Genetic profiles of familial late-onset Alzheimer's disease in China: The Shanghai FLOAD study

Compared with early-onset familial AD (FAD), the heritability of most familial late-onset Alzheimer’s Disease (FLOAD) cases still remains unclear. However, there are few reported genetic profiles of FLOAD to date. In the present study, targeted sequencing of selected candidate genes was conducted for each of 90 probands with FLOAD and 101 unrelated matched normal controls among Chinese Han population. Results show a significantly lower rate of mutation in APP and PSENs, and APOE e4 genetic risk is higher for FLOAD. Among the Chinese FLOAD population, the most frequent variant was CR1 rs116806486 (5.6%, 95% CI (1.8%, 12.5%)), and followed by coding variants of TREM2 (4.4%, 95%CI (1.2%,10.9%)) and novel mutations of ACE (3.3%, 95%CI (0.7%, 9.4%)). Next, we found that novel pathogenic mutations in ACE including frame-shift and nonsense mutations were in association with FLOAD regardless of APOE e4 status. Evidence from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database also supported this finding in different ethnicities. Results of in vitro analysis suggest that frame-shift and nonsense mutations in ACE may be involved in LOAD through decreased ACE protein levels without affecting direct processing of APP.