Limbic-predominant age-related TDP-43 encephalopathy (LATE) …

Peter T Nelson MD PhD

Neurobehavioral & Cognitive Disorders

Updated 06.17.2024
Expires For CME 06.17.2027

Limbic-predominant age-related TDP-43 encephalopathy (LATE)

Author: Peter T Nelson MD PhD

See Contributor Disclosures

Editor: Howard S Kirshner MD

Limbic-predominant age-related TDP-43 encephalopathy (LATE)

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Introduction

Overview

It is increasingly clear that a multitude of pathologies (in a population, and within an individual) can underlie the dementia clinical syndrome. Among the most common and impactful of these is limbic-predominant age-related TDP-43 encephalopathy (LATE), a very common “Alzheimer disease mimic” (16). Thus, the symptoms of LATE are similar to those of Alzheimer disease, and the pathology underlying LATE (TDP-43 proteinopathy) commonly, but not inevitably, co-occurs with Alzheimer disease. LATE affects approximately one quarter of individuals over 80 years of age.

Key points

	• Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a common condition of aging (affects approximately one quarter of individuals over 80 years old).
	• LATE neuropathologic change (LATE-NC) is the pathologic substrate.
	• LATE-NC is characterized by TDP-43 pathology, mostly in the medial temporal lobes.
	• LATE-NC is often comorbid with Alzheimer disease neuropathologic changes (ADNC, ie, amyloid plaques and neurofibrillary tangles).
	• The prevalence of pathologies in persons over the age of 80 are as follows: ADNC+LATE-NC > pure ADNC > pure LATE-NC.
	• The severity of the cognitive impairment is as follows: ADNC+LATE-NC > pure ADNC > pure LATE-NC.

Historical note and terminology

TDP-43 proteinopathy is a disease-associated pathological phenomenon discovered by Dr. Manuela Neumann and colleagues at UPENN, in the Drs. John Trojanowski/Virginia Lee CNDR Lab in 2006, in the context of neurologic diseases along a spectrum of frontotemporal lobar degeneration and amyotrophic lateral sclerosis (21). TDP-43 pathology is also associated with over 20 other neurologic diseases (04), with TDPopathies being analogous to tauopathies. This has produced some confusion in the field.

Clinical manifestations

Presentation and course

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is associated with a range of clinical symptoms that primarily affect cognitive functions, particularly memory. The clinical manifestations of LATE closely mimic those of Alzheimer disease, often leading to diagnostic challenges (14; 18). In this section, we explore the key symptoms of LATE, their progression, and the impact on affected individuals.

Cognitive symptoms

Memory impairment. A primary clinical feature of LATE is memory impairment. The hallmark symptom of LATE is a progressive memory loss that predominantly affects short-term and episodic memory (23; 03). This impairment is often severe enough to interfere with daily functioning and usually remains the chief neurologic deficit, unlike other types of dementia in which non-memory cognitive domains and behavioral changes might be noted earlier or more prominently.

Pure LATE. Pure LATE lacks Alzheimer disease neuropathologic changes (ADNC) and is associated with relatively gradual cognitive decline. The amnestic syndrome in LATE tends to worsen gradually, leading to significant memory deficits over time (14). Unlike more rapidly progressive dementias, the cognitive decline in LATE, when it is the chief pathology present, is typically slow.

Severe symptoms and rapid deterioration when combined with ADNC. Approximately half of dementia in advanced age includes both Alzheimer disease and LATE pathologies, and these individuals are at risk for a more swift and severe disease course (14).

Dementia. This is a clinical syndrome, rather than a particular disease process, analogous to “shortness of breath” (ie, dyspnea), which can have many underlying causes. Thus, many different diseases, including LATE, contribute to dementia. The implications of the term “dementia” are that there is cognitive impairment severe enough to impair activities of daily living, such as feeding oneself.

Mood changes and behavioral changes. Individuals with LATE may experience mood swings, depression, and apathy. These symptoms can complicate the clinical picture, especially in the elderly who may have other comorbid conditions affecting their mood and cognitive status. Neuropsychological disturbances are particularly common when LATE is combined with Alzheimer disease.

Subtle changes in personality and behavior. Family members may notice less social interaction and a general withdrawal from previously enjoyed activities.

Prognosis and complications

The symptoms of “pure” limbic-predominant age-related TDP-43 encephalopathy (LATE) develop more insidiously than those of “pure” Alzheimer disease (10). Initial symptoms are often so mild that they are dismissed as normal aging (16). However, as the disease progresses, memory impairment becomes more prominent and begins to significantly interfere with daily activities. The rate of progression varies widely among individuals but generally occurs over several years. Again, it should be emphasized that up to half of the cases of dementia in advanced age involve both Alzheimer and LATE pathologies (15), and affected individuals with so-called “mixed” pathologies have a more rapid and severe disease course.

Biological basis

Etiology and pathogenesis

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a neurodegenerative disorder affecting older adults and is characterized by the abnormal accumulation of TDP-43 protein in the brain. The exact causes of LATE are not fully understood, but a combination of factors, particularly genetic risk factors, are believed to contribute to its development.

Genetics. Genetics have been strongly implicated in LATE pathoetiology. The major known risk factors for LATE neuropathologic change (LATE-NC) are low-penetrant (ie, they only increase risk but do not render the disease inevitable) variations in the TMEM106B, GRN, APOE, ABCC9, KCNMB2, and WWOX genes and have been linked to altered risk for LATE-NC (or hippocampal sclerosis dementia) (05; 02; 12; 06; 07; 17).

Age. The strongest single risk factor for LATE is advanced age. The prevalence of LATE increases significantly in individuals over 80 years old, and the average patient with LATE is 10 years older than the average patient with severe Alzheimer disease neuropathologic changes (ADNC), suggesting that aging-related biological processes—yet to be comprehensively identified (but which include TMEM106B c-terminal fragments that are deposited in an age-related manner)—play roles in the development of LATE (20).

Comorbid pathologies. Many cases of LATE occur alongside other neurodegenerative diseases, such as Alzheimer disease. This co-occurrence may suggest shared or synergistic risk factors, genetic or environmental, that contribute to neurodegeneration. There also appears to be synergies such that LATE co-occurs with age-related tau astrogliopathy (ARTAG), brain small vessel pathology (arteriolosclerosis), and hippocampal sclerosis (01; 19; 11; 17).

Epidemiology

Prevalence. Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a very common subtype of dementia. This condition is estimated to affect a significant portion of the elderly population, especially those over the age of 80. Studies suggest that LATE neuropathological changes are present in over 30% of individuals over 85 years old, making it one of the more common neurodegenerative conditions in the elderly (08; 15; 22). LATE often coexists with other pathologies, such as Alzheimer disease or cerebrovascular disorders.

Incidence. Specific incidence rates for LATE are challenging to determine due to the overlap of its clinical presentation with other types of dementia; the paucity of population-based studies; potential variations by ethnic group; and, as reliable biomarkers for LATE have not yet been identified, the fact that definitive diagnosis is still possible only through autopsy.

Age. The risk of developing LATE increases with age, and it is rare in individuals under 65 and increasingly common in those over 80.

Sex. Studies have not shown consistent differences between males and females in the prevalence of LATE.

Ethnic and racial groups. Limited data are available on the prevalence of LATE across different ethnic and racial groups. Initial studies have not indicated significant differences in prevalence based on race or ethnicity (13; 09).

Global distribution. LATE has been identified in populations studied around the world. However, differences in study designs, diagnostic criteria, and awareness of the disease may affect reported rates from different countries.

Influence of health systems. The recognition and reporting of LATE may also vary significantly depending on the local healthcare system's capacity to diagnose and record cases of dementia, particularly in settings where detailed neuropathological examinations are less common.

Diagnostic workup

Limbic-predominant age-related TDP-43 encephalopathy (LATE) neuropathologic changes (LATE-NC) in isolation is a clinical mimic of Alzheimer disease and is associated with a slowly progressive, amnestic clinical syndrome. Alternatively, concomitant Alzheimer disease neuropathologic changes (ADNC) and LATE-NC is associated with a more rapid and severe clinical deterioration than either pathology alone. With the emergence of anti-Abeta therapeutics, discrimination of LATE-NC from ADNC is increasingly important for clinical management. Further, co-pathology with LATE-NC may influence outcomes of these emerging therapeutics. Thus, there is a substantial need to identify patients during life with likely underlying LATE-NC to provide appropriate prognostic information and to advance the field towards therapeutics for this condition. Wolk and colleagues proposed criteria for the clinical diagnosis of LATE based on expert opinion to serve as an initial framework for further validation. In the context of progressive episodic memory loss and substantial hippocampal atrophy, clinical criteria are laid out for probable LATE (AB-amyloid biomarker negative) or possible LATE (when Abeta amyloid biomarkers are unavailable or when amyloid is present, but neurodegeneration of the medial temporal lobe is out of proportion to expected pure ADNC).

Notably, biomarkers help with the differential diagnosis.

Magnetic resonance imaging (MRI). MRI scans are used to observe structural changes in the brain. In LATE, MRI may reveal severe atrophy in the medial temporal lobe, particularly in the hippocampus and amygdala, which are key areas affected by TDP-43 pathology, and may indicate hippocampal sclerosis.

Positron emission tomography (PET). Although PET scans are commonly used to detect amyloid and tau pathologies in Alzheimer disease, the absence of marked aberration in these may support the diagnosis of LATE by ruling out significant amyloid or tau burdens indicative of Alzheimer disease. FDG-PET has been suggested to have great promise in selecting cases with LATE-NC–predominant rather than ADNC-predominant pathologic features.

Cerebrospinal fluid (CSF) and blood biomarkers. Biomarkers for neuronal damage, such as tau protein and neurofilaments, can be measured in the CSF and blood. A lack of amyloid-beta and tau relative to the degree of cognitive impairment may suggest LATE if typical Alzheimer pathology is not present.

Vigorous efforts are ongoing to identify specific biomarkers for TDP-43 pathology. These include potential CSF markers or blood-based biomarkers derived from advanced protein assays, which could specifically indicate the presence of abnormal TDP-43.

References

01: Amador-Ortiz C, Lin WL, Ahmed Z, et al. TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease. Ann Neurol 2007;61(5):435-45. PMID 17469117
02: Beecham GW, Hamilton K, Naj AC, et al. Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias. PLoS Genet 2014;10(9):e1004606. PMID 25188341
03: Boyle PA, Wang T, Yu L, et al. To what degree is late life cognitive decline driven by age-related neuropathologies? Brain 2021;144(7):2166-75. PMID 33742668
04: Chornenkyy Y, Fardo DW, Nelson PT. Tau and TDP-43 proteinopathies: kindred pathologic cascades and genetic pleiotropy. Lab Invest 2019;99(7):993-1007. PMID 30742063
05: Dickson DW, Baker M, Rademakers R. Common variant in GRN is a genetic risk factor for hippocampal sclerosis in the elderly. Neurodegener Dis 2010;7(1-3):170-4. PMID 20197700
06: Dugan AJ, Nelson PT, Katsumata Y, et al. Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study. Acta Neuropathol Commun 2021;9(1):152. PMID 34526147
07: Dugan AJ, Nelson PT, Katsumata Y, et al. Association between WWOX/MAF variants and dementia-related neuropathologic endophenotypes. Neurobiol Aging 2022;111:95-106. PMID 34852950
08: Hokkanen SRK, Hunter S, Polvikoski TM, et al. Hippocampal sclerosis, hippocampal neuron loss patterns and TDP-43 in the aged population. Brain Pathol 2018;28(4):548-59. PMID 28833898
09: Huie EZ, Escudero A, Saito N, et al. TDP-43 pathology in the setting of intermediate and high Alzheimer's disease neuropathologic changes: a preliminary evaluation across ethnoracial groups. J Alzheimers Dis 2023;91(4):1291-301. PMID 36617779
10: James BD, Wilson RS, Boyle PA, Trojanowski JQ, Bennett DA, Schneider JA. TDP-43 stage, mixed pathologies, and clinical Alzheimer's-type dementia. Brain 2016 30;139(11):2983-93. PMID 27694152
11: Katsumata Y, Wu X, Aung KZ, et al. Pathologic correlates of aging-related tau astrogliopathy: ARTAG is associated with LATE-NC and cerebrovascular pathologies, but not with ADNC. Neurobiol Dis 2024;191:106412. PMID 38244935
12: Murray ME, Cannon A, Graff-Radford NR, et al. Differential clinicopathologic and genetic features of late-onset amnestic dementias. Acta Neuropathol 2014;128(3):411-21. PMID 24899141
13: Nag S, Barnes LL, Yu L, Wilson RS, Bennett DA, Schneider JA. Limbic-predominant age-related TDP-43 encephalopathy in Black and White decedents. Neurology 2020;95(15):e2056-64. PMID 32759188
14: Nag S, Schneider JA. Limbic-predominant age-related TDP43 encephalopathy (LATE) neuropathological change in neurodegenerative diseases. Nat Rev Neurol 2023;19(9):525-41. PMID 37563264
15: Nelson PT, Brayne C, Flanagan ME, et al. Frequency of LATE neuropathologic change across the spectrum of Alzheimer's disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts. Acta Neuropathol 2022;144(1):27-44. PMID 35697880
16: Nelson PT, Dickson DW, Trojanowski JQ, et al. Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain 2019;142(6):1503-27. PMID 31039256
17: Nelson PT, Fardo DW, Wu X, Aung KZ, Cykowski MD, Katsumata Y. Limbic-predominant age-related TDP-43 encephalopathy (LATE-NC): Co-pathologies and genetic risk factors provide clues about pathogenesis. J Neuropathol Exp Neurol 2024;83(6):396-415. PMID 38613823
18: Nelson PT, Schneider JA, Jicha GA, Duong MT, Wolk DA. When Alzheimer's is LATE: why does it matter? Ann Neurol 2023;94(2):211-22. PMID 37245084
19: Neltner JH, Abner EL, Baker S, et al. Arteriolosclerosis that affects multiple brain regions is linked to hippocampal sclerosis of ageing. Brain 2014;137(Pt 1):255-67. PMID 24271328
20: Neumann M, Perneel J, Cheung S, et al. Limbic-predominant age-related TDP-43 proteinopathy (LATE-NC) is associated with abundant TMEM106B pathology. Acta Neuropathol 2023;146(1):163-6. PMID 37171635
21: Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314(5796):130-3. PMID 17023659
22: Nichols E, Merrick R, Hay SI, et al. The prevalence, correlation, and co-occurrence of neuropathology in old age: harmonisation of 12 measures across six community-based autopsy studies of dementia. Lancet Healthy Longev 2023;4(3):e115-25. PMID 36870337
23: Yu L, Schneider JA, Kapasi A, Bennett DA, Boyle PA. Limbic-predominant age-related TDP-43 encephalopathy and distinct longitudinal profiles of domain-specific literacy. Alzheimer Dis Assoc Disord 2020;34(4):299-305. PMID 32452861
24: References especially recommended by the author or editor for general reading.

Contributors

All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

Peter T Nelson MD PhD

Dr. Nelson of the University of Kentucky has no relevant financial relationships to disclose.
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Editor

Howard S Kirshner MD

Dr. Kirshner of Vanderbilt University School of Medicine has no relevant financial relationships to disclose.
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Patient Profile

Age range of presentation: Typical: Usually affects people over the age of 70, even more so beyond the age of 85 and more with every year afterward

Atypical: Before the age of 70
Sex preponderance: Male:female is 1:1
Heredity: Limbic-predominant age-related TDP-43 encephalopathy (LATE): a “sporadic” (impossible to predict at present exactly which persons will be vulnerable in old age) condition, but there are genetic risk factors, including risk alleles of TMEM106B and GRN genes

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Limbic-predominant age-related TDP-43 encephalopathy (LATE)

Associated Disorders

Hippocampal sclerosis of aging
Arteriolosclerosis
Alzheimer disease

Differential Diagnosis

Alzheimer disease

Also Relevant

Alzheimer disease
Chronic traumatic encephalopathy
Frontotemporal dementia
Memory loss
PART (Primary age-related tauopathy)
- Pre-mild cognitive impairment

Clinical Categories

Neurobehavioral & Cognitive Disorders

Limbic-predominant age-related TDP-43 encephalopathy (LATE) …

Limbic-predominant age-related TDP-43 encephalopathy (LATE)

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Cognitive symptoms

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Anesthesia

References

Contributors

Author

Editor

Patient Profile

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Metal neurotoxicity

Vascular cognitive impairment

Addictive disorders

Automatic-voluntary dissociation

Wilson disease

Pre-mild cognitive impairment

PART (Primary age-related tauopathy)

Anti-LGI1 encephalitis

Limbic-predominant age-related TDP-43 encephalopathy (LATE)

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Cognitive symptoms

Prognosis and complications

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Associated or underlying disorders

Diagnostic workup

Management

Outcomes

Special considerations

Anesthesia

References

Contributors

Author

Editor

Patient Profile

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Metal neurotoxicity

Vascular cognitive impairment

Addictive disorders

Automatic-voluntary dissociation

Wilson disease

Pre-mild cognitive impairment

PART (Primary age-related tauopathy)

Anti-LGI1 encephalitis

This is an article preview.
Start a Free Account
to access the full version.