# Experimental and translational models of Alzheimer’s disease: From neurodegeneration to novel therapeutic insights

## TL;DR

This paper reviews innovative animal and organoid models for Alzheimer’s disease that mimic key features of the disease, offering new ways to study its causes and develop treatments.

## Contribution

The paper introduces novel experimental models, such as optogenetics and synthetic tau fibrils, to induce Alzheimer’s-like pathology in animals and organoids.

## Key findings

- Optogenetic and viral methods induce AD-like pathology in diverse species.
- Bioengineered organoids grafted into hosts allow controlled AD-like feature onset.
- Advanced tools like neuroimaging and multi-omics reveal disease dynamics.

## Abstract

Neurodegeneration on demand represents a groundbreaking approach to modeling Alzheimer’s disease (AD) in animals, enabling precise study of its molecular and behavioral hallmarks. Novel techniques, including optogenetic activation of amyloidogenic pathways, viral vector-mediated delivery of mutated human genes (e.g., APP, MAPT), and synthetic tau fibril analogs, induce AD-like pathology, including amyloid-beta plaques, tau hyperphosphorylation, neuroinflammation, and synaptic loss in diverse species, ranging from transgenic rodents to cephalopods and cannies. Emerging platforms, such as bioengineered neural organoids grafted into immunocompromised hosts, allowed for the controlled onset of AD-like features, providing unique insights into disease progression. Advanced tools like real-time neuroimaging and single-cell multi-omics help elucidate the temporal and cellular dynamics of neurodegeneration. These models provided unparalleled opportunities to dissect AD’s complex mechanisms, including protein misfolding, glial dysregulation, and cognitive decline. However, challenges remained, including interspecies molecular disparities, incomplete replication of human AD complexity, and ethical concerns surrounding cognitive impairment in sentient models. This review explores these innovative strategies, their contributions to understanding AD’s pathogenesis, and their potential to accelerate the development of transformative therapies, while also addressing limitations and future directions for refining these pioneering models.