Entorhinal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX-- is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
The entorhinal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX-- (EC) is a region of the medial temporal lobe allocortex that serves as the principal gateway between the [cerebral cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX-- and the [hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX--. Located in the parahippocampal gyrus, the EC is a critical hub for episodic memory formation, spatial navigation, and temporal coding. It occupies a unique position in neural circuitry as the primary interface through which cortical sensory information enters the hippocampal formation and through which hippocampal output is redistributed to neocortical areas (Witter et al., 2017).
The entorhinal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX-- has gained particular prominence in neurodegeneration research because it is among the earliest brain regions affected in [Alzheimer's Disease (AD)[/diseases/[alzheimers-disease[/diseases/[alzheimers-disease[/diseases/[alzheimers-disease--TEMP--/diseases)--FIX--. [Tau[/entities/[tau-protein[/entities/[tau-protein[/entities/[tau-protein--TEMP--/entities)--FIX-- pathology in the form of [neurofibrillary tangles[/mechanisms/[neurofibrillary-tangles[/mechanisms/[neurofibrillary-tangles[/mechanisms/[neurofibrillary-tangles--TEMP--/mechanisms)--FIX-- first appears in the transentorhinal and entorhinal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX-- during Braak stages I–II, often decades before clinical symptoms emerge (Braak & Braak, 1991). The selective vulnerability of EC layer II [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX--—particularly the stellate cells that give rise to the perforant pathway—is a defining feature of early AD and explains the prominent episodic memory deficits that characterize the disease (Gómez-Isla et al., 1996).
The discovery of grid cells in the medial entorhinal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX-- (MEC), recognized with the 2014 Nobel Prize in Physiology or Medicine awarded to May-Britt Moser and Edvard Moser, transformed understanding of the EC from a simple relay station to an active computational hub for spatial representation and navigation (Hafting et al., 2005).
The entorhinal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX-- occupies the anterior portion of the parahippocampal gyrus in the medial temporal lobe. In humans, it is bounded by the perirhinal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX-- laterally, the hippocampal formation medially and posteriorly, and the [amygdala[/brain-regions/[amygdala[/brain-regions/[amygdala[/brain-regions/[amygdala--TEMP--/brain-regions)--FIX-- anteriorly. The human EC covers approximately 100 mm² of cortical surface, though this area varies considerably between individuals and decreases substantially with aging and in AD (Insausti et al., 1998).
The EC is divided into two major functional subdivisions based on cytoarchitecture, connectivity, and function:
Medial Entorhinal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX-- (MEC): Located posteromedially in humans. Contains grid cells, head-direction cells, speed cells, and border cells. Receives prominent input from the postrhinal (parahippocampal in primates) [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX--, retrosplenial [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX--, and presubiculum. Specializes in processing spatial information including path integration and metric representations of space (Moser et al., 2008).
Lateral Entorhinal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX-- (LEC): Located anterolaterally in humans. Receives dense input from the perirhinal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX--, olfactory [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX--, insular [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX--, and [prefrontal cortex[/brain-regions/[prefrontal-cortex[/brain-regions/[prefrontal-cortex[/brain-regions/[prefrontal-cortex--TEMP--/brain-regions)--FIX--. Processes non-spatial information including object identity, olfactory information, and contextual features of experience. Contains cells that encode temporal information and novelty signals (Tsao et al., 2018).
The EC has a characteristic six-layer structure that is transitional between three-layered allocortex and six-layered neocortex (Canto et al., 2008):
Layer I: Molecular layer containing dendrites and axon terminals. Relatively cell-sparse but rich in synaptic connections from cortical and subcortical afferents.
Layer II: Contains distinctive clusters of [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- called "cell islands," composed of large stellate cells in the MEC and fan cells in the LEC. These cells give rise to the perforant pathway projecting to the hippocampal dentate gyrus and CA3. [Layer II [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- are the first to develop tau pathology in AD and are among the most vulnerable neuronal populations in the brain (Stranahan & Bhatt Mattson, 2010).
Layer III: Contains medium-sized pyramidal [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- that project to hippocampal CA1 and the subiculum via the temporoammonic pathway. This layer provides direct cortical input to the [hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX-- that bypasses the traditional trisynaptic circuit.
Layer IV (Lamina Dissecans): A cell-sparse layer that serves as a landmark separating superficial and deep layers. More prominent in the caudal EC. This layer is acellular in some areas and contains sparse [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- in others.
Layer V: Contains large pyramidal [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- that receive output from the [hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX-- (via CA1 and subiculum) and project to widespread neocortical areas, the [basal ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia--TEMP--/brain-regions)--FIX--, and subcortical structures including the [locus coeruleus[/brain-regions/[locus-coeruleus[/brain-regions/[locus-coeruleus[/brain-regions/[locus-coeruleus--TEMP--/brain-regions)--FIX-- and raphe nuclei.
Layer VI: The deepest cellular layer, containing polymorphic [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- that project to the thalamus, claustrum, and other subcortical targets.
The EC receives convergent input from virtually all sensory modalities and association cortices:
Perirhinal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX--: Projects predominantly to LEC; conveys object-related and multisensory information
Parahippocampal/postrhinal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX--: Projects predominantly to MEC; conveys spatial and contextual information
Prefrontal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX--: Both orbitofrontal and medial prefrontal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX-- project to EC, providing executive and reward-related signals
Olfactory [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX--: Direct olfactory input reaches LEC layer I, making the EC part of the only sensory system that bypasses the thalamus en route to [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX--
Amygdala: Projects to both EC subdivisions, conveying emotional valence information
Thalamus: Nucleus reuniens of the thalamus provides important input to EC layers I and III
Subcortical modulatory systems: [Cholinergic] input from the medial septum and [nucleus basalis of Meynert[/brain-regions/[nucleus-basalis-of-meynert[/brain-regions/[nucleus-basalis-of-meynert[/brain-regions/[nucleus-basalis-of-meynert--TEMP--/brain-regions)--FIX--; noradrenergic input from the [locus coeruleus[/brain-regions/[locus-coeruleus[/brain-regions/[locus-coeruleus[/brain-regions/[locus-coeruleus--TEMP--/brain-regions)--FIX--; dopaminergic input from the ventral tegmental area; serotonergic input from the raphe nuclei
The EC is the primary cortical output to the hippocampal formation:
Perforant pathway: Layer II [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- project to the dentate gyrus, CA3, and CA2 via the perforant path—the major excitatory input to the [hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX--
Temporoammonic pathway: Layer III [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- project directly to CA1 and the subiculum
Cortical feedback: Layer V [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- project back to widespread neocortical regions, enabling the [hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX-- to influence cortical processing and memory consolidation
Subcortical projections: Deep layers project to the [basal ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia[/brain-regions/[basal-ganglia--TEMP--/brain-regions)--FIX--, thalamus, hypothalamus, and brainstem
The discovery of grid cells in MEC layer II revealed that the EC contains an intrinsic metric coordinate system for spatial navigation (Hafting et al., 2005). Grid cells fire in a periodic hexagonal pattern as an animal moves through space, providing a universal spatial metric. Additional spatially modulated cell types in the MEC include:
Head-direction cells: Fire when the animal faces a particular direction, independent of location
Speed cells: Modulate firing rate linearly with running speed
Border cells: Fire when the animal is near environmental boundaries
Object-vector cells: Encode the distance and direction to specific objects in the environment
Together, these cell types form a computational system that supports path integration—the ability to track position through self-motion signals—and provides the spatial framework for episodic memory (Moser et al., 2014).
The EC is essential for the encoding, consolidation, and retrieval of episodic memories (Squire & Zola-Morgan, 1991):
Memory encoding: Sensory information from neocortex converges on the EC, where it is integrated and transmitted to the [hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX-- for binding into coherent episodic representations
Pattern separation: EC layer II input to the dentate gyrus supports the orthogonalization of similar experiences into distinct memory traces
Memory consolidation: During sleep, hippocampal sharp-wave ripples drive reactivation of memory traces that are transmitted back through EC to neocortex for long-term storage
Temporal coding: [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- in LEC encode elapsed time, providing a temporal framework for organizing sequential experiences into episodic memories (Tsao et al., 2018)
Layer 6b contributions: A recently discovered direct excitatory pathway from EC layer 6b [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- to the [hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX-- contributes to both spatial coding and memory (Rozov et al., 2022)
The EC, particularly the LEC, is a critical relay for olfactory information. It receives direct input from the piriform [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX-- and olfactory bulb and transmits odor identity information to the [hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX--, where it can be bound with spatial and temporal context to form olfactory memories.
The entorhinal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX-- is the first cortical region to show pathological changes in AD, with tau pathology appearing in EC layer II (pre-α cells) during Braak stages I–II (Braak & Braak, 1991). This early involvement explains why episodic memory impairment is typically the first cognitive symptom of AD:
Layer II cell islands: Stellate cells in EC layer II show the earliest neurofibrillary tangle formation. These [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- project via the perforant pathway to the [hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX--, and their dysfunction disconnects the [hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX-- from cortical input, producing the hallmark memory deficit of AD.
Pre-tangle changes: Before frank tangle formation, EC layer II [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- show abnormal tau phosphorylation, missorting of tau from axons to somatodendritic compartments, and synaptic dysfunction, suggesting that functional deficits precede structural pathology.
Volume loss: EC volume measured by MRI is reduced in mild cognitive impairment (MCI) and correlates with progression to AD dementia, making EC atrophy a valuable early [biomarker] (de Toledo-Morrell et al., 2004).
Several factors contribute to the selective vulnerability of EC [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- in AD:
High metabolic demand: EC layer II [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- have exceptionally high metabolic activity and depend on [mitochondrial] oxidative phosphorylation, making them susceptible to [oxidative stress[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress[/mechanisms/[oxidative-stress--TEMP--/mechanisms)--FIX-- and energy failure.
Calcium dysregulation: A 2025 study in aged macaque entorhinal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX-- demonstrated that dysregulated calcium signaling, beginning in middle age, may prime tau for hyperphosphorylation in EC [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX--, potentially driving the earliest stages of AD pathology (Bhatt & Bhatt, 2025).
Connectivity-mediated spread: The strong unidirectional projections from EC to [hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX-- may facilitate [prion-like propagation] of misfolded tau along axonal pathways, explaining the stereotypical progression from EC to [hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX-- to association [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX--.
Cholinergic denervation: EC receives heavy cholinergic input from the medial septum and [nucleus basalis of Meynert[/brain-regions/[nucleus-basalis-of-meynert[/brain-regions/[nucleus-basalis-of-meynert[/brain-regions/[nucleus-basalis-of-meynert--TEMP--/brain-regions)--FIX--. Degeneration of these cholinergic projections, which occurs early in AD, deprives EC of trophic support and neuromodulatory regulation.
[amyloid-beta[/entities/[amyloid-beta[/entities/[amyloid-beta[/entities/[amyloid-beta--TEMP--/entities)--FIX-- pathology: While tau pathology begins in EC, [amyloid plaque] formation follows a different spatial pattern, initially affecting neocortex. The interaction between amyloid and tau pathology in the EC may accelerate neurodegeneration, consistent with the [amyloid cascade hypothesis].
The Braak staging system describes six stages of tau pathology progression that originate in the EC (Braak & Braak, 1991):
Braak I–II (Transentorhinal): Tau tangles confined to the transentorhinal and entorhinal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX--. Typically asymptomatic or associated with subjective cognitive decline.
Braak III–IV (Limbic): Tau spreads to [hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX--, amygdala, and cingulate [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX--. Corresponds to mild cognitive impairment (MCI).
Braak V–VI (Neocortical): Widespread neocortical tau pathology. Corresponds to clinical AD dementia with progressive cognitive decline.
Modern tau PET imaging using tracers such as [¹⁸F]flortaucipir has confirmed these staging patterns in living patients and demonstrated that tau accumulation in the entorhinal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX-- is closely associated with local cortical atrophy and memory impairment (Schöll et al., 2016; Cho et al., 2024).
EC volume, measured by high-resolution MRI, and tau PET signal in the EC region are among the most sensitive neuroimaging biomarkers for detecting preclinical AD. The 2024 revised [Alzheimer]'s Association diagnostic criteria incorporate tau PET staging based on the Braak framework, with entorhinal tau accumulation (Braak I) representing the earliest detectable stage of biological AD (Jack et al., 2024).
In behavioral variant [FTD[/diseases/[ftd[/diseases/[ftd[/diseases/[ftd--TEMP--/diseases)--FIX--, the EC shows variable involvement depending on the underlying proteinopathy. FTLD-tau cases with [MAPT[/genes/[mapt[/genes/[mapt[/genes/[mapt--TEMP--/genes)--FIX-- mutations may show EC pathology that resembles but is distinct from AD-type tau pathology. In semantic variant primary progressive aphasia, a subtype of [PPA], the anterior EC is prominently affected.
In [Lewy body dementia[/diseases/[lewy-body-dementia[/diseases/[lewy-body-dementia[/diseases/[lewy-body-dementia--TEMP--/diseases)--FIX-- and [Parkinson's disease[/diseases/[parkinsons[/diseases/[parkinsons[/diseases/[parkinsons--TEMP--/diseases)--FIX-- dementia, the EC accumulates both [alpha-synuclein[/proteins/[alpha-synuclein[/proteins/[alpha-synuclein[/proteins/[alpha-synuclein--TEMP--/proteins)--FIX-- Lewy pathology and co-occurring tau pathology. The combination of these proteinopathies in the EC may contribute to the prominent memory deficits seen in DLB.
[LATE[/diseases/[late[/diseases/[late[/diseases/[late--TEMP--/diseases)--FIX-- involves [TDP-43[/entities/[tdp-43[/entities/[tdp-43[/entities/[tdp-43--TEMP--/entities)--FIX-- pathology that preferentially affects the limbic system, including the [hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus[/brain-regions/[hippocampus--TEMP--/brain-regions)--FIX-- and entorhinal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX--. LATE is increasingly recognized as a common co-pathology in older adults that mimics AD clinically and may interact with AD pathology to accelerate cognitive decline.
The EC is a critical region in temporal lobe epilepsy. Layer III [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- are particularly vulnerable to excitotoxic damage during seizures, and loss of EC [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- contributes to hippocampal sclerosis and chronic epilepsy.
Several mouse models of AD pathology target or involve the entorhinal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX--:
EC-tau mice: Express human mutant tau specifically in EC layer II [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX--, demonstrating that tau pathology can propagate from the EC to downstream hippocampal [neurons[/entities/[neurons[/entities/[neurons[/entities/[neurons--TEMP--/entities)--FIX-- via synaptic connections (de Calignon et al., 2012).
**[APP[/genes/[app[/genes/[app[/genes/[app--TEMP--/genes)--FIX--
The study of Entorhinal [cortex[/brain-regions/[cortex[/brain-regions/[cortex[/brain-regions/[cortex--TEMP--/brain-regions)--FIX-- has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
This section links to atlas resources relevant to this brain region.