Comparative Analysis of Experimental Models in Alzheimer’s Disease Research: From Transgenic Paradigms to Pharmacological Induction

Alzheimer’s disease (AD) represents the leading cause of dementia globally, characterized by progressive cognitive decline, β-amyloid (Aβ) aggregation, tau hyperphosphorylation, neuroinflammation, and synaptic dysfunction. Due to its complex multifactorial nature, the development of appropriate animal models has become indispensable for understanding the pathophysiology of AD and identifying potential therapeutic targets.

This paper provides a comparative analysis of the principal preclinical models used in AD research, encompassing transgenic, pharmacological, and toxin-induced paradigms. Transgenic models, such as 5×FAD, APP/PS1, and 3×Tg-AD, replicate essential molecular and behavioral features of familial AD. The 5×FAD line, carrying five human APP and PSEN1 mutations, develops early and aggressive amyloid pathology with profound cognitive deficits, while the 3×Tg-AD model integrates both amyloid and tau lesions, offering broader pathological relevance. Pharmacological models, including scopolamine- and streptozotocin-induced neurotoxicity, mimic sporadic AD through cholinergic hypofunction and impaired insulin signaling. Toxicological paradigms employing β-amyloid peptides or aluminum compounds reproduce oxidative stress and neuronal loss typical of late-stage pathology.

A critical comparison of these models in terms of construct, face, and predictive validity highlights their differential translational potential and limitations. While transgenic models provide genetic precision, pharmacological paradigms allow reversible and cost-effective testing of neuroprotective agents. Integrative approaches combining genetic, metabolic, and environmental factors promise more faithful recapitulation of human AD. This synthesis underscores the necessity of methodological pluralism, ethical refinement, and data reproducibility to advance preclinical neuroscience and accelerate therapeutic discovery in neurodegenerative research.