In vitro cell-line models of Alzheimer's disease: A systematic review and mechanism-based evidence map of induction paradigms, targeted mechanisms, and validation requirements.

BACKGROUND

In vitro cell-line models are essential for investigating the complex, interconnected mechanisms of Alzheimer's disease (AD). While offering high tractability for mechanism-focused screening, their translational utility depends on the precise alignment of the biological inquiry with the appropriate cellular system, induction strategy, and experimental readouts.

METHODS

This systematic review and mechanism-based evidence map searched PubMed (inception to 1 May 2026), capturing 93 original experimental studies across neuronal, glial, endothelial, and higher-fidelity multicellular systems. Extracted data were structured by cellular model, induction paradigm, targeted mechanism, and interpretive scope.

RESULTS

The synthesized evidence indicates that AD-relevant in vitro systems are not interchangeable whole-disease models, but mechanism-based tools. SH-SY5Y cells are primarily suited for Aβ-associated neuronal toxicity and general screening. Neuro-2a (N2a) systems are optimized for evaluating APP processing and amyloidogenesis. HT-22 cells specifically model oxidative glutamate toxicity and ferroptosis-related injury, while PC12 cells are strictly reserved for NGF-dependent neurite biology and neuroprotection.

CONCLUSIONS

While classical cell lines remain essential for initial mechanistic screening, establishing disease-level relevance requires validation through orthogonal readouts and high-fidelity human models, such as multicellular organoids or blood-brain barrier systems.