The genetic landscape of early‐onset Alzheimer's disease in China

Abstract INTRODUCTION Research on somatic and germline mutations in Chinese individuals with early‐onset Alzheimer's disease (EOAD) has been limited. METHODS We 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. RESULTS The 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. DISCUSSION The 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.