Screening for Genetic Mutations Associated with Early-Onset Alzheimer's Disease in Han Chinese

Early-onset Alzheimer's disease (EOAD) is highly influenced by genetic factors. Numerous mutations in amyloid precursor protein (APP) and presenilin 1 and 2 (PSEN1 and PSEN2) have been identified for EOAD, but they can only account for a small proportion of EOAD cases.

This study aimed to screen genetic mutations and variants associated with EOAD among Han Chinese adults.

This study included 34 patients with EOAD and 26 controls from a population-based study and neurological ward. We first sequenced mutations in APP/PSENs and then performed whole-exome sequencing in the remaining patients with negative mutations in APP/PSENs to screen for additional potential genetic variants. Among patients who were negative in genetic screening tests, we further evaluated the risk burden of genes related to the Aβ metabolism-centered network to search for other probable causes of EOAD.

We identified 7 functional variants in APP/PSENs in 8 patients, including 1 APP mutation (p. Val715Met), 3 PSEN1 mutations (p. Phe177Ser; p. Arg377Met; p. Ile416Thr), and 3 PSEN2 mutations (p. Glu24Lys; p. Gly34Ser; p. Met239Thr). Of the remaining 26 EOAD cases without mutations in APP/PSENs, the proportion of carrying rare variants of genes involved in Aβ and APP metabolism was significantly higher than that of controls (84.6% vs. 73.1%, P=0.042). Thirty-one risk genes with 47 variants were identified in 22 patients. However, in 26 normal subjects, only 20 risk genes with 29 variants were identified in 19 subjects.

Our findings demonstrate the role of APP/PSENs mutations in EOAD, identifying a new PSEN2 missense mutation, and further offer valuable insights into the potential genetic mechanisms of EOAD without APP/PSENs mutations among Han Chinese.