P2-017: Mutation frequency of pathogenic genes in familial Alzheimer's disease in China

Presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) have been recognized as the major pathogenic genes of FAD. However, the frequency and predicted risk factors of these 3 pathogenic genes of FAD in China is still unclear. 160 FAD families have been recruited from Chinese Familial Alzheimer's Disease Network (CFAN, https://www.chinacfan.org/) from Jan 2013 to Dec 2014. According to age at onset (AAO) of the proband, 93 FAD families (58.1%) were classified as early-onset (<65 years old) FAD (EOFAD) and 67 (41.9%) families were late-onset (≥65 years old) AD (LOFAD). Clinical features, neuropsychological assessments, imaging and blood and CSF samples were collected from these pedigrees following standard protocols. Mutational screening of PSEN1, PSEN2, APP genes and genotype analysis of ApoE were performed in all of the 160 FAD families. Twenty-two pedigrees (23.7% of EOFAD) were identified with mutations in PSEN1, PSEN2 or APP. Specifically, 13 (59.1%) were PSEN1 mutations (4 novel and 9 previously reported), 8 (36.4%) were APP mutations (1 novel and 7 reported), and one (4.5%) was PSEN2 novel mutations (Table 1). Compared to FAD families without known mutations, the FAD families with mutations tended to present significantly lower mean age at onset (AAO), affect more family members and more generations, and carry less ApoEε4 allele (Table 2). When the equation was applied as followed: risk score= -1×AAO+3×the number of affected individuals+10×ApoE ε4 positive, the FAD with mutations were predicted very well (area under curve 0.89) with the high sensitivity (68%) and specificity (98%) (Figure 1). For phenotype of FAD families with mutations, there were no group difference in PSEN1 and APP mutations pedigrees in terms of mean AAO (54.4 vs 50.0 years, p=0.383), the number of affected family members (6.5 vs 5.8, p=0.724) and affected generations, or ApoE ε4 status (Table 3). Six novel mutations in PSEN1, PSEN2 or APP were identified in Chinese Han FAD pedigrees. FAD with mutations was significantly predicted by the number of affected individuals, AAO and ApoEε4. No significant difference between APP and PSEN1 mutations was found in China in terms of phenotype.