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.

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.

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.

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.

Genome-wide association study of vascular dementia.

BACKGROUND AND PURPOSE: Most studies investigating the genetics of dementia have focused on Alzheimer disease, but little is known about the genetics of vascular dementia. The aim of our study was to identify new loci associated with vascular dementia. METHODS: We performed a genome-wide association study in the Rotterdam Study, a large prospective population-based cohort study in the Netherlands. We sought to replicate genome-wide significant loci in 2 independent replication samples. RESULTS: In the discovery analysis of 5700 dementia-free individuals, 67 patients developed incident vascular dementia over a mean follow-up time of 9.3 ± 3.2 years. We showed genome-wide significance for rs12007229, which is located on the X chromosome near the androgen receptor gene (OR, 3.7; 95% CI, 2.3-5.8, per copy of the minor allele; P=1.3 × 10(-8)). This association was further confirmed in 2 independent populations (probability value of combined replication samples=0.024). CONCLUSIONS: Our study shows a novel genetic locus for vascular dementia on the X chromosome. Further replication of this finding is required.

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.

Alterations of cholesterol precursor levels in Alzheimer's disease.

Cerebral and extracerebral cholesterol metabolism are altered in Alzheimer's disease (AD) as indicated by reduced plasma levels of the cholesterol elimination products 24S-hydroxycholesterol, which is of cerebral origin, and of 27-hydroxycholesterol, which is formed extracerebrally. However, it has to be evaluated, if changes of cholesterol metabolism in the whole body or in the CNS are exclusively due to the altered elimination of cholesterol or are also due to altered de novo synthesis in AD. We investigated CSF and plasma levels of cholesterol and of its precursors lanosterol, lathosterol and desmosterol in AD patients and non-demented controls. We found CSF levels of cholesterol (p=0.011), absolute levels of all investigated cholesterol precursors (each p<0.001) and ratios of cholesterol precursors/cholesterol (each <0.01) to be lower in AD patients as compared to controls. In plasma, the absolute levels of lanosterol (p=0.026) and lathosterol (p<0.001) and the ratio of lathosterol/cholesterol (p=0.002) but none of the other investigated parameters were reduced in AD patients (p>0.1). Furthermore, ratios of desmosterol/lathosterol in CSF (p=0.023) and plasma (p=0.009) were higher in AD patients as compared to controls. Our data support the hypothesis that cholesterol metabolism is altered in AD and further suggest that especially cholesterol de novo synthesis within the CNS of AD patients might be reduced. These findings raise doubt on a beneficial effect of cholesterol lowering treatment in manifest AD.

Functional neuroanatomy of sustained memory encoding performance in healthy aging and in Alzheimer's disease.

The aim of our study was to examine brain networks involved with sustaining memory encoding performance in healthy aging and in Alzheimer's disease (AD). Since different brain regions are affected by degradation in these two conditions, it might be conceivable that different compensation mechanisms occur to keep up memory performance in aging and in AD. Using an event-related functional magnetic resonance imaging (FMRI) design and a correlation analysis, 8 patients suffering from AD and 29 elderly control subjects were scanned while they studied a list of words for a subsequent memory test. Individual performance was assessed on the basis of a subsequent recognition test, and brain regions were identified where functional activations during study correlated with memory performance. In both groups, successful memory encoding performance was significantly correlated with the activation of the right frontal cortex. Furthermore, in healthy controls, there was a significant correlation of memory performance and the activation of the left medial and lateral temporal lobe. In contrast, in AD patients, increasing memory performance goes along with increasing activation of the hippocampus and a bilateral brain network including the frontal and temporal cortices. Our data show that in healthy aging and in AD, common and distinct compensatory mechanisms are employed to keep up a certain level of memory performance. Both in healthy aging and in patients with AD, an increased level of monitoring and control processes mediated by the (right) frontal lobe seems to be necessary to maintain a certain level of memory performance. In addition, memory performance in healthy older subjects seems to rely on an increased effort in encoding item-specific semantic and contextual information in lateral areas of the (left) temporal lobe. In AD patients, on the other hand, the maintenance of memory performance is related to an increase of activation of the (left) hippocampus in conjunction with a bilateral network of cortical areas that might be involved with phonological and visual rehearsal of the incoming information.

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.

RXRA gene variations influence Alzheimer's disease risk and cholesterol metabolism.

Cholesterol metabolism is altered in Alzheimer's disease (AD). The nuclear hormone receptor Retinoic X Receptor a (RXRa) is a member of the nuclear ligand-activated transcription factor family. RXRs are key regulators of cholesterol synthesis and thus cholesterol metabolism. We performed a systematic screen for gene variants in the RXRA gene. The effect of these gene variants on the risk of AD was investigated in 405 AD patients (mean age: 74.27 +/- 9.37 years; female 78.6%) and 347 controls (mean age: 73.26 +/- 8.37 years; female 57.2%). Furthermore, the influence of RXRA gene variants on CSF and plasma levels of cholesterol, lathosterol and 24S-hydroxycholesterol were evaluated. One of the identified seven SNPs in RXRA influenced AD risk in our single marker analysis (rs3132293: P= 0.006). Haplotype analysis identified a three-marker haplotype (TGC) consisting of rs3118570, rs1536475 and rs3132293, which decreased the risk of AD (P= 0.009). The single marker rs3132293 (P= 0.026) and the TGC haplotype (P= 0.026) influenced CSF lathosterol levels in non-demented controls, and cholesterol levels in the combined sample comprising AD patients and controls (Rs3132293: P= 0.050; TGC haplotype: P= 0.035). 24S-Hydroxycholesterol CSF and plasma levels were also influenced by rs3132293 (CSF: P= 0.004; plasma: P= 0.001) and the TGC haplotype (CSF: P= 0.004; plasma: P= 0.002); this effect was most pronounced in AD patients (rs3132293: CSF: P= 0.009, plasma: P= 0.002; TGC haplotype: CSF: P= 0.019, plasma: P= 0.005). Our results suggest that RXRA gene variants might act as risk factor for AD via an influence on cerebral cholesterol metabolism.

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.

Association of the PPARgamma gene polymorphism Pro12Ala with delayed onset of multiple sclerosis.

PPARs belong to a receptor family of ligand-activated transcription factors involved in the regulation of inflammation. A crucial role both for PPARgamma and for PPARalpha for the regulation of autoimmunity has been clearly demonstrated, as receptor agonists had beneficial effects on several CD4(+) T cell mediated autoimmune diseases including experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. We investigated the association of two common single nucleotide polymorphisms in the PPARA (Leu162Val) and the PPARG (Pro12Ala) genes in 116 patients with clinically definite multiple sclerosis (MS) and 211 age-matched healthy controls. The Ala allele of the PPARG Pro12Ala polymorphism was strongly associated with delayed disease onset (44.1+/-5.3 years vs 34.5+/-4.2 years; p=0.006). No significant differences were found in genotype distributions and allele frequencies of the PPARA Leu162Val and the PPARG Pro12Ala polymorphisms between MS patients and healthy controls, respectively. Our population-based study demonstrates that the Pro12Ala polymorphism resulting in an amino acid exchange in the N-terminal sequence of PPARgamma may influence the onset of MS.

CYP46A1 variants influence Alzheimer's disease risk and brain cholesterol metabolism.

BACKGROUND: Cholesterol 24S-hydroxylase (CYP46) catalyzes the conversion of cholesterol to 24S-hydroxycholesterol, the primary cerebral cholesterol elimination product. Only few gene variations in CYP46 gene (CYP46A1) have been investigated for their relevance as genetic risk factors of Alzheimer's disease (AD) and results are contradictory. METHODS: We performed a gene variability screening in CYP46A1 and investigated the effect of gene variants on the risk of AD and on CSF levels of cholesterol and 24S-hydroxycholesterol. RESULTS: Two of the identified 16 SNPs in CYP46A1 influenced AD risk in our study (rs7157609: p=0.016; rs4900442: p=0.019). The interaction term of both SNPs was also associated with an increased risk of AD (p=0.006). Haplotypes including both SNPs were calculated and haplotype G-C was identified to influence the risk of AD (p=0.005). AD patients and non-demented controls, who were carriers of the G-C haplotype, presented with reduced CSF levels of 24S-hydroxycholesterol (p=0.001) and cholesterol (p<0.001). CONCLUSION: Our results suggest that CYP46A1 gene variations might act as risk factor for AD via an influence on brain cholesterol metabolism.

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.

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.

CETP polymorphisms influence cholesterol metabolism but not Alzheimer's disease risk.

Cholesteryl ester transfer protein (CETP) is a component of the high density lipoprotein (HDL). Variations in the CETP gene may cause CETP deficiency, which is characterized by decreased mass and activity of the protein as well as altered HDL and LDL levels. We investigated the effect of three putative functional CETP polymorphisms (-1946 VNTR, C-629A and I405V) on the risk of Alzheimer's disease (AD) and on cholesterol, lathosterol and 24S-hydroxycholesterol levels in CSF and plasma of AD patients and controls. None of the investigated CETP polymorphisms or haplotypes had any effect on the risk of AD. However, we found that a three marker CETP haplotype (L/C/V) influenced CSF levels of lathosterol and 24S-hydroxycholesterol as well as plasma levels of total cholesterol in controls but not in AD patients. Our data suggest that CETP gene variations influence cerebral and peripheral cholesterol metabolism, but not AD risk.