Neurodegenerative diseases present a significant challenge, requiring a comprehensive understanding of their underlying mechanisms. While behavioral and morphological assessments are valuable, biochemical and molecular methods are essential for examining the complex cellular and molecular events that drive disease progression. This chapter outlines a set of methods for investigating preclinical models of neurodegeneration, focusing on key analytical approaches, from targeted protein analysis to broad-scale “omics” screenings. We will explore the principles, applications, and critical considerations for techniques such as Western blotting, enzyme linked immunosorbent assay (ELISA), and mass spectrometry, as well as genetic and epigenetic analyses. Emphasis is placed on the importance of proper sample handling, the challenges of working with small tissue samples, and the necessity of integrating data from diverse methods to build a complete picture of the disease. This chapter serves as a practical guide for researchers, enabling them to select the most appropriate techniques for validating disease models, discovering novel biomarkers, and assessing the efficacy of therapeutic interventions.