LATE is a term that describes a prevalent medical condition with impaired memory and thinking in advanced age, often culminating in the dementia clinical syndrome. In other words, the symptoms of LATE are similar to those of Alzheimer's disease. The acronym LATE stands for Limbic-predominant Age-related TDP-43 Encephalopathy. "Limbic" is related to the brain areas first involved, "age-related" and the name "LATE" itself refer to the onset of disease usually in persons aged 80 or older. "TDP-43" indicates the aberrant mis-folded protein (or proteinopathy) deposits in the brain that characterize LATE, and "encephalopathy" means illness of brain.
At present, LATE can only be diagnosed with certainty at Autopsy. The terminology used to refer to the brain changes identified in autopsy-confirmed LATE is: LATE neuropathologic change (LATE-NC). The diagnosis of LATE-NC at autopsy requires detection of pathologic TDP-43 protein deposits in the brain. For reasons that are presently unknown, the disease process of LATE-NC preferentially affects medial temporal lobe structures of the brain, particularly the amygdala and hippocampus. In a significant proportion of persons with LATE-NC, there is atrophy, cell loss and astrogliosis in the hippocampus, diagnosable at autopsy (and somewhat less specifically via MRI during life) as hippocampal sclerosis. Brains with LATE-NC and hippocampal sclerosis are relatively more affected clinically than those with LATE-NC alone.
LATE is a very common condition: autopsy studies around the world indicate that LATE-NC is present in the brains of about one-third of people over 85. LATE typically affects persons older than 75 years of age (with some exceptions; please see below) and becomes increasingly prevalent every year in advanced old age. This is in contrast to Alzheimer's disease, which tends to level off and even decrease in prevalence among persons beyond age 85 years. LATE is often comorbid with (i.e., occurs in the same brain as) other pathologic changes that are also associated with dementia, such as Alzheimer's disease and cerebrovascular disease(s).
LATE has a large impact on public health. Clinical-pathologic correlation studies have established that the presence of LATE-NC is associated with impairments in memory and thinking. In older persons whose brains lack Alzheimer's disease-type amyloid plaques and neurofibrillary tangles, the presence of LATE-NC at autopsy is associated with a relatively slow cognitive decline (in comparison with Alzheimer's disease), mostly affecting the memory domain. However, most people (~75%) beyond age 85 have some Alzheimer's disease-type pathology and in this common scenario the impact of LATE-NC is very important. Approximately one-half of persons with Alzheimer's disease pathology also have LATE-NC. In these persons, the presence of LATE-NC is associated with a swifter disease course and with more severe clinical (memory and thinking) impairment than when only Alzheimer's disease pathology is present. A common combination of brain pathologies—with Alzheimer's disease pathology, Lewy body pathology, and LATE-NC in the same brain—tends to affect younger individuals (often <75 yrs of age) and, on average, is associated with more aggressive (faster) cognitive deterioration. With or without co-existing Alzheimer's disease or other brain changes, persons with LATE-NC generally lack the clinical features of frontotemporal dementia (FTD).
Signs and symptoms Cognitive symptoms The hallmark symptom of LATE is a progressive memory loss that predominantly affects short-term and episodic memory. 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. The amnestic syndrome in LATE tends to worsen gradually, leading to significant memory deficits and functional disability over time. Thus, the cognitive decline in LATE, when LATE-NC is the chief illness present, is typically relatively slow.
The term dementia refers to a clinical syndrome, rather than a particular disease process – dementia can be caused by many different subtypes of brain disease, which often occur in combination with each other. The specific implication of the term dementia is that, in the affected individual, there is cognitive impairment severe enough to impair activities of daily living such as feeding oneself. Many diseases in addition to Alzheimer's disease and LATE can (by harming brain function) contribute to the dementia clinical syndrome, and often occur in combination. For example, vascular factors ("stroke" and other blood vessel-affecting conditions, driven by such risk factors as hypertension and diabetes) and other brain diseases can cause or worsen dementia in human populations. However, up to half of severe dementia in advanced age includes both Alzheimer's disease and LATE-NC pathologies, and people with these co-pathologies are at risk for relatively swift and severe disease course.
Causes The exact causes of LATE are not fully understood, but a combination of factors, particularly age and genetic (i.e., inherited from one's biologic parents) risk factors, are believed to contribute to its development. Here we explore these factors based on current research and theories.
Medical and environmental risk factors
The strongest known 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 ten years older than the average patient with Alzheimer's disease, suggesting that aging-related biological processes—yet to be comprehensively identified (but which include TMEM106B C-terminal fragments)—play roles in the development of LATE. Although brain trauma (either single or multiple/chronic traumatic impacts) can produce brain changes that are qualitatively different from LATE-NC there may be interactions between brain trauma and LATE-NC mechanistically. Further, those with brain damage from trauma or other sources may have worse outcomes with a given burden of LATE-NC in the brain. There is indication from broader dementia research that higher educational attainment and engaging in mentally stimulating activities might delay the onset of clinical symptoms in neurodegenerative diseases. Whether this directly affects the risk of developing LATE or just modifies its presentation is still under investigation. While specific lifestyle factors directly causing LATE have not been definitively identified, general factors that affect brain health appear to influence risk of a given amount of pathology being correlated with cognitive impairment. Lifestyle factors that influence susceptibility to dementia include diet, physical activity, social and intellectual stimulation, cardiovascular health, and exposure to toxins. These may impair cognition in reciprocal relation to cognitive reserve. Notably, a 2025 study found that the brain-healthy MIND diet was associated with decreased risk for LATE with HS. Chronic inflammation in the brain is a known factor in many neurodegenerative diseases and may also play a role in LATE. Inflammatory processes could contribute to or exacerbate TDP-43 pathology. Disruptions in normal processing of proteins (proteostasis), which include aberrant post-translational modification, protein folding, protein trafficking, and protein degradation, are likely involved in promoting TDP-43 pathology in LATE. An imbalance in these processes could lead to the accumulation of misfolded TDP-43, contributing to disease progression.
Genetic risk factors
Other major known risk factors for LATE-NC are genetic: variations in the TMEM106B, GRN, APOE, ABCC9, KCNMB2, TPCN1, TMEM68, and WWOX genes have been linked to altered risk for LATE-NC (and/or hippocampal sclerosis dementia). These genetic elements are associated with biochemical changes that affect the stability, aggregation propensity, lysosomal microenvironment, and/or cellular trafficking of TDP-43. For example, the APOE ε4 allele, that confers increased risk for Alzheimer's-type amyloid plaques and neurofibrillary tangles, also increases the risk of LATE-NC; it is also remarkable that inheriting the FTLD risk genetic-variants TMEM106B and GRN/progranulin are also implicated in modifying risk of LATE-NC.
Pathophysiology TDP-43 (Transactive response DNA-binding protein) is a protein that normally resides in cell nuclei, and this protein is involved in regulating gene expression by binding to and modifying nucleic acids. More specifically, TDP-43 plays critical roles in RNA processing, including splicing, stability, and transport. As stated above, in healthy cells, TDP-43 is predominantly found in the cell nucleus. In LATE, TDP-43 protein abnormally accumulates in the cytoplasm of neurons and glial cells, forming pathologic aggregates. This cellular mis-localization is part of a process that disrupts TDP-43's normal nuclear functions and contributes to cellular dysfunction and neuronal death. The exact triggers of TDP-43 aggregation are not fully understood but are believed to involve both genetic predispositions, other co-pathologies occurring in the same brain, and acquired factors that may include mechanical or toxin-related stress. In normal brains and other tissues, the TDP-43 protein helps to ensure proper functioning of genes in the cell; the misfolded TDP-43 may thus impair normal gene expression regulation (so in LATE-NC, there is a loss-of-normal-function), and, the aberrant TDP-43 protein in LATE-NC may induce toxic gains of function also.
LATE neuropathology is graded based on the distribution of TDP-43 inclusions within the brain. Early stages may involve localized TDP-43 pathology in the amygdala, while more advanced stages involve the hippocampus and other medial temporal lobe structures In the individuals affected by the most advanced stage of LATE/LATE-NC, the TDP-43 pathology is far more extensive. For more details on the pathological stages of LATE-NC, see "Pathologic Examination", below.
LATE neuropathology is often associated with hippocampal sclerosis, characterized by severe neuron loss and gliosis in the hippocampus. This pathologic feature (also often readily detectable via brain MRI) significantly contributes to the memory deficits observed in LATE. LATE-NC often coexists with a small blood vessel pathology that affects cerebral arterioles, which is termed arteriolosclerosis. LATE-NC is more common in cases with comorbid tauopathy, including Alzheimer's-type plaques and tangles, primary age-related tauopathy (PART), and age-related tau astrogliopathy (ARTAG).
Diagnosis The diagnosis of LATE in live individuals is challenging because the symptoms of LATE overlap with those of other types of dementia, especially Alzheimer's disease, and there are no widely-used, specific clinical biomarkers (as of February 2026), to predict the presence of the pathology. Thus, at present LATE is diagnosed with certainty only at autopsy, i.e., through neuropathological examination. However, ongoing research aims to refine the antemortem diagnostic criteria and methods. The current approach to diagnosing LATE in living patients involves a combination of clinical evaluation, neuroimaging, and biomarker analysis, as detailed below.
As of June 2025, clinical rubrics have recently come on-line, that can be applied to predict whether a given patient is likely to have LATE-NC given the available clinical information.
In Ref a consensus-based clinical diagnostic rubric was developed, with the goals of identifying "Probable" and "Possible LATE" in the clinical context: Clinical criteria for LATE* Probable LATE
(must have XX; may have X)Possible LATE