LATE & Hippocampal Sclerosis
Limbic-predominant age-related TDP-43 encephalopathy (LATE) is an increasingly recognized neurodegenerative entity characterized by aberrant accumulation of phosphorylated transactive response DNA-binding protein 43 (TDP-43) predominantly within limbic structures. LATE frequently coexists with hippocampal sclerosis (HS) — defined by severe neuronal loss and gliosis in the hippocampal CA1 region and subiculum — and represents one of the most common neuropathologic mimics of Alzheimer disease (AD) in older adults. LATE neuropathologic change (LATE-NC) is found in approximately 40% of autopsied older adults and may be the sole identifiable pathology in up to 20% of individuals older than 85 years with amnestic cognitive impairment. With the advent of anti-amyloid monoclonal antibody therapies for AD, accurate recognition of LATE as a distinct etiologic entity has become critical to avoid unnecessary treatment exposure and to guide appropriate patient counseling.
Bottom Line
- Definition: LATE is a neurodegenerative disease defined by limbic-predominant TDP-43 proteinopathy in older adults; it is the most common cause of hippocampal sclerosis in this population
- Prevalence: LATE-NC is found in ~40% of autopsied older adults; HS is present in 10–20% of adults older than 85 years, with TDP-43 positivity in up to 90% of HS cases
- Staging: LATE-NC follows a stereotyped progression — stage 1 (amygdala), stage 2 (hippocampus), stage 3 (middle frontal gyrus)
- Clinical mimicry: Slowly progressive amnestic-predominant decline closely resembling AD, particularly in individuals older than 75 years
- Distinguishing features vs AD: Older age at onset, longer and milder course, lack of neocortical signs (e.g., apraxia), disproportionate medial temporal atrophy without parietal involvement
- No direct biomarker: No validated antemortem biomarker for TDP-43 exists; diagnosis relies on integrating clinical, imaging, and AD biomarker data
- Copathology: AD + LATE copathology produces faster cognitive decline and greater brain atrophy than either pathology alone
- Therapeutic relevance: Anti-amyloid therapies have no indication for isolated LATE; misdiagnosis exposes patients to ARIA risk without anticipated benefit
Definition, Nosology, and Neuropathologic Staging
In 2019, a consensus working group proposed the term LATE for the clinical disease entity and LATE neuropathologic change (LATE-NC) for the underlying pathology — aberrant localization, phosphorylation, and aggregation of TDP-43 within limbic neurons and glia. The earlier term cerebral age-related TDP-43 with sclerosis (CARTS) similarly placed TDP-43 as the central mechanistic element. Within this framework, hippocampal sclerosis is viewed as a downstream consequence of TDP-43-related neurodegeneration. LATE and HS commonly coexist but neither is necessary nor sufficient for diagnosis of the other.
Key Terminological Distinctions
- LATE: The clinical disease entity associated with LATE-NC — includes cognitive symptoms
- LATE-NC: The neuropathologic finding of limbic-predominant TDP-43 proteinopathy — may be present with or without symptoms
- Hippocampal sclerosis (HS): Severe neuronal loss and gliosis in hippocampal CA1 and subiculum; in older adults, LATE is the most common associated etiology
- Hippocampal sclerosis of aging: HS in an older individual without other risk factors (e.g., epilepsy, trauma); most commonly associated with LATE-NC
LATE-NC is staged based on the stereotyped topographic spread of phosphorylated TDP-43 inclusions. Pathologic hallmarks include loss of normal nuclear TDP-43 localization, TDP-43-positive neuronal cytoplasmic inclusions, and aberrantly phosphorylated TDP-43 in neurons and glia. TDP-43 immunostaining is almost always bilateral even when routine histology shows only unilateral hippocampal neuronal loss.
| LATE-NC Stage | Brain Region | Clinical Correlate | Key Features |
|---|---|---|---|
| Stage 1 | Amygdala | Preclinical; may be cognitively normal or have early memory symptoms | TDP-43 confined to the amygdala; mild semantic deficits may reflect amygdalar dysfunction |
| Stage 2 | Hippocampus (+ amygdala) | Amnestic-predominant impairment; HS often develops | Extension to entorhinal cortex, dentate gyrus; robust association with clinical memory decline |
| Stage 3 | Middle frontal gyrus (+ hippocampus + amygdala) | More pronounced impairment; broader cognitive involvement possible | Neocortical involvement; may overlap pathologically with FTLD-TDP |
Among postmortem-confirmed HS cases in older adults, abnormal TDP-43 proteinopathy has been identified in up to 90%, implicating TDP-43 as mechanistically upstream of hippocampal neurodegeneration. TDP-43 pathology drives greater hippocampal atrophy and more severe impairment independent of coexistent AD, Lewy body disease, or cerebrovascular pathology. After age 85, HS prevalence increases while severe AD neuropathologic change decreases, supporting a distinct process.
Genetic Risk Factors for LATE
- TMEM106B: Most consistently replicated genetic risk factor for LATE-NC and HS; encodes a lysosomal transmembrane protein
- GRN (progranulin): Risk variants associated with both LATE and FTLD-TDP; plays a role in lysosomal function and neuronal survival
- ABCC9: Encodes a subunit of the ATP-sensitive potassium channel (KATP); associated with HS risk
- KCNMB2: Encodes a potassium channel subunit; identified as a risk locus for HS
- APOEε4: Associated with increased LATE-NC risk, though with stronger associations with AD pathology; notably, APOE has no convincing association with primary age-related tauopathy (PART)
Clinical Features
The hallmark syndrome of LATE is insidiously progressive amnestic-predominant cognitive decline in individuals typically older than 75 years. Patients present with repeated questioning, forgetting recent conversations, and difficulty with verbal learning and memory tasks (e.g., word lists, story recall). Concomitant mild semantic deficits — difficulty recalling major world events and emotionally salient historical information — may reflect amygdalar and hippocampal dysfunction. There is no evidence of increased seizure prevalence in LATE-associated HS, distinguishing it from epilepsy-related hippocampal sclerosis.
| Feature | LATE | Alzheimer Disease |
|---|---|---|
| Typical age at onset | >75 years (often >80) | 65–75 years (earlier in familial forms) |
| Clinical course | Longer, milder, slower progression | Progressive, moderate to rapid decline |
| Cognitive profile | Memory-circumscribed; may include mild semantic deficits | Multidomain (memory, visuospatial, executive, language) |
| Neocortical signs | Absent (no prominent apraxia or visuospatial deficits) | Common (apraxia, agnosia, anomia) |
| Office screening | May score normally on MMSE/STMS early despite clear memory deficits | Usually impaired on screening in symptomatic stages |
| Hippocampal atrophy | Disproportionate to clinical severity and neocortical atrophy | Typically proportionate to overall disease burden |
| Amyloid PET | Negative (in isolated LATE) | Positive |
| Overall lifespan | Longer lifespan | Shorter survival after diagnosis |
Why LATE Matters: Diagnostic and Therapeutic Implications
- As many as 15–20% of individuals clinically diagnosed with probable AD dementia lack biological evidence of AD; LATE is one of the most common alternative etiologies
- In anti-amyloid trials (e.g., solanezumab Phase 3), >20% of clinically diagnosed mild AD patients were amyloid PET-negative
- Anti-amyloid therapies (lecanemab, donanemab) have no indication for isolated LATE and carry risks including ARIA-E and ARIA-H
- Misdiagnosis may lead to unnecessary cholinesterase inhibitors and memantine — medications without evidence for benefit in LATE
- In AD + LATE copathology, risks and benefits of disease-modifying therapies may differ dramatically from isolated AD
Neuroimaging Biomarkers
Although no direct antemortem biomarker for TDP-43 exists, neuroimaging integrated with the clinical scenario can support a clinical diagnosis of LATE. The key principle is that LATE produces medial temporal-predominant neurodegeneration without the parietal and lateral temporal involvement seen in typical AD.
MRI Findings
- Amygdalar and hippocampal atrophy is often striking and disproportionate to clinical impairment or neocortical atrophy
- Relative preservation of inferior/lateral temporal, parietal, and precuneus regions
- Anterior-medial temporal lobe atrophy may reflect TDP-43 pathology, whereas posterior hippocampal atrophy is more associated with AD-related tau
- Longitudinal hippocampal volume loss is associated with cognitive decline independent of Aβ or tau PET burden
FDG-PET Findings
- Medial temporal and posterior cingulate hypometabolism without inferior/lateral temporal, precuneus, or parietal hypometabolism supports LATE over AD
- The ratio of inferior to medial temporal metabolism may indicate tau PET negativity (higher likelihood of LATE/HS) in amnestic dementia
- FDG patterns are most sensitive in LATE with coexistent HS rather than LATE in isolation
Integrating Biomarkers for a Clinical Diagnosis of LATE
- Step 1: Identify the clinical syndrome — slowly progressive amnestic-predominant impairment in a patient >75 years with mild intensity and absence of neocortical signs
- Step 2: Brain MRI — disproportionate amygdalar/hippocampal atrophy with relative sparing of parietal and lateral temporal regions
- Step 3: Amyloid biomarkers — negative amyloid PET or normal CSF/plasma Aβ42/40 ratio argues against AD as the sole etiology
- Step 4: FDG-PET (if available) — medial temporal hypometabolism without parietotemporal pattern supports LATE
- Step 5: Consider copathology — in amyloid-positive patients, disproportionate hippocampal atrophy may suggest admixed LATE
- No single test is sufficient; clinical diagnosis requires integration of multiple data points
Copathology and Distinguishing LATE from FTLD-TDP
AD and LATE commonly coexist, with dual pathology producing faster clinical declines and more global impairment than either alone. Individuals with AD and high TDP-43 burden have faster brain atrophy early in the course, making it challenging to differentiate AD from AD + LATE early on. A limbic-predominant subtype of AD has a similar phenotype, highlighting the value of AD biomarkers. TDP-43 is also the primary proteinopathy in ~50% of FTD cases and most ALS cases, but LATE and FTLD-TDP represent distinct entities:
| Feature | LATE | FTLD-TDP |
|---|---|---|
| Typical age at onset | >75 years | 45–65 years |
| Clinical syndrome | Amnestic-predominant cognitive decline | Behavioral (bvFTD), language (PPA), or motor (FTD-MND/ALS) |
| TDP-43 distribution | Limbic-predominant (amygdala → hippocampus → frontal) | Variable by subtype (types A–E); often widespread neocortical |
| Genetic associations | TMEM106B, GRN (risk variants), ABCC9 | C9orf72, GRN (loss-of-function mutations), VCP |
| Hippocampal sclerosis | Common (~70–90%) | Uncommon |
| Diagnostic overlap | Late-stage LATE-NC (stage 3) may be difficult to discriminate from early FTLD-TDP pathologically | |
Fluid Biomarkers and Diagnostic Challenges
Fluid biomarker development for TDP-43 remains without clinical successes. No antibody-based assay reliably detects phosphorylated TDP-43 in CSF. Blood-based measures face challenges due to TDP-43 molecular structure and limitations in detecting brain-enriched shorter fragments. Emerging approaches include astrocyte-derived extracellular vesicles measuring TDP-43 in blood and seed amplification assays applied to olfactory mucosa, both requiring further validation.
Current Diagnostic Limitations
- LATE can currently be definitively diagnosed only at autopsy
- MRI and FDG-PET findings are supportive but not specific — also seen in limbic-predominant AD, PART, and argyrophilic grain disease
- Patients may score normally on screening tools (MMSE, STMS) despite clear memory impairment, leading to missed diagnosis
- High prevalence of copathology in older adults complicates attribution of symptoms to a single etiology
- Most research cohorts have predominantly comprised non-Hispanic White individuals; diverse population studies are critically needed
Differential Diagnosis of Amnestic Syndromes in the Elderly
LATE belongs in the differential alongside AD, primary age-related tauopathy (PART), argyrophilic grain disease, Lewy body disease, and cerebrovascular disease for any older individual with slowly progressive amnestic impairment. PART — medial temporal neurofibrillary tangles (3R + 4R tau) without Aβ plaques — is nearly ubiquitous in the oldest old (~20% of centenarians) and is typically mild or asymptomatic. Integration of clinical features and biomarkers helps prioritize among these entities:
| Feature | AD | LATE/HS | PART | DLB | FTLD |
|---|---|---|---|---|---|
| Peak age group | 65–85 | >80 | >90 | 65–80 | 45–65 |
| Amnestic-only | ++ | +++ | ++ | + | + |
| Multidomain | ++++ | + | + | +++ | ++ |
| Progression rate | Moderate | Very slow | Very slow | Variable | Variable |
| Hippocampal atrophy | +++ | ++++ | ++ | + | ++ |
| Amyloid PET | Positive | Negative | Negative | Often positive | Negative |
| Tau PET | Positive | Negative | Emerging | Variable | Variable |
References
- Ramanan VK, Graff-Radford J. LATE, hippocampal sclerosis, and primary age-related tauopathy. Continuum (Minneap Minn). 2024;30(6, Dementia):1726-1743.
- Nelson PT, Dickson DW, Trojanowski JQ, et al. Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. Brain. 2019;142(6):1503-1527.
- Nelson PT, Lee EB, Cykowski MD, et al. LATE-NC staging in routine neuropathologic diagnosis: an update. Acta Neuropathol. 2023;145(2):159-173.
- Nelson PT, Schneider JA, Jicha GA, Duong MT, Wolk DA. When Alzheimer's is LATE: why does it matter? Ann Neurol. 2023;94(2):211-222.
- Nag S, Yu L, Capuano AW, et al. Hippocampal sclerosis and TDP-43 pathology in aging and Alzheimer disease. Ann Neurol. 2015;77(6):942-952.
- Nelson PT, Schmitt FA, Lin Y, et al. Hippocampal sclerosis in advanced age: clinical and pathological features. Brain. 2011;134(Pt 5):1506-1518.
- Botha H, Mantyh WG, Murray ME, et al. FDG-PET in tau-negative amnestic dementia resembles that of autopsy-proven hippocampal sclerosis. Brain. 2018;141(4):1201-1217.
- Nelson PT, Brayne C, Flanagan ME, et al. Frequency of LATE neuropathologic change across the spectrum of Alzheimer's disease neuropathology. Acta Neuropathol. 2022;144(1):27-44.
- Josephs KA, Martin PR, Weigand SD, et al. Protein contributions to brain atrophy acceleration in Alzheimer's disease and primary age-related tauopathy. Brain. 2020;143(11):3463-3476.
- Robinson JL, Porta S, Garrett FG, et al. Limbic-predominant age-related TDP-43 encephalopathy differs from frontotemporal lobar degeneration. Brain. 2020;143(9):2844-2857.
- Crary JF, Trojanowski JQ, Schneider JA, et al. Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol. 2014;128(6):755-766.
- Butler Pagnotti RM, Pudumjee SB, Cross CL, Miller JB. Cognitive and clinical characteristics of patients with LATE. Neurology. 2023;100(9):e2027-e2035.
- Nag S, Schneider JA. LATE neuropathological change in neurodegenerative diseases. Nat Rev Neurol. 2023;19(9):525-541.
- Hanseeuw BJ, Jacobs HIL, Schultz AP, et al. Association of pathologic and volumetric biomarker changes with cognitive decline. Neurology. 2023;101(24):e2533-e2544.
- Ramanan VK, Armstrong MJ, Choudhury P, et al. Antiamyloid monoclonal antibody therapy for Alzheimer disease: emerging issues. Neurology. 2023;101(9):842-852.