staging of limbic-predominant age-related TDP-43 encephalopathy (LATE), a recently recognized brain disorder that mimics Alzheimer disease-type dementia at autopsy.¹

LATE is defined by the misfolding of TDP-43, a pathology that is commonly associated with hippocampal sclerosis, and one that can produce similar clinical symptoms of cognitive impairment as seen in Alzheimer disease. Misfolded TDP-43 is very common in older populations, with approximately 25% of adults aged ≥85 having enough of the misfolded protein to affect their cognitive abilities. First author Peter T. Nelson, MD, PhD, professor, University of Kentucky Sanders-Brown Center on Aging, and colleagues described an urgent need for research focused on the condition, including in vitro and animal models.

“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 disease not Alzheimer disease in older adults?'” Richard J. Hodes, MD, director of the National Institute on Aging (NIA), part of the National Institutes of Health (NIH), said in a statement. “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 as well.”

The report includes consensus-based recommendations, which consist of guidelines for the diagnosis and staging of LATE-neuropathological change (LATE-NC). LATE-NC, they noted, is defined by stereotypical TDP-43 proteinopathy both with or without simultaneous hippocampal sclerosis pathology, in older adults.²

“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 Nina Silverberg, PhD, director of the Alzheimer’s Disease Centers Program at NIA, in a statement.

The genetic research that has been conducted so far suggests that 5 genes have risk alleles for this condition: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. Although these risk variants show similar pathogenetic devices to both frontotemporal lobar degeneration and Alzheimer disease, they are also suggestive of disease-specific mechanisms which underlie LATE. Nelson and colleagues denote that LATE is distinguished from frontotemporal lobar degeneration as its TDP-43 pathology is epidemiologically different—generally affecting older patients—and the rather restricted neuroanatomical distribution of its proteinopathy.

"[Clinicians should know that] just because one has cognitive impairment doesn’t mean they have Alzheimer disease," Nelson told NeurologyLive^®. "Lots of different diseases can contribute. Around half of cognitive impairment is not related to Alzheimer at all. It’s an exciting thing to have a new terminology for a disease—that, granted, has been here all the time—which affects millions of Americans."

They proposed an anatomically-based preliminary staging scheme for the routine autopsy work in LATE-NC, which includes TDP-43 immunohistochemistry on tissue from 3 brain areas: the amygdala, the hippocampus, and the middle frontal gyrus. This, the investigators wrote, reflects the hierarchical pattern of brain involvement in LATE-NC, and thus the first through third stages of the condition.

Nelson et al. detailed that LATE-NC seems to impact the medial temporal lobe structures preferentially, although this does not exclude other areas, as neuroimaging studies have demonstrated that patients with LATE-NC also had atrophy in the medial temporal lobes and the frontal cortex, among others.

“Recent research and clinical trials in Alzheimer disease have taught us two things: First, not all of the people we thought had Alzheimer have it; second, it is very important to understand the other contributors to dementia,” Silverberg said. “Noting the trend in research implicating TDP-43 as a possible Alzheimer 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.”

The guidelines also explain that a number of individuals with LATE-NC appear to have comorbid brain pathologies, such as amyloid-β plaques and tauopathy. “Given that the ‘oldest-old’ are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health,” they wrote. To address this, a working group was convened to develop the diagnostic criteria with the aim of stimulating investigation into the condition and to promote awareness of this newly identified pathway to dementia.

"We need biomarkers to detect the disease in the clinical setting, and novel therapies for the disease itself. But just knowing about the complexity and heterogeneity is helpful in terms of developing clinical trials for dementia," Nelson told NeurologyLive^®. "This will facilitate new research, and, I think it is good for patients to know that the landscape of dementia-related diseases is more complex than previously thought."

"Clinicians should be aware that the future is likely to bring a very different set of practices, designed to detect the detailed repertoire of diseases in a patient, and assign an appropriate therapeutic regimen," he added.

The full guidelines can be accessed in the journal Brain.

REFERENCES

1. Nelson PT, Dickson DW, Trokanowski JQ, et al. Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain. Published online April 30, 2019. doi: 10.1093/brain/awz099.

2. Guidelines proposed for newly defined Alzheimer’s-like brain disorder [press release]. Rockville, MD: NIH; Published April 30, 2019. nia.nih.gov/news/guidelines-proposed-newly-defined-alzheimers-brain-disorder. Accessed May 2, 2019.