An 86-year-old woman develops classic amnestic symptoms of Alzheimer’s disease in her last years of life, but upon autopsy, her brain bears but a modest burden of Aβ plaques and tau tangles. Instead, TDP-43 inclusions crowd her limbic regions. This would be a typical case of limbic-predominant age-related TDP-43 encephalopathy (LATE), a common neurodegenerative disease christened by an international cadre of pathologists, clinicians, and epidemiologists in a consensus report published April 30 in Brain. They predict the disease will account for one in five clinical AD diagnoses. Its pattern of TDP-43 pathology is at least somewhat distinct from that observed in frontotemporal dementia (FTD). In their paper, drafted following a workshop in Atlanta last fall, researchers led by Peter Nelson of the University of Kentucky in Lexington summed up decades of research leading up to the coining of the term. They describe LATE’s features, propose ways to classify and diagnose it, and call for the development of specific biomarkers and therapeutics.
- LATE: Limbic-predominant age-related TDP-43 encephalopathy.
- Distribution of TDP-43 pathology is distinct from FTD.
- Clinical features are similar to those of Alzheimer’s.
Carol Brayne of the University of Cambridge, U.K., is one of the paper’s 35 co-authors. She said the report may help shift the dementia field away from its focus on AD neuropathology, a move she considers crucial in light of the mixed pathological jumble often present in the oldest brains upon autopsy. “For too long, millions of dollars have been chasing an idea of mechanisms with elegant research that is aimed at an assumed pathology, instead of looking at what is really there in the population. This paper helps to shift the narrative,” Brayne wrote to Alzforum.
Other researchers in the field expressed reservations about designating LATE—primarily a neuropathological entity—as its own disease. “The construct of LATE will give TDP-43 the recognition that it deserves and hopefully bring TDP-43 to the forefront of Alzheimer’s disease research,” commented Keith Josephs of the Mayo Clinic in Rochester, Minnesota. “That said, LATE is not a new disease. It may not even be a disease, given that 20 percent of individuals who die with normal cognition will have LATE. Instead, LATE is a rebranding of science, a catchy acronym, but if you can get by all the hype it is really just TDP-43 in the brains of old people, including those with plaques and tangles.”
Relatively few people make it into their 80s without some form of neuropathology arising in their brain, and mixed pathology is the norm. Neuropathologists commonly observe cytoplasmic inclusions of phosphorylated TDP-43 in postmortem brain samples with or without the Aβ plaques and neurofibrillary tangles that define AD.
Inclusions containing this RNA-binding protein were first implicated in ALS and FTD more than a decade ago (Neumann et al., 2006; Cairns et al., 2007). Soon after, neuropathologists led by Dennis Dickson at the Mayo Clinic in Jacksonville, Florida, spotted TDP-43 pathology in people who had had symptoms of AD, not FTD (Amador-Ortiz et al., 2007). It often accompanied hippocampal sclerosis—a shrunken hippocampus ravaged by gliosis. More than a decade prior, Dickson had described curious cases of hippocampal sclerosis in people with dementia without much AD pathology (Dickson et al., 1994).
Researchers now suspect that a large proportion of those cases, as well as cases more recently classified as suspected non-Alzheimer’s disease pathophysiology (SNAP), are caused by TDP-43 pathology (Sep 2015 conference news; Cykowski et al, 2017).
In the past decade, several studies have described the clinical and pathological course of this TDP-43 proteinopathy, newly dubbed LATE. One measured TDP-43 pathology in postmortem brain samples from nearly 1,000 deceased participants in the Rush Memory and Aging Project and Religious Orders Study (ROS-MAP) (James et al., 2016). Half of the participants had TDP-43 pathology, and 37 percent had both TDP-43 and AD pathology. People with both were more likely to have had clinical dementia than those who had either. This study proposed a pathological staging scheme, in which TDP-43 pathology hits the amygdala in stage 1, then the hippocampus and entorhinal cortex in stage 2, and finally the neocortex in stage 3. Once the pathology extends beyond the amygdala, it correlates with cognitive impairment.
The consensus report suggests this scheme for neuropathological staging of LATE, citing MRI support for the idea that the amygdala and hippocampal regions are affected in people who were later confirmed to have LATE.
LATE’s Mark on the Brain. LATE-specific atrophy patterns averaged from ROSMAP brain samples that were later confirmed to have LATE. Darker colors represent more atrophy. Rows are different brain views; each displayed with four different cut points. [Courtesy of Nelson et al., Brain 2019.]
LATE-associated TDP-43 pathology often co-occurs with hippocampal sclerosis, but the latter is not a requirement for a neuropathological diagnosis of LATE. Compared with the pattern of TDP-43 pathology seen in FTD—which also affects the hippocampus and neocortex—that observed in LATE leans more limbic, with less cortical atrophy, and crops up in older adults (Nelson et al., 2011).
What are clinical manifestations of this proposed new disease? The authors say LATE has a lot in common with AD. Episodic memory wanes early, other cognitive domains later. When this happens without substantial AD pathology, the memory loss is more gradual and less severe than in AD (Boyle et al., 2017; Nag et al., 2017). However, in people who also have abundant Aβ plaques and tau tangles, LATE neuropathology exacerbates cognitive symptoms beyond what would be expected for AD alone (Josephs et al., 2015).
Given the clinical ambiguity of LATE, Ian Mackenzie of the University of British Columbia in Vancouver, Canada, who was not involved in drafting the report, thinks it should have been named based on its pathology instead. “The authors propose the term LATE for a disease/condition that has no criteria other than the associated pathology,” Mackenzie noted. “It would be more logical to come up with a new name for the pathology, for example Limbic Predominant Age-related TDP-43 Proteinopathy, and then propose the existence of an LPATP-associated clinical syndrome which still needs to be defined,” he wrote to Alzforum. Mackenzie also noted that pathological differences between LATE and FTLD-TDP still need to be addressed.
Manuela Neumann of the German Center for Neurodegenerative Diseases in Tübingen raised similar issues. “How useful is the introduction of a new disease that is defined and can be diagnosed so far only by neuropathological findings obtained postmortem?” she wrote.
How common is LATE? ROSMAP researchers, led by Julie Schneider at Rush, reanalyzed data from their cohort to account for its proposed neuropathological staging. The consensus paper notes that this pathology was detected in one in five brains from people older than 80, extrapolating that 15 percent to 20 percent of clinically diagnosed AD cases at that age are attributable to LATE. They estimate the impact of LATE at about half that of AD in old people, and equal to the combined impact of all vascular neuropathologies. This would make LATE about 100 times more prevalent than FTD.
The report summarized data implicating genes in LATE neuropathology or hippocampal sclerosis, naming risk alleles in GRN, TMEM106b, ABCC9, KCNMB2, and APOE.
With the proposed new disease’s clinical resemblance to AD, how will researchers tell the two apart during life? No fluid biomarkers or PET tracers exist to detect TDP-43 pathology, though researchers are working on the problem, Nelson said. TDP-43’s intracellular location and small pathological burden make biomarker development challenging. For now, the best a diagnostician can do is follow a process of elimination. For example, using the AT(N) system for classifying AD where amyloid=A, tau=T, and neurodegeneration=(N), they might suspect LATE neuropathology in people who are A-T-N+, or A+T-N+ (Aug 2016 news). FDG-PET scans detect flagging metabolism in the medial temporal lobe in people with negative tau PET scans who later were found to have LATE neuropathology (Botha et al., 2018).
Even when AD pathology co-exists, specific atrophy patterns might be able to pick up LATE neuropathology, co-author John Trojanowski of the University of Pennsylvania in Philadelphia pointed out. He noted that UPenn researchers led by Christos Davatzikos have developed algorithms to detect AD and PD-specific atrophy patterns in MRI data, and suggested similar algorithms could be developed for LATE (Davatzikos et al., 2009).
“The full range of TDP-43 pathology across the whole brain in relation to dementia in the population has not yet been fully described,” noted consensus co-author Sally Hunter of the University of Cambridge, U.K. “This lack of clarity coupled with a lack of biomarkers specific for TDP-43 leads to difficulties in selecting well-defined and meaningful cases and controls both for research and for randomized controlled trials,” she wrote.
The co-occurrence of AD and LATE neuropathology in old age complicates interpretation of AD-specific treatment trials, and may even obscure positive results, Nelson noted. Until specific biomarkers for LATE neuropathology exist, clinical trials will need to be powered to account for TDP-43 proteinopathy, the authors wrote.
Once biomarkers exist, they will facilitate drug-discovery efforts targeted at LATE, for example at its TDP-43 aggregates. Given that comorbid neuropathologies in people at risk for LATE could potentially interact (Robinson et al., 2018), Trojanowski proposed an immunotherapeutic cocktail of antibodies aimed at Aβ, tau, TDP-43, and α-synuclein.—Jessica Shugart
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- Staging of Alzheimer’s, the Second: Neurodegeneration Does Not Equal Tauopathy
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