Precision Medicine in Neurodegenerative Disorders, Part One, Volume 192 in the Handbook of Clinical Neurology deals with the "Why" in the approach to slow the progression of accelerated brain aging. This volume is intended to provide a scholarly background on the framework, basic science and conceptual pitfalls related to disease-modifying efforts in Parkinson's, Alzheimer's and other neurodegenerative disorders. Among topics covered are different models of precision medicine, the lumping-versus-splitting tension in biomarker development and therapeutics, and the rationale for replacing the convergence of the prevailing autopsy-based nosology of neurodegenerative diseases with the divergence of a systems biology approach to human diseases. Specific chapters are dedicated to the promise of genetic subtypes and the lessons in disease modification offered by the fields of oncology and cystic fibrosis that can be adapted to the field of neurodegeneration. Matching a biology-correcting therapy with those biologically suitable to benefit from such therapy represents the vision and mission of precision medicine, the highest level of personalized medicine.