Alzheimer's disease (AD) is a complex disease that is likely influenced by many genetic and environmental factors. Citing evidence that iron may play a role in AD pathology, Robson et al.[Robson et al.(2004); J Med Genet 41:261-265] reported that epistatic interaction between rs1049296 (P589S) in the transferrin gene (TF) and rs1800562 (C282Y) in the hemochromatosis gene (HFE) results in significant association with risk for AD. In this study we attempted to replicate their findings in a total of 1,166 cases and 1,404 controls from three European and European American populations. Allele and genotype frequencies were consistent across the three populations. Using synergy factor analysis (SFA) and Logistic Regression analysis we tested each population and the combined sample for interactions between these two SNPs and risk for AD. We observed significant association between bi-carriers of the minor alleles of rs1049296 and rs1800562 in the combined sample using SFA (P = 0.0016, synergy factor = 2.71) and adjusted SFA adjusting for age and presence of the APOE epsilon 4 allele (P = 0.002, OR = 2.4). These results validate those of the previous report and support the hypothesis that iron transport and regulation play a role in AD pathology.(c) 2009 Wiley-Liss, Inc.

We undertook a two-stage genome-wide association study (GWAS) of Alzheimer's disease (AD) involving over 16,000 individuals, the most powerful AD GWAS to date. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the apolipoprotein E (APOE) locus (most significant SNP, rs2075650, P = 1.8 x 10(-157)) and observed genome-wide significant association with SNPs at two loci not previously associated with the disease: at the CLU (also known as APOJ) gene (rs11136000, P = 1.4 x 10(-9)) and 5' to the PICALM gene (rs3851179, P = 1.9 x 10(-8)). These associations were replicated in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with Alzheimer's disease in the combined dataset (rs11136000, P = 8.5 x 10(-10), odds ratio = 0.86; rs3851179, P = 1.3 x 10(-9), odds ratio = 0.86).

Psychotic symptoms are common in individuals with Alzheimer's disease (AD), and define a phenotype associated with more rapid cognitive and functional decline. Evidence suggests that psychotic symptoms may be influenced by genetic factors, and recent studies in schizophrenia, bipolar affective disorder (BPAD) and Alzheimer's disease with psychosis (AD+P) suggest that psychosis susceptibility or modifier genes may act across diseases. We hypothesised that oligodendrocyte lineage transcription factor 2 (OLIG2), a regulator of white matter development and a candidate gene for schizophrenia, may also be associated with psychotic symptoms in AD. We genotyped 11 SNPs in OLIG2 previously tested for association with schizophrenia (Georgieva et al., 2006) and tested these for association with AD and AD+P. Significant evidence for association of psychotic symptoms within cases was identified for two SNPs, rs762237 (allelic P=0.002, OR=1.42, corrected P=0.019) and rs2834072 (allelic P=0.004, OR=1.41, corrected P=0.05).

OBJECTIVE: To determine the effects of early life education, mid life employment and later life retirement age on the age of onset (AOO) of Alzheimer's disease (AD). METHODS: Multiple regression analyses were carried out using data for 1320 probable AD cases, of which 382 were males with employment and retirement age data, using informant based information on education and employment. RESULTS: No relation was found between years of education, best qualification obtained, or employment variables in males and the AOO of AD. A significant effect of later retirement age in delaying the AOO of AD was seen in males. CONCLUSIONS: In this study no effect of education or employment was seen, although this may be due to limited variance in the study population. The significant effect of retirement age may have several explanations, the most interesting of which would be the suggestion that active employment later in life allows an individual to prolong their cognitive assets above the threshold for dementia. Copyright (c) 2009 John Wiley & Sons, Ltd.

INTRODUCTION: Although there is evidence for distinct behavioural sub-phenotypes in Alzheimer's disease (AD), their inter-relationships and the effect of clinical variables on their expression have been little investigated. METHODS: We have analysed a sample of 1850 probable AD patients from the UK and Greece with 10 item Neuropsychiatric Inventory (NPI) data. We applied a Multiple Indicators Multiple Causes (MIMIC) approach to investigate the effect of MMSE, disease duration, gender, age and age of onset on the structure of a four-factor model consisting of "psychosis","moods","agitation" and "behavioural dyscontrol". RESULTS: Specific clinical variables predicted the expression of individual factors. When the inter-relationship of factors is modelled, some previously significant associations are lost. For example, lower MMSE scores predict psychosis, agitation and behavioural dyscontrol factors, but psychosis and mood predict the agitation factor. Taking these associations into account MMSE scores did not predict agitation. CONCLUSIONS: The complexity of the inter-relations between symptoms, factors and clinical variables is efficiently captured by this MIMIC model.

The MAPT gene that encodes Tau is located on chromosome 17q21, in a region, which has evolved to form two major haplotypes, H1 and H2. There is strong evidence that the H1 haplotype, and a sub-haplotype (H1C), are overrepresented and associated with increased risk for the sporadic tauopathies, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Both PSP and CBD cases display Tau pathology similar to Late-Onset Alzheimer's Disease (LOAD). However, numerous association studies investigating the genetic involvement of MAPT in LOAD have generated conflicting results. Here we have used a large LOAD case-control sample to genotype SNPs that have been shown to define H1/H2 status and intra-H1 variability. Single marker association analyses found no evidence that any of the SNPs are associated with risk of LOAD. When gender and APOE4 status were taken into account we observed suggestive association for SNP rs242557 (P = 0.02). Stratification of the sample revealed association with rs242557 only in APOE4 positive individuals (P = 0.01 recessive model), however this result would not survive multiple correction. There was no significant difference in H1/H2 haplotype distribution between cases and controls. We also tested the association of specific sub-haplotypes on the H1 background and likewise results were negative. No effect was observed on disease age of onset for any of the markers studied. In summary, we find no evidence for allelic or haplotypic association, with SNPs in the MAPT gene and LOAD. SNP rs242557 is nominally significant in the APOE4 positive individuals. None of the SNPs studied modified AAO for LOAD.(c) 2009 Wiley-Liss, Inc.

ABSTRACT: BACKGROUND: Late-onset Alzheimer's disease (LOAD) is an age related neurodegenerative disease with a high prevalence that places major demands on healthcare resources in societies with increasingly aged populations. The only extensively replicable genetic risk factor for LOAD is the apolipoprotein E gene. In order to identify additional genetic risk loci we have conducted a genome-wide association (GWA) study in a large LOAD case - control sample, reducing costs through the use of DNA pooling. METHODS: DNA samples were collected from 1,082 individuals with LOAD and 1,239 control subjects. Age at onset ranged from 60 to 95 and Controls were matched for age (mean = 76.53 years, SD = 6.33), gender and ethnicity. Equimolar amounts of each DNA sample were added to either a case or control pool. The pools were genotyped using Illumina HumanHap300 and Illumina Sentrix HumanHap240S arrays testing 561,494 SNPs. 114 of our best hit SNPs from the pooling data were identified and then individually genotyped in the case - control sample used to construct the pools. RESULTS: Highly significant association with LOAD was observed at the APOE locus confirming the validity of the pooled genotyping approach. For 109 SNPs outside the APOE locus, we obtained uncorrected p-values [less than or equal to] 0.05 for 74 after individual genotyping. To further test these associations, we added control data from 1400 subjects from the 1958 Birth Cohort with the evidence for association increasing to 3.4x10-6 for our strongest finding, rs727153. rs727153 lies 13kb from the start of transcription of lecithin retinol acyltransferase (phosphatidylcholine--retinol O-acyltransferase, LRAT). Five of seven tag SNPs chosen to cover LRAT showed significant association with LOAD with a SNP in intron 2 of LRAT, showing greatest evidence of association (rs201825, p-value = 6.1 x 10-7 ). CONCLUSIONS: We have validated the pooling method for GWA studies by both identifying the APOE locus and by observing a strong enrichment for significantly associated SNPs. We provide evidence for LRAT as a novel candidate gene for LOAD. LRAT plays a prominent role in the Vitamin A cascade, a system that has been previously implicated in LOAD.

A recent scan of single nucleotide polymorphisms (SNPs) in the region 40-107 Mb on chromosome 10q in a large Japanese case-control cohort identified six SNPs in or near the dynamin-binding protein gene (DNMBP) that were associated with late onset Alzheimer's disease (LOAD) in individuals lacking the APOE epsilon4 allele [Kuwano et al.(2006); Hum Mol Genet 15:2170-2182]. We genotyped these six SNPs in 1,212 unrelated Caucasian patients of UK origin with LOAD and 1,389 ethnically, gender and age matched control subjects. We did not observe a statistically significant association with the risk of LOAD for any of the six SNPs in the sample as a whole. When stratifying the sample by APOE one SNP (intergenic SNP rs11190302) was associated with LOAD in individuals lacking the epsilon4 allele (genotypic P = 0.027, allelic P = 0.066). However this association was in the opposite direction to that detected in the Japanese population. It remains to be determined whether DNMBP is associated with LOAD.(c) 2008 Wiley-Liss, Inc.

Late-onset Alzheimer's disease (LOAD) is a genetically complex neurodegenerative disorder. Currently, only the epsilon4 allele of the Apolipoprotein E gene has been identified unequivocally as a genetic susceptibility factor for LOAD. Others remain to be found. In 2002 we observed genome-wide significant evidence of linkage to a region on chromosome 10q11.23-q21.3 [Myers et al.(2002) Am J Med Genet 114:235-244]. Our objective in this study was to test every gene within the maximum LOD-1 linkage region, for association with LOAD. We obtained results for 528 SNPs from 67 genes, with an average density of 1 SNP every 10 kb within the genes. We demonstrated nominally significant association with LOAD for 4 SNPs: rs1881747 near DKK1 (P = 0.011, OR = 1.24), rs2279420 in ANK3 (P = 0.022, OR = 0.79), rs2306402 in CTNNA3 (P = 0.024, OR = 1.18), and rs5030882 in CXXC6 (P = 0.046, OR = 1.29) in 1,160 cases and 1,389 controls. These results would not survive correction for multiple testing but warrant attempts at confirmation in independent samples.(c) 2007 Wiley-Liss, Inc.

We have studied the impact of the apolipoprotein E gene (APOE) on the chromosome 19 linkage peak from an analysis of sib-pairs affected by Alzheimer's disease. We genotyped 417 affected sib-pairs (ASPs) collected in Sweden and Norway (SWE), the UK and the USA for 10 microsatellite markers on chromosome 19. The highest Zlr (3.28, chromosome-wide P-value 0.036) from the multipoint linkage analysis was located approximately 1 Mb from APOE, at marker D19S178. The linkage to chromosome 19 was well explained by APOE in the whole sample as well as in the UK and USA subsamples, as identity by descent (IBD) increased with the number of epsilon4 alleles in ASPs. There was a suggestion from the SWE subsample that linkage was higher than would be expected from APOE alone, although the test for this did not reach formal statistical significance. There was also a significant age at onset (aao) effect on linkage to chromosome 19q13 in the whole sample, which manifested itself as increased IBD sharing in relative pairs with lower mean aao. This effect was partially, although not completely, explained by APOE. The aao effect varied considerably between the different subsamples, with most of the effect coming from the UK sample. The other samples showed smaller effects in the same direction, but these were not significant.(c) 2007 Wiley-Liss, Inc.