Evaluation of multiple presenilin 2 SNPs for association with early‐onset sporadic Alzheimer disease

Abstract

The presenilin genes encode proteins that modify, mediate, or perform similar functions to gamma-secretase, the enzyme responsible for converting amyloid beta precursor protein (APP) into beta-amyloid. Mutations in the presenilin genes cause an increased production of Abeta42, the aberrant form of beta-amyloid found in the neural plaques of Alzheimer disease patients. Previously reported association studies of presenilin 2 (PSEN2) polymorphisms with early-onset Alzheimer disease (EOAD) have produced contradictory results. In an effort to resolve these differences, we tested eight single nucleotide polymorphisms in and around the 3' region of the PSEN2 gene for association with EOAD. An initial set of Scottish EOAD cases (n = 121) and controls (n = 152) was screened using the genotyping method dynamic allele-specific hybridization (DASH). No significant differences were seen between allele or genotype frequencies of cases and controls. However, when conditioned on the risk allele (epsilon 4) APOE, three polymorphisms showed allelic association with a P value below 0.05. These same polymorphisms were in near 100% linkage disequilibrium with each other (P < 5 x 10(-5)), and in each, one of the homozygous genotypes was absent in controls but present in the cases. Replication in an independent set of Scottish EOAD cases (n = 84) and controls (n = 173) did not confirm this finding. From this study we find no evidence to suggest that variations in the PSEN2 gene pose as major risk factors for sporadic EOAD.

Cholesterol retention in Alzheimer's brain is responsible for high β- and γ-secretase activities and Aβ production

“…Another possible explanation is that βand γ-secretases in AD brain may have intrinsic sensitivity to cholesterol and therefore low cholesterol levels are needed to stimulate their activities. Single nucleotide polymorphisms (SNP) in genes encoding γ-secretase components modify AD risk (Yasuda et al, 1999;Dermaut et al, 2002;Howell and Brookes, 2002). Whether any SNP affects secretase sensitivity to cholesterol requires further investigation.…”

Genetic Association between Presenilin 2 Polymorphisms and Alzheimer's Disease and Dementia of Lewy Body Type in a Japanese Population

“…Replication studies of the SNP rs8383 have been previously performed [ 5 , 29 ]. The abovementioned meta-analysis for rs8383 showed that the polymorphism is associated with a heightened risk of AD [ 5 ].…”

Presenilin-2 polymorphisms and risk of sporadic AD: Evidence from a meta-analysis

“…The recessive genetic model, however, did not a yield statistically significant association between the C allele and AD (CC vs. TT+TC: OR=1.14, 95% CI=0.93-1.41). In the subtype analysis by APOE ε4 allele status using the available data (Combarros et al, 1999;Howell and Brookes, 2002;Singleton et al, 1997), significant association was found in the recessive genetic model for the APOE ε4 positive contrasts (OR=2.40, 95% CI=1.22-4.71). However, the APOE ε4 negative contrasts did not yield statistically significant (Table S1).…”

“…1, Tables 1 and 2) published from 1997 to 2009 (Brookes et al, 1997;Combarros et al, 1999;Giedraitis et al, 2009;Howell and Brookes, 2002;Prince et al, 2001;Singleton et al, 1997). The sample sizes of the AD case group ranged from 81 to 202 and the number of controls ranged from 78 to 383.…”

“…The sample sizes of the AD case group ranged from 81 to 202 and the number of controls ranged from 78 to 383. Only three studies carried out subtype analysis by APOE ε4 status (Combarros et al, 1999;Howell and Brookes, 2002;Singleton et al, 1997). Of these six studies, AD cases of four studies were diagnosed by NINCDS-ADRDA criteria (Combarros et al, 1999;Giedraitis et al, 2009;Howell and Brookes, 2002;Prince et al, 2001), one by DSM-IIIR criteria (Brookes et al, 1997), and another one by clinical symptoms and neuropathology (Singleton et al, 1997).…”