INTRODUCTIONResearch on somatic and germline mutations in Chinese individuals with early-onset Alzheimer's disease (EOAD) has been limited. METHODSWe conducted whole-genome sequencing of blood DNA from 108 patients with EOAD and 116 controls. The analysis included somatic and germline mutations across coding and non-coding regions, mutational signature determination, pathway enrichment identification, and predictive model. RESULTSThe mutational burden was significantly higher in the EOAD group compared to the control group. The prevalence of single-base substitution signature 5, which is strongly associated with aging, was much higher in patients with EOAD than in controls. EOAD-specific somatic mutations were identified in genes such as MIR31HG, TUBB4B, and APP. Germline mutations in DOCK3, PCSK5, and PDE4D were significantly associated with age of dementia onset. Furthermore, a predictive model comprising 15 mutations demonstrated an area under the curve of 0.78. DISCUSSIONThe accumulation of senescence-related somatic mutations may increase the risk of developing EOAD. Highlights Whole genome sequencing was used to find somatic and germline mutations in Chinese individuals with early-onset Alzheimer's disease (EOAD). Total number and burden of blood somatic mutations were significantly higher. The prevalence of single-base substitution signature 5 was notably elevated in EOAD. EOAD-specific somatic mutations were identified in MIR31HG, TUBB4B, and APP. DOCK3, PCSK5, and PDE4D germline mutations were associated with the age of EOAD onset.