While aging remains the most significant risk factor for neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD) or Parkinson’s disease (PD), the biological pathways that are altered in healthy aging vs. pathologic aging leading to neurodegeneration remain to be elucidated. Since the genome remains invariant throughout the lifespan, it is essential to understand the effects of aging on the proteome as proteins play an integral role in all cellular functions and mediate the effects of epigenetic alterations. In addition, while the brain remains protected by the blood-brain barrier, there is increasing evidence that events such as systemic inflammation, metabolic dysfunction significantly affect the risk for the development of various NDs.