5xFAD & APP/PS1 Mice – Comparison of Amyloid-β Models

Q: What are the APP/PS1 and 5xFAD mouse models?

The APP/PS1 and 5xFAD mouse models are double-transgenic Alzheimer's disease models engineered to overexpress mutated human Amyloid Precursor Protein (APP) and Presinilin 1 (PSEN1). These familial Alzheimer's disease (FAD) mutations increase the production of amyloid-β (Aβ), resulting in accelerated Aβ plaque deposition in the brain. APP/PS1 (e.g. ARTE10) shows moderate, age-dependent Aβ accumulation. 5xFAD expresses five FAD mutations and develops highly aggressive, early-onset Aβ pathology. Both models are widely used to investigate mechanisms of Aβ aggregation, neuroinflammation, and early Alzheimer's disease progression. Feature APP/PS1 (Biospective's ARTE10) 5xFAD Promoter Thy1 neuronal promoter Thy1 neuronal promoter Mutations APP: Swedish (K670N/M671L) PSEN1: M146V APP: Swedish, Florida, London PSEN1: M146L, L286V Pathology Onset Aβ deposition begins ~3-4 months Aβ deposition as early as 2 months Tau Pathology Absent (unless co-pathology model) Absent Human Relevance Moderately progressive Aβ pathology; suitable for modeling early-to-mid AD-like stages and longitudinal studies Highly aggressive early-onset Aβ pathology; models severe familial AD mutation effects

Q: How do amyloid-β plaques develop over time in each model?

Both the APP/PS1 and 5xFAD mouse models exhibit progressive amyloid-β (Aβ) pathology, but differ in onset, progression speed, plaque characteristics, and functional impact. These differences influence experimental design, therapeutic timing, and endpoint selection. Aβ Pathology Development in APP/PS1 (ARTE10) vs. 5xFAD Pathology Feature APP/PS1 (Biospective's ARTE10) 5xFAD First Plaques Detected ~3-4 months ~2 months Peak Deposition ~8-10 months (progressive, gradual accumulation) ~5 months (rapid, extensive deposition) Regional Pattern Cortex and hippocampus with age-dependent spread; moderate plaque density Dense deposition in cortex, hippocampus, subiculum; broader and earlier involvement Plaque Type Larger, more compact plaques Dense-core plaques; increased Aβ42/Aβ40 ratio Cognitive Decline Onset Mid-adulthood (typically after 6 months) depending on task sensitivity Early deficits detectable around 4-5 months Motor Dysfunction Typically minimal or late-onset; subtle changes only in advanced ages Can show early motor abnormalities due to aggressive pathology APP/PS1 mice develop Aβ pathology more gradually and with larger plaques, while 5xFAD mice develop plaques earlier and more aggressively.

Q: How do neuroinflammatory profiles differ between the models?

Both the APP/PS1 (Biospective's ARTE10) and 5xFAD models develop neuroinflammation. However, the timing, magnitude, and associated neurodegenerative changes differ substantially between them. 5xFAD shows markedly earlier and more robust immune activation, while APP/PS1 displays a slower, more progressive inflammatory response. Neuroinflammatory and Neurodegenerative Features in APP/PS1 (ARTE10) vs. 5xFAD Feature APP/PS1 (Biospective's ARTE10) 5xFAD Microglia and Astrocyte Activation Gradual, age-dependent activation; detectable after ~4 months Strong, early activation (as early as 2 months) Dystrophic Neurites Present in mid-to-late stages; less extensive than in 5xFAD Abundant and observed early (~3 months) Synaptic Loss Moderate synaptic alterations appearing later in disease progression (~8-10 months) Pronounced and early synaptic loss (~4 months) Neuronal Loss Typically minimal or limited Detectable neuronal loss due to aggressive pathology (~9-12 months) 5xFAD provides stronger inflammatory and neurodegenerative phenotypes - useful for inflammasome, microglial, synaptic, and neuroimmune research.

Q: Which model is better suited for cerebrovascular and ARIA studies?

Both models exhibit vascular changes, but their cerebrovascular involvement, presence of cerebral amyloid angiopathy (CAA), and suitability for ARIA assessments differ. Overall, the APP/PS1 (ARTE10) model is generally preferred for vascular and ARIA-focused research, due to its more gradual amyloid progression and clearer cerebrovascular readouts. Cerebrovascular Features in APP/PS1 (ARTE10) vs. 5xFAD Feature APP/PS1 (Biospective's ARTE10) 5xFAD CAA (Cerebral Amyloid Angiopathy) Consistent CAA development CAA present; more variable ARIA-E / ARIA-H Suitability Well-suited for evaluating ARIA effects Suitable only when crossed with APOE4 APP/PS1 (ARTE10) is the preferred model for cerebrovascular and ARIA mechanism research.

Q: What are the key advantages of using the APP/PS1 model in AD research?

The APP/PS1 model offers several advantages that make it highly valuable for AD research: Slower, more physiologically relevant disease progression Minimal non-cognitive or motor confounds Suitable for studying cerebrovascular pathology and ARIA mechanisms Robust but progressive microgliosis and astrogliosis

Q: Which model is recommended for therapeutic efficacy testing, imaging studies, or behavioral profiling?

The optimal model depends on the research question and specific pathology or functional endpoint. APP/PS1 (ARTE10) is preferred for gradual, progressive, and behaviorally stable studies, while 5xFAD is favored for rapid-onset and aggressive amyloid investigations. Recommended Models by Research Application Research Application Recommended Model Reason Early, rapid amyloid pathology 5xFAD Extremely early Aβ deposition, high Aβ42 production, and rapid dense-core plaque formation. Microglial / astroglial activation and inflammasome pathways Both models (context dependent) APP/PS1 for progressive pathology 5xFAD for rapid, early pathology Strong and robust neuroinflammatory activation ARIA and cerebrovascular amyloid studies APP/PS1 (ARTE10) Trackable vascular pathology; suitable for evaluating ARIA-H and cerebrovascular changes longitudinally. Gradual, stable cognitive-decline modeling APP/PS1 (ARTE10) Stable, age-dependent cognitive deficits; ideal for long-term behavioral profiling. Anti-amyloid immunotherapy efficacy Both models (context dependent) APP/PS1 for longitudinal tracking 5xFAD for rapid screening APP/PS1 enables extended therapeutic windows and imaging; 5xFAD allows early, high-burden pathology for rapid efficacy readouts. Amyloid-tau interaction studies APP/PS1 (Biospective ARTE10 + human Tau co-pathology model) Provides a controlled system for co-pathology mechanisms.

Last Updated: November 26, 2025

Authors: Rafael Pérez-Medina-Carballo, M.D., Ph.D., Alexa Brown, Ph.D., and Barry J. Bedell, M.D., Ph.D.

This resource describes:

Summary

This Resource provides a comparative, mechanistic overview of the 5xFAD and APP/PS1 transgenic mouse models - two of the most widely used models for studying amyloid-β-driven Alzheimer's disease (AD) pathology. Both models overexpress human APP and PSEN1 with familial AB mutations to accelerate Aβ plaque formation, yet they differ substantially in the timing and regional distribution of pathology, as well as in their neuroinflammatory and cerebrovascular profiles.

The APP/PS1 model shows a regionally concentrated accumulation of Aβ in the cortex and hippocampus, and develops cerebrovascular amyloid angiopathy (CAA) in specific lines, while maintaining relatively stable motor behavior. In contrast, 5xFAD mice exhibit early, progressive and widespread Aβ deposition accompanied by a rapid onset of microgliosis & astrogliosis and behavioral impairments.

This comparison summarizes their genetic design, temporal progression of pathology, inflammatory and vascular phenotypes, and relevance for ARIA studies - along with limitations such as the absence of tauopathy - to support informed model selection for AD therapeutic research.

What are the APP/PS1 and 5xFAD mouse models?

The APP/PS1 and 5xFAD mouse models are widely used double-transgenic Alzheimer’s disease (AD) models, specifically designed to accelerate and intensify amyloid-β (Aβ) pathology. These models overexpress mutated human Amyloid Precursor Protein (APP) and Presenilin 1 (PSEN1) - genes known to cause early-onset familial Alzheimer's disease (FAD) - thereby driving rapid Aβ plaque formation (Sasaguri, 2017; Fang, 2024).

While both models exhibit robust Aβ deposition, they differ markedly in their:

Genetic composition
Speed of pathology development
Aβ plaque characteristics
Neuroinflammatory profile
Behavioral deficits

Importantly, tauopathy does not naturally develop in these models (although Biospective has developed an APP/PS1 and human Tau co-pathology model for advanced AD research). These two transgenic mouse models serve as valuable tools for exploring the mechanisms underlying AD and for testing new therapeutic interventions.

Comparative Overview of the APP/PS1 and 5xFAD Mouse Models in Alzheimer's Disease Research

Category	APP/PS1 (ARTE10)	5xFAD
Genetics	Human APP (Swedish) Human PSEN1 (M146V) Thy1 promoter	Human APP (Swedish, Florida, London) Human PSEN1 (M146L, L286V) Thy1 promoter
Disease Progression	Aβ plaque deposition begins: 3-4 months Progressive cortical and hippocampal pathology with high plaque burden and vascular pathology by 9 months-of-age Increasing neuroinflammation (microglia + astrocytes) with disease burden	Earliest plaques detected: as early as 2 months Massive plaque burden in cortex & hippocampus Strong and early microgliosis and astrogliosis Rapidly emerging behavioral impairments
Key Features	Moderate rate of amyloid accumulation - ideal for longitudinal studies Well-established and reproducible pathology Stable motor function Suitable for therapeutic studies targeting: Aβ accumulation Neuroinflammatory responses NLRP3 Inflammasome & ASC Early-stage intervention strategies	One of the fastest and most aggressive Aβ models Ideal for: Rapid therapeutic screening Studying severe and early amyloid pathology and neuroinflammation

Comparative overview of APP/PS1 and 5xFAD Alzheimer's disease mouse models, highlighting key differences in genetic background, temporal dynamics of amyloid-β deposition, associated neuroinflammatory and neurodegenerative readouts, and research-relevant phenotypic features.

What are the characteristics of both models in relation to amyloid-beta pathology, neuroinflammation, and cerebrovascular changes?

What are differences in Amyloid-β Pathology between APP/PS1 and 5xFAD mice?

APP/PS1 model

The APP/PS1 model exhibits accelerated and robust Aβ pathology, with deposits appearing as early as 3 to 4 months of age, primarily concentrated in the cerebral cortex and hippocampus (Zhong, 2024).
Impairments in spatial memory and overall cognitive function are observed around 6 months, although some studies have reported memory impairment as early as 17 weeks (Fang, 2024; Noto, 2025).
Histological analysis shows the presence of dense and mature senile plaques by 8 months (Shen, 2018).
Aβ deposition in these mice is associated with a range of downstream effects, including synaptic dysfunction and minor neuronal loss near the amyloid plaques at around 8 to 10 months (Zhong, 2024).
Overall, motor skills generally remain intact (Webster, 2013).

Explore Spatial Pathology:
For detailed spatial analysis of Aβ and inflammatory cells in the APP/PS1 model, see our Innovation: Amyloid-β & the Inflammatory Microenvironment in an APP/PS1 Mouse Model of Alzheimer’s Disease.

5xFAD model

In the 5xFAD model, amyloid plaques become easily identifiable throughout the brain starting at 2 months, with their accumulation peaking around 5 months, although the disease may progress over time (Oblak, 2021; Bader, 2023; Padua, 2024).
Initial extracellular amyloid plaques form in the subiculum of the hippocampus and the frontal cortex, later spreading to other regions of the brain. Increased pro-inflammatory cytokines, such as IL-1β and TNF-α, are also observed (Fang, 2024).
Impairments in spatial memory begin around 4 to 5 months (Fang, 2024).
Motor dysfunctions start to develop at approximately 9 months (Zhong, 2024).

Brain sections of the APP/PS1 (ARTE10) transgenic mouse model and wild-type mice at various time points, stained for Aβ (red), Iba-1 (green), GFAP (violet), and DAPI counterstain (blue).

What are differences in Neuroinflammation between APP/PS1 and 5xFAD mice?

APP/PS1 model

In this model, there is increased activation of microglia and astrocytes observed as early as 4 months of age (Zhong, 2024; Fang, 2024).
By 6-7 months, there is a noticeable increase in the number of Iba-1 positive microglial cells, predominantly around the amyloid deposits in the hippocampus (Campos, 2023).
The accumulation of multivesicular bodies, endosomes, and lysosomes, has been reported (Zhong, 2024).
Clear neurodegeneration in the striatum is evident by 1 year of age (Fang, 2024).
The ARTE10 model has been used to target the inflammasome pathway with a novel anti-ASC immunotherapy

5xFAD model

In the 5xFAD model, reactive microglia and astrocytes can be detected by 2 months (Padua, 2024).
Dystrophic neurites start to appear by 3 months, leading to observable deficiencies in synaptic transmission by approximately 4 months of age (Padua, 2024).
By 1 year of age, microgliosis and astrogliosis are evident in both the cortex and hippocampus (Oblak, 2021; Fang, 2024).
There is a significant loss of synapses around 6 months, leading to a 40% loss of neurons by 1 year, with a substantial decline in neuronal health observed by approximately 9 months (Fang, 2024; Padua, 2024).
Apathy-like behaviors have been observed to positively correlate with Aβ pathology, particularly the presence of soluble Aβ42 in the prefrontal cortex and hippocampus (Keszycki, 2023).

What are differences in Cerebrovascular Pathology between APP/PS1 and 5xFAD mice?

Cerebrovascular dysfunction, including cerebral amyloid angiopathy (CAA), plays a significant role in the initial pathogenic changes associated with AD.

APP/PS1 model

While the standard APP/PS1 model shows limited CAA, certain models exhibit CAA (Fang, 2024). The ARTE10 model has extensive CAA by 9 months of age.
In APP/PS1 mouse models with the Swedish and ΔE9 mutations, the onset of CAA can begin as early as 6 months of age, accompanied by extensive plaque formation and elevated levels of Aβ42 (Noto, 2025).
An APP/PS1 rat model (TgF344) incorporates the Swedish and ΔE9 mutations with a PrP promoter and develops CAA, amyloid plaques, cognitive impairment, and neurofibrillary tangles (NFT) (Fang, 2024).
Decreased cerebral blood flow in the left hippocampus, left thalamus, and right cortex has been detected in 8-month-old APP/PS1 mice using arterial spin labeling (ASL) MRI, indicating vascular dysfunction in this AD model (Shen, 2018).
The deposition of amyloid on the vascular wall disrupts the integrity and morphology of the arterial basement membrane in APP/PS1 mouse models. As CAA progresses, there is a decrease in vascular smooth muscle cell coverage and impairment of Aβ clearance mechanisms, including intramural periarterial drainage and perivascular CSF influx (Kim, 2020).

5xFAD model

Overall, this model is generally regarded as having limited cerebrovascular dysfunction (Fang, 2024).
However, it has been reported that CAA can be observed as early as 3 months of age. Impaired neurovascular coupling is observed at 12 months, although cerebral blood flow remains unchanged (Fang, 2024).

Timeline of the pathological characteristics of APP/PS1 and 5xFAD mouse models for AD.

What are differences in Amyloid-Related Imaging Abnormalities (ARIA) Modeling between APP/PS1 and 5xFAD mice?

ARIA, which include edema/effusion (ARIA-E) and hemosiderosis/microhemorrhage (ARIA-H), are adverse events associated with anti-Aβ antibody treatments (Hampel, 2023; Grenon, 2024).

These abnormalities are more common in individuals who are carriers of the APOE4 allele.
Most cases of ARIA are asymptomatic. However, ARIA can lead to symptoms such as headache, confusion, nausea, vomiting, and dysfunction in vision and gait.
MRI monitoring is crucial for identifying and managing ARIA.
Typically, ARIA resolves within 3 to 4 months through the adjustment or discontinuation of the medication.
Spontaneous ARIA can also occur in humans who have CAA.

Therefore, animal models are essential for a deeper understanding of the pathophysiology of ARIA.

APP/PS1 model

Given the extensive CAA and vascular pathology in the ARTE10 model (at ~9 months of age), there is significant potential to utilize this model to study ARIA in pharmacological studies of anti-amyloid therapies (e.g. immunotherapy).
Recent studies have employed the APP/PS1 model carrying the APOE4 gene to explore the vascular side effects of anti-amyloid therapy in AD (Grenon, 2024).
The APP/PS1-21 model has been used to evaluate microhemorrhages when treated with the murine precursor mIgG2a antibody representing Bapineuzumab, 3D6, and ABBV‑916, the murine precursor of a clinical stage human IgG1 monoclonal antibody which binds to N-terminal truncated, pyroglutamate-modified at amino acid position 3, Aβ (Aβ_pE3) under development by AbbVie (Liao, 2025).

5xFAD model

This model is not commonly used for ARIA studies in the literature. However, a recent investigation examined the therapeutic effects of anti-APOE (HAE-4) in 5xFAD mice expressing the APOE4 allele (Xiong, 2021). As such, the 5xFAD x APOE4 double transgenic model can be used to study ARIA events.

Are Neurofibrillary Tangles (NFTs) present in APP/PS1 and 5xFAD mice?

Both models are characterized by the absence of neurofilbrillary tangles (NFTs), which are crucial pathological features of AD. To overcome this limitation, Biospective has developed and characterized and APP/PS1/hTau amyloid-beta and tau co-pathology mouse model, see: Amyloid-Beta & Tau Co-Pathology Mouse Model (APP/PS1/hTau).

How does the APP/PS1 model compare to the 5xFAD model?

Pathologic Feature	APP/PS1	5xFAD	Advantage of using APP/PS1 model
Amyloid pathology	Aβ plaques start to deposit around 3-4 months of age. Pathology can typically progresses in the hippocampus and cortex.	Exhibits aggressive and rapid pathology with extracellular plaques appearing by 2 months. Initial plaques develop in the subiculum of the hippocampus and cortical layer V, regions that have the highest density of amyloid deposits. This model also leads to motor impairment.	Slower, more realistic disease progression, with significantly larger plaques. Avoids behavioral (non-cognitive) and motor confounds since it does not display significant anxiety, depressive-like behaviors, or motor deficits (Locci, 2021).
Neuroinflammation	Microgliosis and astrogliosis are detectable by 4 months of age. Neurodegeneration is observed at 12 months.	Exhibits early neuroinflammation, with astrogliosis and microgliosis observable as early as 2 months. Displays overlapping molecular signatures with human AD for neuroinflammation (Zhong, 2024).	Potential for studying lysosomal and phagocytic dysfunction, as the overexpression or depletion of TDP-43 in APP/PS1 mice affects lysosomal Aβ levels or microglial phagocytosis (Meneses, 2021). Can be used to study the NLRP3 inflammasome and ASC.
Cerebrovascular pathology	CAA is present by 6 to 9 months, and its progression is linked to impaired perivascular clearance.	Limited cerebrovascular dysfunction, but CAA may develop in 3 months.	This model develops CAA more consistently along with a significant decreased blood flow in hippocampus, thalamus, and cortex.
ARIA modeling	APOE4-carrying APP/PS1 mice show Aβ deposition in the cerebral vasculature and show a trend toward increased hemosiderin deposits. Aged APP/PS1 have been used to study ARIA-H for anti-amyloid immunotherapies (Liao, 2025).	Despite its limited cerebrovascular dysfunction, this model has been used to assess pretargeted imaging approaches entering the brain (Lopes van den Broek, 2022). 5xFAD x APOE4 can also be used to study ARIA.	Evidence shows the potential of this model in studying ARIA in APP/PS1 models with or without the APOE mutation.

This table provides a side-by-side comparison of APP/PS1 and 5xFAD models across four key pathologic features: amyloid-β pathology, neuroinflammation, cerebrovascular pathology, and ARIA modeling. It also highlights the advantages of using APP/PS1 model in each of the areas.

Our team would be happy to answer any questions about the 5xFAD & APP/PS1 Mice or provide specific information about the models we use for therapeutic efficacy studies.

Discover more about our Neurodegenerative Diseases Models

Alzheimer's Disease Models

AMYLOID-β TRANSGENIC MOUSE MODELS

AMYLOID-BETA & TAU CO-PATHOLOGY MOUSE MODEL (APP/PS1/HTAU)

FAQs

What are the APP/PS1 and 5xFAD mouse models?

How do amyloid-β plaques develop over time in each model?

How do neuroinflammatory profiles differ between the models?

Which model is better suited for cerebrovascular and ARIA studies?

What are the key advantages of using the APP/PS1 model in AD research?

Which model is recommended for therapeutic efficacy testing, imaging studies, or behavioral profiling?

References

Liao, F., Calvo-Rodriguez, M., Chhaya, M., Sefrin, J.P., Charych, E.I., Mezler, M., Clausznitzer, D., McGlame, E.J., Zhao, K., Rodgers, A., Cao, Y., Secker, P.F., Fernandez Garcia-Agudo, L., Huang, L., Klein, C., Dellovade, T., Karran, E. Anti-pyroglutamate-3 Aβ immunotherapy engages microglia and inhibits amyloid accumulation in transgenic mouse models of Aβ amyloidosis. Acta Neuropathol., 55, 2025. . PMID: 40455292

Oblak, A.L., Lin, P.B., Kotredes, K.P., Pandey, R.S., Garceau, D., Williams, H.M., Uyar, A., O'Rourke, R., O'Rourke, S., Ingraham, C., Bednarczyk, D., Belanger, M., Cope, Z.A., Little, G.J., Williams, S.G., Ash, C., Bleckert, A., Ragan, T., Logsdon, B.A., . . . Lamb, B.T. Comprehensive evaluation of the 5xFAD mouse model for preclinical testing applications: A MODEL-AD study. ,: 713726, 2021;

Keywords

a lipid-transport protein involved for cholesterol metabolism and neural repair. The gene has three major alleles - , , and . The variant is the greatest genetic risk factor for late-onset Alzheimer’s disease. ApoE4 alters microglial morphology and function, promoting a chronic reactive state with reduced ability to clear neurotoxic protein aggregates. ApoE4 is associated with increased Aβ plaque accumulation, tau pathology, neuronal damage, and sustained neuroinflammation.

: BBB is a highly selective semipermeable layer of endothelial cells between the circulatory system and the brain. This layer forms a barrier that protects the brain from harmful or unwanted substances in the blood. Increased BBB permeability can result from neurological diseases and traumatic injuries and can be visible with gadolinium scans. Increased BBB permeability is a key factor in MS lesion formation, allowing immune cells to enter the brain and cause inflammation.

a protein that plays a crucial role in maintaining the stability and function of neurons in the brain. It is predominantly found in neurons, where it stabilizes microtubules, which are part of the cell's cytoskeleton. Microtubules are essential for maintaining cell shape, enabling intracellular transport, and facilitating cellular division. Hyperphosphorylation of tau is evident in various neurodegenerative diseases, where the abnormally phosphorylated molecules lead to the detachment of tau from the microtubules. These detached tau proteins can aggregate to form insoluble fibrils, known as neurofibrillary tangles. Diseases impacted by tau aggregation are called tauopathies, and include Alzheimer's disease, progressive supranuclear palsy, frontotemporal dementia (FTD), and corticobasal degeneration.

5xFAD & APP/PS1 Mice – A Comparison of Amyloid-β Mouse Models for Alzheimer's Disease Research

This Resource compares 5xFAD & APP/PS1 mouse models of Alzheimer’s disease, including amyloid-beta pathology, neuroinflammation, and cerebrovascular disease.

Summary

What are the APP/PS1 and 5xFAD mouse models?

Comparative Overview of the APP/PS1 and 5xFAD Mouse Models in Alzheimer's Disease Research

What are the characteristics of both models in relation to amyloid-beta pathology, neuroinflammation, and cerebrovascular changes?

How does the APP/PS1 model compare to the 5xFAD model?

Discover more about our Neurodegenerative Diseases Models

Alzheimer's Disease Models

AMYLOID-β TRANSGENIC MOUSE MODELS

AMYLOID-BETA & TAU CO-PATHOLOGY MOUSE MODEL (APP/PS1/HTAU)

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