PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer's disease

Abstract

IntroductionThe PSENs/APP mutation distribution in Chinese patients with familial Alzheimer's disease (FAD) remains unclear. We aimed to analyze the genetic features of Chinese FAD pedigrees with and without PSENs/APP mutations.MethodsIn total, 1330 patients with Alzheimer's disease (AD) or mild cognitive impairment in 404 pedigrees were enrolled from the Chinese Familial Alzheimer's Disease Network. PSENs/APP mutations and APOE frequencies were determined.ResultsIn total, 13.12% of pedigrees carried PSENs/APP missense mutations, 3.71% carried PSENs/APP synonymous/untranslated region variants, and 83.17% did not carry PSENs/APP mutations. Eleven missense mutations were first identified. In patients without PSENs/APP mutations, 44.31% carried one APOEε4 allele, and 14.85% two APOEε4 alleles.DiscussionThe new PSENs/APP mutations indicate heterogeneity in AD pathogenesis between Chinese and other ethnic groups. The low mutation rate suggests the involvement of other genes/factors in Chinese FAD. APOEε4 might be a major gene for some FAD without PSENs/APP mutations.

The Genetics of Alzheimer’s Disease in the Chinese Population

“…For instance, the CFAN discovered a lower detection rate of APP/PSEN mutations in the Chinese FAD population than that reported in Caucasians [45]. Additionally, it is also evident from the published studies that not all the susceptibility genes commonly found in Caucasian populations are present in Chinese AD patients [45,85]. For example, the CFAN reported a novel mutation in APP (M722K) in Chinese FAD patients, which was not found in other populations.…”

“…Besides, it is also of great value to compare the difference in genetic risk factors between Chinese population and other populations worldwide, as this may contribute to explain the heterogeneity in disease phenotypes and the development of specific treatments. For instance, the CFAN discovered a lower detection rate of APP/PSEN mutations in the Chinese FAD population than that reported in Caucasians [45]. Additionally, it is also evident from the published studies that not all the susceptibility genes commonly found in Caucasian populations are present in Chinese AD patients [45,85].…”

“…The probands carrying these mutations are likely to show highly heterogeneous phenotypes, based on the descriptions of the authors [39]. A recent study from CFAN reported ten missense mutations in PSEN1, and four of all ten mutations (including p.M139L, p.G111V, p.K311R and p.V97L) have been demonstrated to affect Aβ levels in previous reports [45].…”

“…For example, the CFAN reported a novel mutation in APP (M722K) in Chinese FAD patients, which was not found in other populations. Several mutations in PSEN1, including N24S, V97L, G111V, M139L, L172W, and K311R, were also first identified in the Chinese population [45]. Variation in the susceptibility genes in LOAD has also been reported between Chinese and Caucasian populations.…”

“…Using cell models, Wang et al demonstrated that the M722K mutation also elevates the ratio of Aβ42 to Aβ40 and increases tau phosphorylation at the S202/204 sites [37]. The M722K mutation of APP has been further confirmed in the Chinese Familial Alzheimer's Disease Network (CFAN) cohort study [45]. It is evident that most of the mutations in APP in familial AD occur around the cleavage site of γ-secretase ( Figure 1 and Table 1), which may suggest the significance of these mutations in modulating the generation of Aβ in the brain.…”