Experimental modeling of Alzheimer's disease: Translational lessons from cross-taxon analyses

Abstract

Alzheimer's disease (AD) is a severely debilitating neurodegenerative disease with a rapidly increasing global prevalence, poorly understood causes, and no efficient treatments. Experimental models are valuable for studying AD pathogenesis, including amyloid beta and tau accumulation, synaptic dysfunction, and neuroinflammation. While no model fully reproduces the disease, we take an evolutionary biology approach to discuss available models across taxa, from mammals (rodents, primates) to zebrafish, Drosophila melanogaster, and Caenorhabditis elegans. Evaluating their strengths and limitations provides insight into disease mechanisms and may refine research strategies for improved diagnostics and therapeutic screening. Traditional models have significantly contributed to AD research, yet their translational limitations highlight the need for physiologically relevant alternatives. Integrating humanized rodent models, zebrafish, organoids, and induced pluripotent stem cell-based systems-along with advances in bioengineering and genetic editing-may offer a more comprehensive framework to bridge the gap between preclinical research and clinical application. HIGHLIGHTS: Experimental models across rodents, primates, zebrafish, fruit flies, and worms provide key insights into Alzheimer's disease (AD). Cross-taxon comparisons assess strengths and weaknesses in AD models. Evolutionary biology approaches refine experimental strategies for AD research. Diverse animal models improve understanding of AD pathogenesis. Cross-species models enhance diagnostics and therapeutic strategy development.

Keywords: Alzheimer's disease; animal models; cross‐taxon analyses; evolutionary psychiatry; translation medicine.

FIGURE 1

The multifactorial nature of Alzheimer's disease (AD). Early familial AD, most often caused by mutations in APP, PSEN1, or PSEN2 genes, accounts for 1% to 5% of AD cases. The exact causes of late‐onset sporadic AD (sAD), which accounts for > 95% of AD cases, remain largely unknown, but may involve complex gene x environment x aging interactions. Both forms of AD lead to the formation of amyloid plaques (Aβ) and neurofibrillary abnormalities, oxidative stress, synaptic dysfunction, neuroinflammation, neurodegeneration, and ultimately cognitive decline and motor and other behavioral deficits.

FIGURE 2

Comparison of selected animal model species presently used in Alzheimer's disease (AD) research (top panel). Bottom panel compares features of mouse and rat models of AD, emphasizing their relevance. Both models demonstrate amyloid beta (Aβ) plaque deposition, a core pathological feature of AD. Mouse models enable focusing on drug screening and genetic/transgenic models, whereas rat models with larger brain size enable more precise neuroanatomical manipulations and advanced cognitive assessments, with a greater capacity for neurophysiological experiments.

FIGURE 3

Summary of traditional approaches to modeling Alzheimer's disease (AD) in rodent models (top panel). Bottom panel illustrates common animal models used in AD research, categorized into genetic, aging, and injection models across species, such as mice, rats, non‐human primates, zebrafish, and invertebrates. Each cross‐point shows models (lines) applied in a specific group, with advantages of the animal models is provided. Aβ, amyloid beta; D‐gal, D‐ (+)‐galactose; LPS, lipopolysaccharide; p‐tau, phosphorylated tau; ROS, reactive oxygen species.

FIGURE 4

Comparative analyses of major model organisms used in AD research, including primates, rodents, fish, Drosophila melanogaster, and Caenorhabditis elegans, highlighting their main advantages and limitation for AD modeling. AD, Alzheimer's disease; NFT, neurofibrillary tangle.