Distinguishing true from false positives in genomic studies: p values.

Distinguishing true from false positive findings is a major challenge in human genetic epidemiology. Several strategies have been devised to facilitate this, including the positive predictive value (PPV) and a set of epidemiological criteria, known as the "Venice" criteria. The PPV measures the probability of a true association, given a statistically significant finding, while the Venice criteria grade the credibility based on the amount of evidence, consistency of replication and protection from bias. A vast majority of journals use significance thresholds to identify the true positive findings. We studied the effect of p value thresholds on the PPV and used the PPV and Venice criteria to define usable thresholds of statistical significance. Theoretical and empirical analyses of data published on AlzGene show that at a nominal p value threshold of 0.05 most "positive" findings will turn out to be false if the prior probability of association is below 0.10 even if the statistical power of the study is higher than 0.80. However, in underpowered studies (0.25) with a low prior probability of 1 × 10(-3), a p value of 1 × 10(-5) yields a high PPV (>96 %). Here we have shown that the p value threshold of 1 × 10(-5) gives a very strong evidence of association in almost all studies. However, in the case of a very high prior probability of association (0.50) a p value threshold of 0.05 may be sufficient, while for studies with very low prior probability of association (1 × 10(-4); genome-wide association studies for instance) 1 × 10(-7) may serve as a useful threshold to declare significance.

Frequency and burden of potentially treatable symptoms in glioma patients with stable disease.

Background & aims: Glioma patients experience a multitude of symptoms that negatively affect their health-related quality of life. Symptoms vary greatly across disease phases, and the patients' stable phase might be particularly suitable for assessing and treating symptoms. Identifying symptoms and patients' needs is a first step toward improving patient care. In glioma patients with stable disease, we assessed the frequency and burden of patient-reported symptoms, examined how these symptoms co-occur, and also determined whether patients would consider treatment to ameliorate specific symptoms. Methods: In this retrospective study, patients rated the frequency and burden of seventeen symptoms on a seven-point Likert scale and stated whether they would consider treatment for these symptoms. Correlations between frequency, burden, and considering treatment were evaluated with Kendall's Tau correlation coefficients. Based on partial correlations between symptom frequencies we visualized the symptoms as a network. Results: Fifty-two glioma patients with stable disease were included (31 WHO grade II/III, 21 WHO grade IV). The top five symptoms were fatigue, memory problems, reduced physical fitness, concentration problems, and drowsiness. Fatigue had the highest median frequency (4.5, interquartile range 2.5). Over half of the patients experienced three or more symptoms simultaneously and associations between all symptoms were depicted as a network. Overall, 35% of patients would consider treatment for at least one symptom. The wish to undergo symptom treatment correlated only moderately with symptom frequency and burden (range of correlations 0.24-0.57 and 0.28-0.61, respectively). Conclusion: Glioma patients with stable disease experience multiple symptoms with a consequently high symptom burden. Despite the high prevalence of symptoms, the inclination for symptom management interventions was relatively low. The most frequent and burdensome symptoms and the way they are interrelated could serve as a roadmap for future research on symptom management in these patients.

Incomplete patient information exchange and unnecessary repeat diagnostics during oncological referrals in the Netherlands: exploring the role of information exchange.

Data management in transmural care is complex. Without digital innovations like Health Information Exchange (HIE), patient information is often dispersed and inaccessible across health information systems between hospitals. The extent of information loss and consequences remain unclear. We aimed to quantify patient information availability of referred oncological patients and to assess its impact on unnecessary repeat diagnostics by observing all oncological multidisciplinary team meetings (MDTs) in a tertiary hospital. During 84 multidisciplinary team meetings, 165 patients were included. Complete patient information was provided in 17.6% (29/165, CI = 12.3-24.4) of patients. Diagnostic imaging was shared completely in 52.5% (74/141, CI = 43.9-60.9), imaging reports in 77.5% (100/129, CI = 69.2-84.2), laboratory results in 55.2% (91/165, CI = 47.2-62.8), ancillary test reports in 58.0% (29/50, CI = 43.3-71.5), and pathology reports in 60.0% (57/95, CI = 49.4-69.8). A total of 266 tests were performed additionally, with the main motivation not previously performed followed by inconclusive or insufficient quality of previous tests. Diagnostics were repeated unnecessarily in 15.8% (26/165, CI = 10.7-22.4) of patients. In conclusion, patient information was provided incompletely in majority of referrals discussed in oncological multidisciplinary team meetings and led to unnecessary repeat diagnostics in a small number of patients. Additional research is needed to determine the benefit of Health Information Exchange to improve data transfer in oncological care.

Linkage analysis for plasma amyloid beta levels in persons with hypertension implicates Aß-40 levels to presenilin 2.

Plasma concentrations of Aß40 and Aß42 rise with age and are increased in people with mutations that cause early-onset Alzheimer's disease (AD). Amyloid beta (Aß) plasma levels were successfully used as an (endo)phenotype for gene discovery using a linkage approach in families with dominant forms of disease. Here, we searched for loci involved in Aß plasma levels in a series of non-demented patients with hypertension in the Erasmus Rucphen Family study. Aß40 and Aß42 levels were determined in 125 subjects with severe hypertension. All patients were genotyped with a 6,000 single nucleotide polymorphisms (SNPs) illumina array designed for linkage analysis. We conducted linkage analysis of plasma Aß levels. None of the linkage analyses yielded genome-wide significant logarithm of odds (LOD) score over 3.3, but there was suggestive evidence for linkage (LOD > 1.9) for two regions: 1q41 (LOD = 2.07) and 11q14.3 (LOD = 2.97), both for Aß40. These regions were followed up with association analysis in the study subjects and in 320 subjects from a population-based cohort. For the Aß40 region on chromosome 1, association of several SNPs was observed at the presenilin 2 gene (PSEN2) (p = 2.58 × 10(-4) for rs6703170). On chromosome 11q14-21, we found some association (p = 3.1 × 10(-3) for rs2514299). This linkage study of plasma concentrations of Aß40 and Aß42 yielded two suggestive regions, of which one points toward a known locus for familial AD.

Interaction of insulin and PPAR-α genes in Alzheimer's disease: the Epistasis Project.

Altered glucose metabolism has been described in Alzheimer's disease (AD). We re-investigated the interaction of the insulin (INS) and the peroxisome proliferator-activated receptor alpha (PPARA) genes in AD risk in the Epistasis Project, including 1,757 AD cases and 6,294 controls. Allele frequencies of both SNPs (PPARA L162V, INS intron 0 A/T) differed between Northern Europeans and Northern Spanish. The PPARA 162LL genotype increased AD risk in Northern Europeans (p = 0.04), but not in Northern Spanish (p = 0.2). There was no association of the INS intron 0 TT genotype with AD. We observed an interaction on AD risk between PPARA 162LL and INS intron 0 TT genotypes in Northern Europeans (Synergy factor 2.5, p = 0.016), but not in Northern Spanish. We suggest that dysregulation of glucose metabolism contributes to the development of AD and might be due in part to genetic variations in INS and PPARA and their interaction especially in Northern Europeans.

[A drug induced deviation of the eyes: the oculogyric crisis]. / De oculogyre crisis.

An oculogyric crisis is a tonic conjugated deviation of the eyes, usually upward. We present two cases with a drug induced oculogyric crisis. The differential diagnoses should include epilepsy, a functional neurological movement disorder, ocular tics, ocular dyskinesia or ocular bobbing. Typically, in an oculogyric crisis the patient's awareness is intact; accompanied signs can be blepharospasm, neck flexion, jaw opening with or without tongue protrusion and autonomic symptoms. The underlying pathophysiology seems an imbalance between cholinergic and dopaminergic pathways. Most frequently an oculogyric crisis is caused by antidopaminergic medications, for example neuroleptics and metoclopramide. Treatment of medication-induced oculogyric crisis with parenteral anticholinergics typically leads to a fast remission of symptoms. Consider tocontinue anticholinergic therapy orally for a few days.

A multidisciplinary neuro-oncological triage panel reduces the time to referral and treatment for patients with a brain tumor.

BACKGROUND: Regional collaboration and appropriate referral management are crucial in neuro-oncological care. Lack of electronic access to medical records across health care organizations impedes interhospital consultation and may lead to incomplete and delayed referrals. To improve referral management, we have established a multidisciplinary neuro-oncological triage panel (NOTP) with digital image exchange and determined the effects on lead times, costs, and time investment. METHODS: A prospective cohort study was conducted from February 2019 to March 2020. All newly diagnosed patients referred to Brain Tumor Center Amsterdam were analyzed according to referral pathway: (1) standard referral (SR), (2) NOTP. The primary outcome was lead time, defined as time-to-referral, time-to-treatment, and total time (median days [interquartile range]). Secondary outcomes were costs and time investment. RESULTS: In total, 225 patients were included, of whom 153 had SR and 72 NOTP referral. Patients discussed in the NOTP were referred more frequently for first neurosurgical consultation (44.7% vs 28.8%) or combined neurological and neurosurgical consultation (12.8% vs 2.5%, P = .002). Time-to-referral was reduced for NOTP referral compared to SR (1 [0.25-4] vs 6 [1.5-10] days, P < .001). Total time decreased from 27 [14-48] days for the standard group to 15 [12-38.25] days for the NOTP group (P = .040). Costs and time investment were comparable for both groups. CONCLUSION: Implementation of digital referral to a multidisciplinary NOTP is feasible and leads to more swift patient-tailored referrals at comparable costs and time investment as SR. This quality improvement initiative has the potential to improve collaboration and coordination of multidisciplinary care in the field of neuro-oncology.

The dopamine ß-hydroxylase -1021C/T polymorphism is associated with the risk of Alzheimer's disease in the Epistasis Project.

BACKGROUND: The loss of noradrenergic neurones of the locus coeruleus is a major feature of Alzheimer's disease (AD). Dopamine ß-hydroxylase (DBH) catalyses the conversion of dopamine to noradrenaline. Interactions have been reported between the low-activity -1021T allele (rs1611115) of DBH and polymorphisms of the pro-inflammatory cytokine genes, IL1A and IL6, contributing to the risk of AD. We therefore examined the associations with AD of the DBH -1021T allele and of the above interactions in the Epistasis Project, with 1757 cases of AD and 6294 elderly controls. METHODS: We genotyped eight single nucleotide polymorphisms (SNPs) in the three genes, DBH, IL1A and IL6. We used logistic regression models and synergy factor analysis to examine potential interactions and associations with AD. RESULTS: We found that the presence of the -1021T allele was associated with AD: odds ratio = 1.2 (95% confidence interval: 1.06-1.4, p = 0.005). This association was nearly restricted to men < 75 years old: odds ratio = 2.2 (1.4-3.3, 0.0004). We also found an interaction between the presence of DBH -1021T and the -889TT genotype (rs1800587) of IL1A: synergy factor = 1.9 (1.2-3.1, 0.005). All these results were consistent between North Europe and North Spain. CONCLUSIONS: Extensive, previous evidence (reviewed here) indicates an important role for noradrenaline in the control of inflammation in the brain. Thus, the -1021T allele with presumed low activity may be associated with misregulation of inflammation, which could contribute to the onset of AD. We suggest that such misregulation is the predominant mechanism of the association we report here.

Cathepsin D (C224T) polymorphism in sporadic and genetic Creutzfeldt-Jakob disease.

Accumulation of cathepsin D immunoreactive lysosomes correlates with tissue pathology in sporadic Creutzfeldt-Jakob disease (CJD) brains. The C-to-T transition within exon 2 of the cathepsin D (CTSD) gene is associated with altered enzymatic activity. Possession of the TT genotype is a risk factor for variant CJD. To verify the association between the CTSD position 224T allele and the risk for and survival in sporadic and genetic CJD, we genotyped 540 sporadic, 101 genetic CJD, and 723 control individuals. Genotype data and duration of illness were compared using multiple logistic regression and Kruskal-Wallis test. Multivariate survival analysis was performed using Cox's regression model. The distribution of CTSD position 224 alleles was approximately the same in all groups. We observed a trend for shorter survival in sporadic CJD patients harboring the T allele at position 224 of the CTSD gene in particular in sporadic CJD patients with the prion protein gene position 129 MM genotype. We conclude that the CTSD position 224 polymorphism alone is not a significant risk or disease-modifying factor in sporadic or genetic CJD.

The Current Status of Immune Checkpoint Inhibitors in Neuro-Oncology: A Systematic Review.

The introduction of immune checkpoint inhibitors (ICI), as a novel treatment modality, has transformed the field of oncology with unprecedented successes. However, the efficacy of ICI for patients with glioblastoma or brain metastases (BMs) from any tumor type is under debate. Therefore, we systematically reviewed current literature on the use of ICI in patients with glioblastoma and BMs. Prospective and retrospective studies evaluating the efficacy and survival outcomes of ICI in patients with glioblastoma or BMs, and published between 2006 and November 2019, were considered. A total of 88 studies were identified (n = 8 in glioblastoma and n = 80 in BMs). In glioblastoma, median progression-free (PFS) and overall survival (OS) of all studies were 2.1 and 7.3 months, respectively. In patients with BMs, intracranial responses have been reported in studies with melanoma and non-small-cell lung cancer (NSCLC). The median intracranial and total PFS in these studies were 2.7 and 3.0 months, respectively. The median OS in all studies for patients with brain BMs was 8.0 months. To date, ICI demonstrate limited efficacy in patients with glioblastoma or BMs. Future research should focus on increasing the local and systemic immunological responses in these patients.

Replication by the Epistasis Project of the interaction between the genes for IL-6 and IL-10 in the risk of Alzheimer's disease.

BACKGROUND: Chronic inflammation is a characteristic of Alzheimer's disease (AD). An interaction associated with the risk of AD has been reported between polymorphisms in the regulatory regions of the genes for the pro-inflammatory cytokine, interleukin-6 (IL-6, gene: IL6), and the anti-inflammatory cytokine, interleukin-10 (IL-10, gene: IL10). METHODS: We examined this interaction in the Epistasis Project, a collaboration of 7 AD research groups, contributing DNA samples from 1,757 cases of AD and 6,295 controls. RESULTS: We replicated the interaction. For IL6 rs2069837 AA x IL10 rs1800871 CC, the synergy factor (SF) was 1.63 (95% confidence interval: 1.10-2.41, p = 0.01), controlling for centre, age, gender and apolipoprotein E epsilon4 (APOEepsilon4) genotype. Our results are consistent between North Europe (SF = 1.7, p = 0.03) and North Spain (SF = 2.0, p = 0.09). Further replication may require a meta-analysis. However, association due to linkage disequilibrium with other polymorphisms in the regulatory regions of these genes cannot be excluded. CONCLUSION: We suggest that dysregulation of both IL-6 and IL-10 in some elderly people, due in part to genetic variations in the two genes, contributes to the development of AD. Thus, inflammation facilitates the onset of sporadic AD.

Pathologically confirmed autoimmune encephalitis in suspected Creutzfeldt-Jakob disease.

OBJECTIVE: To determine the clinical features and presence in CSF of antineuronal antibodies in patients with pathologically proven autoimmune encephalitis derived from a cohort of patients with suspected Creutzfeldt-Jakob disease (CJD). METHODS: The Dutch Surveillance Centre for Prion Diseases performed 384 autopsies on patients with suspected CJD over a 14-year period (1998-2011). Clinical information was collected from treating physicians. Antineuronal antibodies were tested in CSF obtained postmortem by immunohistochemistry on fresh frozen rat brain sections, by Luminex assay for the presence of well-characterized onconeural antibodies, and by cell-based assays for antibodies against NMDAR, GABABR1/2, GABAAR GLUR1/2, LGI1, Caspr2, and DPPX. RESULTS: In 203 patients, a diagnosis of definite CJD was made, while in 181 a variety of other conditions were diagnosed, mainly neurodegenerative. In 22 of these 181, the neuropathologist diagnosed autoimmune encephalitis. One patient was excluded because of lack of clinical information. Inflammatory infiltrates were predominantly perivascular and consisted mainly of T cells. The predominant locations were basal ganglia and thalamus (90%) and temporal lobes and hippocampus (81%). In 6 patients (29%), antineuronal antibodies were detected in postmortem CSF, directed against Hu, NMDAR, GABABR1/2, Caspr2, and an unidentified synaptic antigen in 2. The most frequent symptoms were dementia (90%), gait disturbance (86%), cerebellar signs (67%), and neuropsychiatric symptoms (67%). Immunopathologic and clinical findings did not differ between autoantibody-negative patients and patients with antineuronal antibodies. CONCLUSIONS: It is important to consider immune-mediated disorders in the differential diagnosis of rapidly progressive neurologic deficits.

Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

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.

Plasma ß amyloid and the risk of Alzheimer's disease in Down syndrome.

Extracellular deposition of amyloid beta peptide (Aß) has been implicated as a critical step in the pathogenesis of Alzheimer's disease (AD). In Down syndrome (DS), Alzheimer's disease is assumed to be caused by the triplication and overexpression of the gene for amyloid precursor protein (APP), located on chromosome 21. Plasma concentrations of Aß1-40 and Aß1-42 were determined in a population based study of 506 persons with DS, who were screened annually for dementia. We used Cox proportional hazards models to determine the risk of dementia. Demented persons with DS have a significantly higher plasma Aß1-40 concentration than the nondemented (p = 0.05). Those with the highest concentrations of Aß1-40 and Aß1-42 have a higher risk to develop dementia. The risk to develop dementia during follow-up (mean 4.7 years) increased to 2.56 (95% confidence interval, 1.39-4.71) for Aß1-42 and 2.16 (95% confidence interval, 1.14-4.10) for Aß1-40. High plasma concentration of plasma Aß1-40 and Aß1-42 are determinants of the risk of dementia in persons with DS.

Human prion diseases in the Netherlands (1998-2009): clinical, genetic and molecular aspects.

Prion diseases are rare and fatal neurodegenerative disorders that can be sporadic, inherited or acquired by infection. Based on a national surveillance program in the Netherlands we describe here the clinical, neuropathological, genetic and molecular characteristics of 162 patients with neuropathologically confirmed prion disease over a 12-year period (1998-2009). Since 1998, there has been a relatively stable mortality of Creutzfeldt-Jakob disease (CJD) in the Netherlands, ranging from 0.63 to 1.53 per million inhabitants per annum. Genetic analysis of the codon 129 methionine/valine (M/V) polymorphism in all patients with sporadic CJD (sCJD) showed a trend for under-representation of VV cases (7.0%), compared with sCJD cohorts in other Western countries, whereas the MV genotype was relatively over-represented (22,4%). Combined PrP(Sc) and histopathological typing identified all sCJD subtypes known to date, except for the VV1 subtype. In particular, a "pure" phenotype was demonstrated in 60.1% of patients, whereas a mixed phenotype was detected in 39.9% of all sCJD cases. The relative excess of MV cases was largely accounted for by a relatively high incidence of the MV 2K subtype. Genetic analysis of the prion protein gene (PRNP) was performed in 161 patients and showed a mutation in 9 of them (5.6%), including one FFI and four GSS cases. Iatrogenic CJD was a rare phenomenon (3.1%), mainly associated with dura mater grafts. Three patients were diagnosed with new variant CJD (1.9%) and one with variably protease-sensitive prionopathy (VPSPr). Post-mortem examination revealed an alternative diagnosis in 156 patients, most commonly Alzheimer's disease (21.2%) or vascular causes of dementia (19.9%). The mortality rates of sCJD in the Netherlands are similar to those in other European countries, whereas iatrogenic and genetic cases are relatively rare. The unusual incidence of the VV2 sCJD subtype compared to that reported to date in other Western countries deserves further investigation.

Transferrin and HFE genes interact in Alzheimer's disease risk: the Epistasis Project.

Iron overload may contribute to the risk of Alzheimer's disease (AD). In the Epistasis Project, with 1757 cases of AD and 6295 controls, we studied 4 variants in 2 genes of iron metabolism: hemochromatosis (HFE) C282Y and H63D, and transferrin (TF) C2 and -2G/A. We replicated the reported interaction between HFE 282Y and TF C2 in the risk of AD: synergy factor, 1.75 (95% confidence interval, 1.1-2.8, p = 0.02) in Northern Europeans. The synergy factor was 3.1 (1.4-6.9; 0.007) in subjects with the APOEε4 allele. We found another interaction, between HFE 63HH and TF -2AA, markedly modified by age. Both interactions were found mainly or only in Northern Europeans. The interaction between HFE 282Y and TF C2 has now been replicated twice, in altogether 2313 cases of AD and 7065 controls, and has also been associated with increased iron load. We therefore suggest that iron overload may be a causative factor in the development of AD. Treatment for iron overload might thus be protective in some cases.

Interactions between PPAR-α and inflammation-related cytokine genes on the development of Alzheimer's disease, observed by the Epistasis Project.

OBJECTIVE: Neuroinflammation contributes to the pathogenesis of sporadic Alzheimer's disease (AD). Variations in genes relevant to inflammation may be candidate genes for AD risk. Whole-genome association studies have identified relevant new and known genes. Their combined effects do not explain 100% of the risk, genetic interactions may contribute. We investigated whether genes involved in inflammation, i.e. PPAR-α, interleukins (IL) IL- 1α, IL-1ß, IL-6, and IL-10 may interact to increase AD risk. METHODS: The Epistasis Project identifies interactions that affect the risk of AD. Genotyping of single nucleotide polymorphisms (SNPs) in PPARA, IL1A, IL1B, IL6 and IL10 was performed. Possible associations were analyzed by fitting logistic regression models with AD as outcome, controlling for centre, age, sex and presence of apolipoprotein ε4 allele (APOEε4). Adjusted synergy factors were derived from interaction terms (p<0.05 two-sided). RESULTS: We observed four significant interactions between different SNPs in PPARA and in interleukins IL1A, IL1B, IL10 that may affect AD risk. There were no significant interactions between PPARA and IL6. CONCLUSIONS: In addition to an association of the PPARA L162V polymorphism with the AD risk, we observed four significant interactions between SNPs in PPARA and SNPs in IL1A, IL1B and IL10 affecting AD risk. We prove that gene-gene interactions explain part of the heritability of AD and are to be considered when assessing the genetic risk. Necessary replications will require between 1450 and 2950 of both cases and controls, depending on the prevalence of the SNP, to have 80% power to detect the observed synergy factors.

Common variants at 12q14 and 12q24 are associated with hippocampal volume.

Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 × 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 × 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 × 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 × 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 × 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.

Association of HSP70 and its co-chaperones with Alzheimer's disease.

The heat shock protein (HSP) 70 family has been implicated in the pathology of Alzheimer's disease (AD). In this study, we examined common genetic variations in the 80 genes encoding HSP70 and its co-chaperones. We conducted a study in a series of 462 patients and 5238 unaffected participants derived from the Rotterdam Study, a population-based study including 7983 persons aged 55 years and older. We genotyped a total of 12,053 Single Nucleotide Polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. Replication was performed in two independent cohort studies, the Framingham Heart study (FHS; n = 806) and Cardiovascular Health Study (CHS; n = 2150). When adjusting for multiple testing, we found a small but consistent, though not significant effect of rs12118313 located 32 kb from PFDN2, with an OR of 1.19 (p-value from meta-analysis = 0.003). However this SNP was in the intron of another gene, suggesting it is unlikely this SNP reflects the effect of PFDN2. In a formal pathway analysis we found nominally significant evidence for an association of BAG, DNAJA and prefoldin with AD. These findings corroborate with those of a study of 2032 AD patients and 5328 controls, in which several members of the prefoldin family showed evidence for association to AD. Our study did not reveal evidence for a genetic variant if the HSP70 family with a major effect on AD. However, our findings of the single SNP analysis and pathway analysis suggest that multiple genetic variants in prefoldin are associated with AD.