Scientific Poster: Animal Models of Alzheimer's Disease - History of Animal Models for Therapeutic Discovery

Introduction

• Alzheimer's Disease (AD), the most common cause of dementia, is characterized by progressive cognitive decline and neuropathies including amyloid-β (Aβ) plaques, Tau neurofibrillary tangles, neuroinflammation, and synaptic loss.
• Since the 1980's, mouse models have played a central role in advancing the understanding of AD.
• Overexpression of human Amyloid Precursor Protein (APP) mutations linked to familial AD paved the early adoption of mouse models for AD research.  
• Newer mouse models have incorporated Tau pathology, presenilin mutations, additional mechanisms, and even humanized immune system to better mimic disease complexity. 
• Despite translational limitations, these models have enabled major breakthroughs in elucidating pathogenic cascades, identifying molecular targets, and guiding preclinical drug development.
• The evolution of AD mouse models—from single-gene transgenics to next-generation knock-ins and humanized chimeric systems—reflects an ongoing effort to generate more pathophysiological and translationally relevant models.

Discussion

• While decades of Alzheimerʼs disease (AD) research in mouse models have yielded invaluable mechanistic insights, translation to successful clinical therapies remains limited. A key contributor to this gap is the physiological divergence between current models and the human disease trajectory. Many established transgenic lines exhibit early and aggressive amyloid deposition or Tau pathology, often driven by supraphysiological overexpression of mutant human genes that represent rare familial forms of AD. These models accelerate pathology for experimental practicality but fail to capture the gradual, age-dependent progression and heterogeneous staging observed in sporadic, late-onset AD—the form that predominates in patients.
• Moreover, current models frequently lack important comorbid features such as cerebrovascular dysfunction, metabolic impairment, and microglial and astrocytic diversity that evolve over the human disease course. As clinical diagnostic frameworks increasingly emphasize biomarker-based staging (e.g., A/T/N systems reflecting amyloid, Tau, and neurodegeneration status), preclinical models must evolve to reflect these dynamic, overlapping pathological phases.
• Future efforts should prioritize physiologically relevant systems that integrate humanized immune and glial components, age-appropriate gene regulation, and progressive pathology across molecular and functional domains. Knock-in models, induced pluripotent stem cell (iPSC)-derived chimeras, and multi-omic longitudinal mapping in rodents offer promising avenues to align preclinical staging with clinical phenotypes. By developing models that more faithfully mirror disease initiation, propagation, and symptomatic progression, the field can improve predictive validity and ultimately enhance the translational success of Alzheimerʼs therapeutics.