A systematic review of the epidemiology of suicide in Iraq and Kurdistan region.

OBJECTIVES: The suicide rate has increased in Iraq in recent years, making it a major public health concern. This systematic review examines the prevalence of suicidal behaviours in the Iraq and Kurdistan region. MATERIALS AND METHODS: This study adhered to the PRISMA guidelines, conducting searches on PubMed, MEDLINE, Web of Science, and Google Scholar. Out of 153 initially identified publications, only 18 full articles met the inclusion criteria, with 135 articles excluded due to reasons such as eligibility criteria, duplication, predatory publications and lack of relevance and lack of quality data. RESULTS: The suicide crude rate in Iraq (excluding Kurdistan) rose from 1.09 to 1.31 per 100,000 between 2015 and 2016, while Kurdistan had an estimated rate of 3.83 per 100,000 during the same period. Limited data on reference group sizes and population figures make specific rate calculations challenging. Suicide is more prevalent among women, those aged 15-40, and individuals with mental disorders. Contributing factors include domestic violence, mental health issues, and traditional norms. Urban residents generally have higher suicide rates than rural residents. Common suicide behaviours include self-immolation, hanging, firearms, jumping from heights, and self-poisoning with pesticides. CONCLUSION: The prevalence of suicide in Iraq, as indicated by this systematic review, requires urgent attention and effective public health initiatives. The interplay of social, economic, cultural, and psychological factors emphasizes the need for comprehensive prevention programs. Additionally, a crucial requirement is the implementation of a standardised method for collecting suicide data to improve epidemiological understanding.

The prevalence of psychiatric disorders among Yazidi people results from ISIS invasion and consecutive trauma: A systematic review.

BACKGROUND: The Yazidi community is a Kurdish minority of the population that lives mainly in Iraq. In history, they suffered from many problems and disasters, including the most recent brutal invasion by ISIS, which significantly impacted their mental health. AIMS: Our objective is to examine the prevalence of psychiatric disorders among Yazidi people resulting from the invasion of ISIS in 2014. METHODS: A systematic review was performed using the PRISMA protocol. 252 publications were initially identified in PubMed, EMBASE, Scopus, and Google Scholar using relevant keywords. Finally, 23 full articles were included for data extraction. The inclusion criteria were English papers that investigated Yazidi's psychiatric problems, regardless of gender, or age. However, letters to editors, systematic reviews, and studies that examine general physical health were excluded. RESULTS: A total of 252 publications were identified; 217 were assessed for eligibility, of which 23 studies met eligibility criteria and were included in the present systematic review. According to the findings, the Yazidi people were severely affected by persecution, forced migration, massacres, and ISIS violence in the recent period and suffered from a variety of mental and psychiatric problems. The most prevalent mental disorders among Yazidi people of all ages and sexes are PTSD, depression, and anxiety disorders. CONCLUSION: This study indicates that the Yazidi minority is a traumatized population. According to the results of the current systematic review, the Yazidi have suffered from a variety of mental and psychological disorders, most commonly PTSD, depression, and anxiety. Eventually, addressing these challenges should be prioritized to improve the quality of life of Yazidis through implications for intervention.

PLCG2 protective variant p.P522R modulates tau pathology and disease progression in patients with mild cognitive impairment.

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aß1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aß1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.

Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer's disease.

Late onset Alzheimer's disease is the most common form of dementia for which about 30 susceptibility loci have been reported. The aim of the current study is to identify novel genes associated with Alzheimer's disease using the largest up-to-date reference single nucleotide polymorphism (SNP) panel, the most accurate imputation software and a novel gene-based analysis approach which tests for patterns of association within genes, in the powerful genome-wide association dataset of the International Genomics of Alzheimer's Project Consortium, comprising over 7 million genotypes from 17,008 Alzheimer's cases and 37,154 controls. In addition to earlier reported genes, we detected three novel gene-wide significant loci PPARGC1A (p = 2.2 × 10-6), RORA (p = 7.4 × 10-7) and ZNF423 (p = 2.1 × 10-6). PPARGC1A and RORA are involved in circadian rhythm; circadian disturbances are one of the earliest symptoms of Alzheimer's disease. PPARGC1A is additionally linked to energy metabolism and the generation of amyloid beta plaques. RORA is involved in a variety of functions apart from circadian rhythm, such as cholesterol metabolism and inflammation. The ZNF423 gene resides in an Alzheimer's disease-specific protein network and is likely involved with centrosomes and DNA damage repair.

The Epistasis Project: A Multi-Cohort Study of the Effects of BDNF, DBH, and SORT1 Epistasis on Alzheimer's Disease Risk.

Pre-synaptic secretion of brain-derived neurotrophic factor (BDNF) from noradrenergic neurons may protect the Alzheimer's disease (AD) brain from amyloid pathology. While the BDNF polymorphism (rs6265) is associated with faster cognitive decline and increased hippocampal atrophy, a replicable genetic association of BDNF with AD risk has yet to be demonstrated. This could be due to masking by underlying epistatic interactions between BDNF and other loci that encode proteins involved in moderating BDNF secretion (DBH and Sortilin). We performed a multi-cohort case-control association study of the BDNF, DBH, and SORT1 loci comprising 5,682 controls and 2,454 AD patients from Northern Europe (87% of samples) and Spain (13%). The BDNF locus was associated with increased AD risk (odds ratios; OR = 1.1-1.2, p = 0.005-0.3), an effect size that was consistent in the Northern European (OR = 1.1-1.2, p = 0.002-0.8) but not the smaller Spanish (OR = 0.8-1.6, p = 0.4-1.0) subset. A synergistic interaction between BDNF and sex (synergy factor; SF = 1.3-1.5 p = 0.002-0.02) translated to a greater risk of AD associated with BDNF in women (OR = 1.2-1.3, p = 0.007-0.00008) than men (OR = 0.9-1.0, p = 0.3-0.6). While the DBH polymorphism (rs1611115) was also associated with increased AD risk (OR = 1.1, p = 0.04) the synergistic interaction (SF = 2.2, p = 0.007) between BDNF (rs6265) and DBH (rs1611115) contributed greater AD risk than either gene alone, an effect that was greater in women (SF = 2.4, p = 0.04) than men (SF = 2.0, p = 0.2). These data support a complex genetic interaction at loci encoding proteins implicated in the DBH-BDNF inflammatory pathway that modifies AD risk, particularly in women.

Effect of agomelatine 25-50 mg on functional outcomes in patients with major depressive disorder.

PURPOSE: The purpose of this work is to investigate the effect of agomelatine on functioning compared with placebo in patients suffering from Major Depressive Disorder (MDD). METHODS: Data from two randomized, parallel, double-blind, placebo-controlled short-term agomelatine trials conducted by the manufacturer, one in adult and one in older patients, that evaluated the effect on social functioning, were pooled. The short term effect of agomelatine on social functioning was assessed using the Sheehan Disability Scale (SDS), according to SDS total and sub-item scores, as well as on functional response and remission rates. The Hamilton Depression rating scale was used to quantify severity of depression symptoms. A meta-analytic method using a random effect model was used to assess differences in treatment. RESULTS: In total, 633 patients (422 on agomelatine; 211 on placebo) were included in the analyses. At endpoint, there was a significant difference in favor of agomelatine vs placebo of 3.47 (0.62) (95% confidence interval: [2.26; 4.67]; P < 0.001) on the SDS total score. Rates of symptomatic response and remission according to HAM-D17 total score were significantly higher in patients taking agomelatine (54.3% and 18.3% respectively) than in those taking placebo (29.4% and 9.5% respectively) with respective differences of 24.9%, p < 0.001 and 9.3%, p < 0.001. The functional response rates were 52.9% on agomelatine and 34.5% on placebo, with a significant placebo-agomelatine difference in favor of agomelatine of 18.30 ±â€¯4.39% (95% CI: [9.69; 26.91], p < 0.001). The functional remission rates were 22.3% with agomelatine and 10.2% with placebo, with a significant difference in favor of agomelatine of 11.7 ±â€¯3.11% (95% CI: [5.61; 17.79], p < 0.001). Combined symptomatic and functional response rates were 42.1% on agomelatine and 23.2% on placebo (p < 0.001), and the combined symptomatic and functional remission rates were 13.9% on agomelatine and 6.8% on placebo (p < 0.005). CONCLUSION: This study confirms the efficacy of agomelatine in improving social functioning in MDD patients.

Antidepressant effect in older depressed patients: the lessons of two agomelatine trials.

The present paper reports in parallel the findings of the two phase III trials that evaluated the efficacy of agomelatine in older depressed patients. It describes how the particular methodological innovations (particularly in relation to patient selection, design and accuracy of diagnosis of depression) introduced in study 2 have improved the quality of recruitment of patients and the assay sensitivity. Study 1 lacked assay sensitivity, and among the many differences with study 2, the inclusion of unexpected mildly ill patients could have inflated the placebo response. The increased demands on investigators in study 2 appear to have reduced the placebo effect and showed a robust benefit of agomelatine. The two agomelatine studies offer the opportunity to discuss hypotheses that have been raised to explain the low level of response of older patients to available antidepressants.

Little evidence for community treatment orders - a battle fought with heavy weapons.

This editorial discusses the pros and cons of community treatment orders (CTOs) from the perspective of community general adult psychiatry. There is little scientific evidence supporting the application of CTOs. Preconditions of a CTO to work are likely to be met by few patients. The time for the application of a CTO may be better spent for patient-centred care until there is sufficient new and robust evidence that identifies the patients that might profit.

Anxiety disorders and physical comorbidity: increased prevalence but reduced relevance of specific risk factors for hospital-based mortality during a 12.5-year observation period in general hospital admissions.

Anxiety disorders (AD) are associated with an increase in physical comorbidities, but the effects of these diseases on hospital-based mortality are unclear. Consequently, we investigated whether the burden of physical comorbidity and its relevance on hospital-based mortality differed between individuals with and without AD during a 12.5-year observation period in general hospital admissions. During 1 January 2000 and 30 June 2012, 11,481 AD individuals were admitted to seven General Manchester Hospitals. All comorbidities with a prevalence ≥ 1 % were compared with those of 114,810 randomly selected and group-matched hospital controls of the same age and gender, regardless of priority of diagnoses or specialized treatments. Comorbidities that increased the risk of hospital-based mortality (but not mortality outside of the hospital) were identified using multivariate logistic regression analyses. AD individuals compared to controls had a substantial excess comorbidity, but a reduced hospital-based mortality rate. Twenty-two physical comorbidities were increased in AD individuals compared with controls, which included cardiovascular diseases and their risk factors. The most frequent physical comorbidities in AD individuals were hypertension, asthma, cataract, and ischaemic heart disease. Risk factors for hospital-based mortality in AD individuals were lung cancer, alcoholic liver disease, respiratory failure, heart failure, pneumonia, bronchitis, non-specific dementia, breast cancer, COPD, gallbladder calculus, atrial fibrillation, and angina. The impact of atrial fibrillation, angina, and gallbladder calculus on hospital-based mortality was higher in AD individuals than in controls. In contrast, other mortality risk factors had an equal or lower impact on hospital-based mortality in sample comparisons. Therefore AD individuals have a higher burden of physical comorbidity that is associated with a reduced risk of general hospital-based mortality. Atrial fibrillation, angina, and gallbladder calculus are major risk factors for general hospital-based mortality in AD individuals.

Bipolar disorder and comorbidity: increased prevalence and increased relevance of comorbidity for hospital-based mortality during a 12.5-year observation period in general hospital admissions.

BACKGROUND: Bipolar disorder (BD) is associated with an increase of psychiatric and physical comorbidities, but the effects of these disorders on general hospital-based mortality are unclear. Consequently, we investigated whether the burden of comorbidity and its relevance on hospital-based mortality differed between individuals with and without BD during a 12.5-year observation period in general hospital admissions. METHODS: During 1 January 2000 and 30 June 2012, 621 individuals with BD were admitted to three General Manchester Hospitals. All comorbidities with a prevalence ≥1% were compared with those of 6210 randomly selected and group-matched hospital controls of the same age and gender, regardless of priority of diagnoses. Comorbidities that increased the risk for hospital-based mortality (but not mortality outside of the hospitals) were identified using multivariate logistic regression analyses. RESULTS: Individuals with BD had a more severe course of disease than controls that was associated with a higher total number of in-hospital deaths. Individuals with BD compared to controls had a substantial higher burden of comorbidities, the most frequent comorbidities included asthma, type-2 diabetes mellitus (T2DM), and alcohol dependence. 18 other diseases with a surplus of diabetes related complications were also increased. Fourteen comorbidities contributed to the prediction of hospital-based mortality in univariate analyses. Risk factors for hospital-based mortality in multivariate analyses were ischemic stroke, pneumonia, bronchitis, chronic obstructive pulmonary disease, T2DM, and hypertension. The impact of T2DM on hospital-based mortality was higher in individuals with BD than in controls. LIMITATIONS: The study design was not assigned to assess the type of BD, the current bipolar status, and if individuals with BD were treated with medication. It was neither possible to compare drug effects, nor to compare the adherence to treatment between samples. CONCLUSION: In one of the largest samples of individuals with BD in general hospitals, the excess comorbity in individuals with BD compared to controls is in particular caused by asthma and T2DM. T2DM and its complications cause significant excess hospital-based mortality in individuals with BD.

Comorbidity and its relevance on general hospital based mortality in major depressive disorder: a naturalistic 12-year follow-up in general hospital admissions.

Major depressive disorder (MDD) is associated with physical comorbidity, but the risk factors of general hospital-based mortality are unclear. Consequently, we investigated whether the burden of comorbidity and its relevance on in-hospital death differs between patients with and without MDD in a 12-year follow-up in general hospital admissions. During 1 January 2000 and 30 June 2012, 9604 MDD patients were admitted to three General Manchester Hospitals. All comorbidities with a prevalence ≥1% were compared with those of 96,040 age-gender matched hospital controls. Risk factors of in-hospital death were identified using multivariate logistic regression analyses. Crude hospital-based mortality rates within the period under observation were 997/9604 (10.4%) in MDD patients and 8495/96,040 (8.8%) in controls. MDD patients compared to controls had a substantial higher burden of comorbidity. The highest comorbidities included hypertension, asthma, and anxiety disorders. Subsequently, twenty-six other diseases were disproportionally increased, many of them linked to chronic lung diseases and to diabetes. In deceased MDD patients, chronic obstructive pulmonary disease and type-2 diabetes mellitus were the most common comorbidities, contributing to 18.6% and 17.1% of deaths. Furthermore, fifteen physical diseases contributed to in-hospital death in the MDD population. However, there were no significant differences in their impact on mortality compared to controls in multivariate logistic regression analyses. Thus in one of the largest samples of MDD patients in general hospitals, MDD patients have a substantial higher burden of comorbidity compared to controls, but they succumb to the same physical diseases as their age-gender matched peers without MDD.

Physical comorbidity and its relevance on mortality in schizophrenia: a naturalistic 12-year follow-up in general hospital admissions.

Schizophrenia is a major psychotic disorder with significant comorbidity and mortality. Patients with schizophrenia are said to suffer more type-2 diabetes mellitus (T2DM) and diabetogenic complications. However, there is little consistent evidence that comorbidity with physical diseases leads to excess mortality in schizophrenic patients. Consequently, we investigated whether the burden of physical comorbidity and its relevance on hospital mortality differed between patients with and without schizophrenia in a 12-year follow-up in general hospital admissions. During 1 January 2000 and 31 June 2012, 1418 adult patients with schizophrenia were admitted to three General Manchester NHS Hospitals. All comorbid diseases with a prevalemce ≥1% were compared with those of 14,180 age- and gender-matched hospital controls. Risk factors, i.e. comorbid diseases that were predictors for general hospital mortality were identified using multivariate logistic regression analyses. Compared with controls, schizophrenic patients had a higher proportion of emergency admissions (69.8 vs. 43.0%), an extended average length of stay at index hospitalization (8.1 vs. 3.4 days), a higher number of hospital admissions (11.5 vs. 6.3), a shorter length of survival (1895 vs. 2161 days), and a nearly twofold increased mortality rate (18.0 vs. 9.7%). Schizophrenic patients suffered more depression, T2DM, alcohol abuse, asthma, COPD, and twenty-three more diseases, many of them diabetic-related complications or other environmentally influenced conditions. In contrast, hypertension, cataract, angina, and hyperlipidaemia were less prevalent in the schizophrenia population compared to the control population. In deceased schizophrenic patients, T2DM was the most frequently recorded comorbidity, contributing to 31.4% of hospital deaths (only 14.4% of schizophrenic patients with comorbid T2DM survived the study period). Further predictors of general hospital mortality in schizophrenia were found to be alcoholic liver disease (OR = 10.3), parkinsonism (OR = 5.0), T1DM (OR = 3.8), non-specific renal failure (OR = 3.5), ischaemic stroke (OR = 3.3), pneumonia (OR = 3.0), iron-deficiency anaemia (OR = 2.8), COPD (OR = 2.8), and bronchitis (OR = 2.6). There were no significant differences in their impact on hospital mortality compared to control subjects with the same diseases except parkinsonism which was associated with higher mortality in the schizophrenia population compared with the control population. The prevalence of parkinsonism was significantly elevated in the 255 deceased schizophrenic patients (5.5 %) than in those 1,163 surviving the study period (0.8 %, OR = 5.0) and deceased schizophrenic patients had significantly more suffered extrapyramidal symptoms than deceased control subjects (5.5 vs. 1.5 %). Therefore patients with schizophrenia have a higher burden of physical comorbidity that is associated with a worse outcome in a 12-year follow-up of mortality in general hospitals compared with hospital controls. However, schizophrenic patients die of the same physical diseases as their peers without schizophrenia. The most relevant physical risk factors of general hospital mortality are T2DM, COPD and infectious respiratory complications, iron-deficiency anaemia, T1DM, unspecific renal failure, ischaemic stroke, and alcoholic liver disease. Additionally, parkinsonism is a major risk factor for general hospital mortality in schizophrenia. Thus, optimal monitoring and management of acute T2DM and COPD with its infectious respiratory complications, as well as the accurate detection and management of iron-deficiency anaemia, of diabetic-related long-term micro- and macrovascular complications, of alcoholic liver disease, and of extrapyramidal symptoms are of utmost relevance in schizophrenia.

The sex-specific associations of the aromatase gene with Alzheimer's disease and its interaction with IL10 in the Epistasis Project.

Epistasis between interleukin-10 (IL10) and aromatase gene polymorphisms has previously been reported to modify the risk of Alzheimer's disease (AD). However, although the main effects of aromatase variants suggest a sex-specific effect in AD, there has been insufficient power to detect sex-specific epistasis between these genes to date. Here we used the cohort of 1757 AD patients and 6294 controls in the Epistasis Project. We replicated the previously reported main effects of aromatase polymorphisms in AD risk in women, for example, adjusted odds ratio of disease for rs1065778 GG=1.22 (95% confidence interval: 1.01-1.48, P=0.03). We also confirmed a reported epistatic interaction between IL10 rs1800896 and aromatase (CYP19A1) rs1062033, again only in women: adjusted synergy factor=1.94 (1.16-3.25, 0.01). Aromatase, a rate-limiting enzyme in the synthesis of estrogens, is expressed in AD-relevant brain regions ,and is downregulated during the disease. IL-10 is an anti-inflammatory cytokine. Given that estrogens have neuroprotective and anti-inflammatory activities and regulate microglial cytokine production, epistasis is biologically plausible. Diminishing serum estrogen in postmenopausal women, coupled with suboptimal brain estrogen synthesis, may contribute to the inflammatory state, that is a pathological hallmark of AD.

The efficacy of agomelatine in elderly patients with recurrent major depressive disorder: a placebo-controlled study.

OBJECTIVE: The present placebo-controlled study evaluated the efficacy, tolerability, and safety of 8-week treatment with agomelatine (25-50 mg/d by mouth) in elderly patients with major depressive disorder (MDD). METHOD: Elderly outpatients aged ≥ 65 years with a primary diagnosis of moderate to severe episode of recurrent MDD (DSM-IV-TR) were recruited in 27 clinical centers in Argentina, Finland, Mexico, Portugal, and Romania from November 2009 to October 2011. The primary outcome measure was the 17-item Hamilton Depression Rating Scale (HDRS17) total score. RESULTS: A total of 222 elderly patients entered the study (151 in the agomelatine group, 71 in the placebo group), including 69 patients aged 75 years and older. Agomelatine improved depressive symptoms in the elderly population, as evaluated by the HDRS17 total score, in terms of last postbaseline value (agomelatine-placebo difference: mean estimate [standard error] = 2.67 [1.06] points; P = .013) and response to treatment (agomelatine, 59.5%; placebo, 38.6%; P = .004). The agomelatine-placebo difference according to the Clinical Global Impressions-Severity of Illness scale (CGI-S) score was 0.48 (0.19). The agomelatine-placebo difference (estimate [standard error]) for remission on the HDRS17 was 6.9% (4.7%) and did not achieve statistical significance (P = .179, post hoc analysis). Clinically relevant effects of agomelatine were confirmed on all end points in the subset of severely depressed patients (HDRS17 total score ≥ 25 and CGI-S score ≥ 5 at baseline). Agomelatine was well tolerated by patients, with only minimal distinctions from placebo. CONCLUSIONS: The present study provides the first evidence that an 8-week treatment with agomelatine 25-50 mg/d efficiently relieves depressive symptoms and is well tolerated in elderly depressed patients older than 65 years. TRIAL REGISTRATION: Controlled-Trials.com identifier: ISRCTN57507360.

Cardiovascular Risk Profiles amongst Women in a Multiethnic Population in Inner City Britain: A Potential Impact of Anaemia.

The risk of diabetes is markedly reduced in men with iron deficiency anaemia (IDA). The nature of this relationship in women is not clear, nor is there information about the influence of ethnicity, given the increased susceptibility of diabetes amongst South Asians and Afro-Caribbeans. We reviewed 3563 patients with a diagnosis of anaemia from 2000 to 2007. The age-adjusted prevalence of vitamin B12 deficiency and IDA was calculated, together with cardiovascular comorbidities amongst Caucasians, South Asians, and Afro-Caribbeans. The prevalence of vitamin B12 deficiency (women only) or IDA was markedly higher in South Asians compared to Caucasians and Afro-Caribbeans. Among women with IDA, diabetes was more prevalent among South Asians (45%, 95% CI 39.0-51.0) compared to Caucasians (3.0%, 2.1-4.0); P < 0.001. Among South Asian women with vitamin B12 deficiency, the prevalence of diabetes was reduced 8.5% (5.2-12.0). South Asian women with vitamin B12 deficiency had a higher prevalence of myocardial infarction (MI) and ischemic heart disease (IHD), but this relationship was reversed in IDA. IDA is associated with a greater prevalence of diabetes in South Asian women, but it is not coordinated by a greater risk of macrovascular complications. Given the cardiovascular impact of diabetes in South Asians, this association merits further study in relation to its pathophysiological implication.

Discovery by the Epistasis Project of an epistatic interaction between the GSTM3 gene and the HHEX/IDE/KIF11 locus in the risk of Alzheimer's disease.

Despite recent discoveries in the genetics of sporadic Alzheimer's disease, there remains substantial "hidden heritability." It is thought that some of this missing heritability may be because of gene-gene, i.e., epistatic, interactions. We examined potential epistasis between 110 candidate polymorphisms in 1757 cases of Alzheimer's disease and 6294 control subjects of the Epistasis Project, divided between a discovery and a replication dataset. We found an epistatic interaction, between rs7483 in GSTM3 and rs1111875 in the HHEX/IDE/KIF11 gene cluster, with a closely similar, significant result in both datasets. The synergy factor (SF) in the combined dataset was 1.79, 95% confidence interval [CI], 1.35-2.36; p = 0.00004. Consistent interaction was also found in 7 out of the 8 additional subsets that we examined post hoc: i.e., it was shown in both North Europe and North Spain, in both men and women, in both those with and without the ε4 allele of apolipoprotein E, and in people older than 75 years (SF, 2.27; 95% CI, 1.60-3.20; p < 0.00001), but not in those younger than 75 years (SF, 1.06; 95% CI, 0.59-1.91; p = 0.84). The association with Alzheimer's disease was purely epistatic with neither polymorphism showing an independent effect: odds ratio, 1.0; p ≥ 0.7. Indeed, each factor was associated with protection in the absence of the other factor, but with risk in its presence. In conclusion, this epistatic interaction showed a high degree of consistency when stratifying by sex, the ε4 allele of apolipoprotein E genotype, and geographic region.