Why patient stratification matters in sporadic Alzheimer’s disease research
Patient stratification is becoming increasingly important for developing in vitro models of sporadic Alzheimer’s disease (sAD). As the field moves toward using multiple iPSC lines and multicellular systems, there is a growing recognition that any single donor background cannot represent Alzheimer’s disease. The availability of iPSCs from donors with sporadic Alzheimer’s disease, as well as unaffected age‑matched controls, provides a structured foundation for building more complex models.
A key factor in stratification is the APOE genotype, which plays a central role in the development and progression of late‑onset Alzheimer’s disease¹,². ApoE variants influence amyloid‑beta clearance, tau pathology, neuroinflammation, and lipid metabolism, and the E4 allele is recognised as the strongest genetic risk factor for late‑onset AD³.
APOE genotypes span E2/E3, E3/E3, E3/E4, and E4/E4 backgrounds, allowing researchers to examine disease‑relevant mechanisms across genetically diverse lines. Evidence from human iPSC studies shows why an APOE background is critical for AD modeling:
- APOE4 neurons, including StrataStem/Axol homozygous APOE4 lines, exhibit elevated Aβ42 secretion compared to controls and APOE3⁵,⁶,⁹
- APOE4 neurons and cerebral organoids show increased phosphorylated tau (p-tau), disrupted lipid metabolism, α‑synuclein accumulation (suggestive of cross-pathology vulnerability), and impaired organelle homeostasis, while APOE3 backgrounds display fewer of these changes⁵,⁶,⁹
- APOE4 astrocytes exhibit reduced Aβ uptake, cholesterol accumulation, mitochondrial dysfunction, elevated reactive oxygen species (ROS), and senescence‑associated inflammatory activation, compromising neuronal support⁶,⁸.
- APOE4 organoids demonstrate impaired cortical neurodevelopment, reduced excitatory neuron populations, increased gliogenesis, and hyperexcitability, indicating early vulnerability even before hallmark AD pathology emerges⁷.
These genotype‑specific differences help explain the heterogeneity of sAD and highlight the importance of incorporating APOE‑stratified lines into in vitro model design.
Documented donor information, including APOE genotype, age, gender, diagnosis, and family and medical history, supports the design of patient‑stratified models. This information allows researchers to select donors representing different clinical and genetic categories, enabling the construction of cohort‑based studies that capture variability in disease onset and pathology. Because sAD develops from a combination of genetic and environmental factors, this variability is essential for building in vitro systems that more closely mirror the complexity of human disease.
Multi‑cell iPSC systems for physiologically relevant disease modeling
Stratification extends further when multiple CNS‑relevant cell types are generated from each donor, including cortical neurons, astrocytes, and microglia. iPSC AD models increasingly incorporate multi‑cell and multi‑line approaches, using both 2D and 3D co‑culture systems, to study how disease‑associated phenotypes emerge across different cell types within the same donor background.
APOE4‑dependent phenotypes vary across neural lineages:
- In neurons, APOE4 drives increased Aβ42 secretion, synaptic vulnerability, perturbed gene networks, and impaired intracellular trafficking⁶.
- In astrocytes, APOE4 induces lipid dysregulation, impaired Aβ clearance, metabolic stress, and robust inflammatory signatures that negatively impact neuronal viability⁶,⁸.
- In microglia, APOE4 reduces Aβ phagocytosis and shifts cells toward more reactive, pro‑inflammatory states⁶.
- In organoids, APOE4 alters neuronal‑glial ratios, disrupts network maturation, and accelerates early circuit dysfunction⁵,⁷.
When evaluated across stratified donor cohorts, these multi‑cell systems support the identification of genotype‑specific and diagnosis‑specific differences in neuronal physiology, glial activation, metabolic resilience, and neuroimmune responses¹.
Differentiating multiple iPSC lines into various CNS cell types enables robust cohort‑level assessment of neurodegenerative processes. Such studies demonstrate how stratified donor groups can be used to evaluate variability in drug responses and to explore mechanistic differences underlying sAD progression³. These findings highlight the importance of patient‑stratified systems for supporting pre‑clinical discovery, target validation, and therapeutic screening.
Overall, the alignment of patient‑stratified iPSC cohorts, multi‑cell culture systems, and genetically diverse donor backgrounds is reshaping the landscape of preclinical AD research.
Axol Bioscience-StrataStem sporadic Alzheimer’s disease iPSC line collection and Early Access axoCells™ neural stem cells
To support patient‑stratified research, Axol Bioscience, in partnership with StrataStem, offers a comprehensive collection of sporadic Alzheimer’s disease (sAD) iPSC lines that enable the development of in vitro models of complex sAD using donor‑specific and genetically relevant backgrounds for drug discovery and research. Alongside this collection, we offer Early Access axoCells™ neural stem cells derived from patient‑specific iPSCs representing multiple APOE genotypes. These early access models reflect our commitment to expanding access to physiologically relevant human systems for neurodegeneration, ensuring that high‑quality cells from clinically characterized sAD and control donors are available to the global research community.
Learn more about our collection: https://axolbio.com/publications/axol-bioscience-sporadic-alzheimers-disease-line-collection/
Explore the Early Access axoCells™: https://axolbio.com/axocells-neurons-and-neuroinflammatory-cells/axocells-cortical-excitatory-neurons/
References
1. Raulin AC, Doss SV, Trottier ZA, Ikezu TC, Bu G, Liu CC. ApoE in Alzheimer’s disease: pathophysiology and therapeutic strategies. Molecular Neurodegeneration. 2022.
2.Serrano‑Pozo A, Das S, Hyman BT. APOE and Alzheimer’s disease: advances in genetics, pathophysiology, and therapeutic approaches. The Lancet Neurology. 2021.
3. Jackson RJ, Hyman BT, Serrano‑Pozo A. Multifaceted roles of APOE in Alzheimer disease. Nature Reviews Neurology. 2024.
4. Williams D. et al., 2026. Reported in: Alzheimer’s Research UK. “APOE4 and APOE3 gene variants linked to at least 7 in 10 Alzheimer’s cases, study suggests.” 2026. https://www.alzheimersresearchuk.org/news/apoe4-and-apoe3-gene-variants-linked-to-at-least-7-in-10-alzheimers-cases-study-suggests/
5. Zhao J. et al. 2021. Apolipoprotein E regulates lipid metabolism and α‑synuclein pathology in human iPSC‑derived cerebral organoids. Acta Neuropathologica. https://link.springer.com/article/10.1007/s00401-021-02361-9
6. Lin Y‑T. et al. 2018. APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC‑derived brain cell types. Neuron. https://dspace.mit.edu/handle/1721.1/126369
7. Meyer‑Acosta K.K. et al. 2024. APOE4 impacts cortical neurodevelopment and alters network formation in human brain organoids. bioRxiv. https://www.sciencedirect.com/science/article/pii/S2213671125001419
8. Cáceres‑Palomo L. et al. 2026. Human iPSC‑derived APOE4/4 Alzheimer’s disease astrocytes exhibit a senescent and pro‑inflammatory state that compromises neuronal support. Journal of Neuroinflammation. https://link.springer.com/article/10.1186/s12974-025-03607-z
