Association between presenilin-1 Glu318Gly mutation and familial Alzheimer's disease in the Australian population

Abstract

Mutations in the presenilin-1 (PS-1) gene on chromosome 14 account for the majority of earlyonset familial Alzheimer's disease (FAD) cases. To date, more than 90 mutations have been identified and, while most of these mutations are completely penetrant, the Glu318Gly mutation has been suggested to be partially penetrant. These findings indicate that it may play a similar role to apolipoprotein E (APOE)-⑀4 by acting as a genetic risk factor for AD. In the current study, a total of 682 subjects were tested to assess the frequency of the Glu318Gly mutation in AD in the Australian population. The Glu318Gly mutation was identified in six sporadic late-onset AD patients, four FAD patients (unrelated) and in nine control subjects. The frequency of this mutation was highest in the familial AD group (8.7%) and lowest in control subjects (2.2%). When the mutation frequencies were compared, we found a statistically significant difference between the latter two groups (Fisher's exact test, P Ͻ 0.05). The genotype frequency of the Glu318Gly mutation in all AD cases and controls in the Australian population was 2.8%. This frequency is comparable to that observed for the Dutch population (3.2%), but not for the Finnish population (6.8% and 6.0%) or the Spanish population (5.3%). These findings show that the frequency of the Glu318Gly mutation is increased in FAD patients, suggesting a potential role as a genetic risk factor contributing to the pathogenesis of familial AD.

Late onset familial Alzheimer's disease: novel presenilin 2 mutation and PS1 E318G polymorphism

“…The pathogenic role of PS1 Glu318Gly polymorphism has been so far debated in the literature [9][10][11]. From our study it is impossible to obtain a conclusive response about its pathogenicity: we cannot exclude involvement of the polymorphism in causing the disease, in association (or not) with APOE genotype and PS2 mutation.…”

Molecular Genetic Analysis of the APP, PSEN1, and PSEN2 Genes in Finnish Patients With Early-onset Alzheimer Disease and Frontotemporal Lobar Degeneration

“…26 In addition, significant associations between the E318G mutation and familial late-onset AD have been reported in Australian and Italian populations. 42,43 In our cohort, the E318G variant was detected with similar frequencies among the cases of eoAD and FTLD and among the healthy controls, suggesting no association with eoAD. In previous Finnish, Australian, and Italian studies, a connection has been observed between late-onset AD and E318G, suggesting that the increased risk may be age dependent and that the variation may contribute more to late-onset AD.…”

“…In previous Finnish, Australian, and Italian studies, a connection has been observed between late-onset AD and E318G, suggesting that the increased risk may be age dependent and that the variation may contribute more to late-onset AD. 26,42,43 In our series, the frequency of ApoEE4 allele carriers was very high in the entire eoAD group (61.4%) and even higher in the familial eoAD cases (70.1%), being 2 times higher than the frequency in controls (33.7%). The ApoEE4 allele of the ApoE gene is by far the most firmly established genetic risk factor for both familial and sporadic late-onset AD and also for eoAD.…”

Alzheimer’s Disease Genetics: From the Bench to the Clinic

“…Screening for APP mutations in exons 16–17 in 40 late-onset AD families identified one pathogenic APP mutation (E693G) with incomplete penetrance in a single family (reviewed in (Guerreiro et al, 2012a)). Screening for mutations in PSEN1 has been performed mainly in early-onset AD families, although a small number of late onset AD cases (>60 years; <100 families) were also screened leading to the report of some late onset AD families carrying mutations in PSEN1 (Arango et al, 2001; de Silva et al, 2001; Devi et al, 2000; Kauwe et al, 2007; Larner et al, 2007; Rogaeva et al, 2001; Scacchi et al, 2007; Taddei et al, 2002). …”