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

ε4 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%)]

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

ε4 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.