Neurodegenerative disorders are a set of slowly evolving neuropathological conditions with progressive loss of function and eventually death of neurons participating in motor, sensory or cognitive functions, including for example Alzheimer's, Parkinson's, Huntington's diseases, and amyotrophic lateral sclerosis. The onset age, progression rate, and symptoms of neurodegenerative disorders are extremely heterogeneous, like the Alzheimer’s disease (AD) with symptom onset ranging from age 20-100 years and progression to AD dementia taking 2-20 years. Multifaceted factors contribute to such a heterogeneity, including repeatedly proved contribution of sex, education, genotype, and toxic proteins of amyloid-β plaques and neurofibrillary tau tangles. Recent evidence supported a broad range of proteins with substantial contribution beyond the above factors to the heterogeneity in AD. However, the exact extent and the critical proteins of the proteomic contribution are still largely unknown. To address these issues, we perform large-scale proteomic analyses on cerebral spinal fluid across the AD continuum to examine the proteomic contribution to aging and Alzheimer’s disease.