Emerging concepts towards a translational framework in Alzheimer's disease

Area of Science:

• Neuroscience
• Pathology
• Pharmacology

Background:

• Alzheimer's disease (AD) is the leading cause of dementia, yet therapeutic strategies targeting its pathological hallmarks have largely failed.
• Understanding the precise molecular mechanisms of AD pathogenesis remains a critical challenge for effective treatment development.

Purpose of the Study:

• To review current findings and emerging concepts integrating molecular mechanisms with clinical approaches in AD research.
• To propose a refined workflow for preclinical animal studies that incorporates multimodal biomarkers used in human clinical trials.
• To delineate critical pathways for accelerating drug discovery and translation for AD.

Main Methods:

• Literature review of critical findings in AD pathogenesis and therapeutic strategies.
• Discussion of emerging ideas for conceptualizing and modeling AD.
• Proposal of an integrated experimental framework for animal studies.

Main Results:

• Identified consistent failures in clinical trials targeting established AD pathological hallmarks.
• Highlighted the need for refined conceptualization, modeling, and assessment in AD research.
• Proposed a novel workflow for animal studies integrating clinical multimodal biomarkers.

Conclusions:

• Refining the conceptualization and experimental approaches is crucial for developing successful AD therapies.
• An integrated framework incorporating molecular mechanisms and clinical biomarkers can accelerate drug discovery.
• Addressing unresolved questions through this framework may lead to effective disease-modifying strategies for AD.