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.

Prevention

There is no known preventive therapy or behavior to decrease the risk of limbic-predominant age-related TDP-43 encephalopathy (LATE).

Differential diagnosis

Confusing conditions

The primary confusing condition with limbic-predominant age-related TDP-43 encephalopathy (LATE) is Alzheimer disease. However, LATE commonly co-occurs with Alzheimer disease (15).

Associated or underlying disorders

Commonly associated underlying disorders are hippocampal sclerosis of aging, Alzheimer disease, and arteriolosclerosis (17).

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.

Management

Outcomes

There are currently no management guidelines, but it is theoretically possible that persons with LATE-NC may be relatively refractory to clinical intervention with anti-Abeta immunotherapies.

Special considerations

Anesthesia

It is unknown whether limbic-predominant age-related TDP-43 encephalopathy (LATE) leads to altered susceptibility to anesthesia complications or side effects.