Analysis of complement system and its related factors in Alzheimer's disease.

Alzheimer's disease (AD) is a primary cause of dementia. The complement system is closely related to AD pathology and may be a potential target for the prevention and treatment of AD. In our study, we conducted a bioinformatics analysis to analyze the role of the complement system and its related factors in AD using Gene Expression Omnibus (GEO) data. We also conducted a functional analysis. Our study verified that 23 genes were closely related to differentially expressed complement system genes in diseases after intersecting the disease-related complement system module genes and differentially expressed genes. The STRING database was used to predict the interactions between the modular gene proteins of the differential complement system. A total of 21 gene proteins and 44 interaction pairs showed close interactions. We screened key genes and created a diagnostic model. The predictive effect of the model was constructed using GSE5281 and our study indicated that the predictive effect of the model was good. Our study also showed enriched negative regulation of Notch signaling, cytokine secretion involved in the immune response pathway, and cytokine secretion involved in immune response hormone-mediated apoptotic signaling pathway. We hope that our study provides a promising target to prevent and delay the onset, diagnosis, and treatment of AD.

MicroRNA-125a-3p Modulate Amyloid ß-Protein through the MAPK Pathway in Alzheimer's Disease.

BACKGROUND: MicroRNA (miR)-125a-3p is reported to play an important role in some central nervous system diseases, such as Alzheimer's disease (AD). However, a study has not been conducted on the mechanism of miR-125a-3p in the pathological process of AD. METHODS: First, we assessed the expression of miR-125a-3p in AD cohort. Subsequently, we altered the expressions of miR-125a-3p to assess its role in cell viability, cell apoptosis, amyloid-ß (Aß) metabolism, and synaptic activity. Finally, we identified its potential mechanism underlying AD pathology. RESULTS: This study unveiled the potential function of miR-125a-3p through modulating amyloid precursor protein processing. Additionally, miR-125a-3p influenced cell survival and activated synaptic expression through the modulation of Aß metabolism in the mitogen-activated protein kinase (MAPK) pathway via fibroblast growth factor receptor 2. CONCLUSION: Our study indicates that targeting miR-125a-3p may be an applicable therapy for AD in the future. However, more in vitro and in vivo studies with more samples are needed to confirm these results.

Morphological and Structural Network Analysis of Sporadic Alzheimer's Disease Brains Based on the APOE4 Gene.

BACKGROUND: Alzheimer's disease (AD) is an increasingly common type of dementia. Apolipoprotein E (APOE) gene is a strong risk factor for AD. OBJECTIVE: Here, we explored alterations in grey matter structure (GMV) and networks in AD, as well as the effects of the APOEɛ4 allele on neuroimaging regions based on structural magnetic resonance imaging (sMRI). METHODS: All subjects underwent an sMRI scan. GMV and cortical thickness were calculated using voxel-based morphological analysis, and structural networks were constructed based on graph theory analysis to compare differences between AD and normal controls. RESULTS: The volumes of grey matter in the bilateral inferior temporal gyrus, right middle temporal gyrus, right inferior parietal lobule, right limbic lobe, right frontal lobe, left anterior cingulate gyrus, and bilateral olfactory cortex of patients with AD were significantly decreased. The cortical thickness in patients with AD was significantly reduced in the left lateral occipital lobe, inferior parietal lobe, orbitofrontal region, precuneus, superior parietal gyrus, right precentral gyrus, middle temporal gyrus, pars opercularis gyrus, insular gyrus, superior marginal gyrus, bilateral fusiform gyrus, and superior frontal gyrus. In terms of local properties, there were significant differences between the AD and control groups in these areas, including the right bank, right temporalis pole, bilateral middle temporal gyrus, right transverse temporal gyrus, left postcentral gyrus, and left parahippocampal gyrus. CONCLUSION: There were significant differences in the morphological and structural covariate networks between AD patients and healthy controls under APOEɛ4 allele effects.

A review of autophagy mechanism of statins in the potential therapy of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegeneration csharacterized by amyloid-ß (Aß) deposition and abnormally phosphorylated Tau protein aggregation. Autophagy, as an important cellular metabolic activity, is closely related to the production, secretion and clearance of Aß peptide and Tau phosphorylation level. Therefore, autophagy may become a potential target for AD treatment. A large number of molecules are involved in the mammalian target of rapamycin (mTOR)-dependent or mTOR-independent pathway of autophagy. More and more evidences show that statins can intervene autophagy by regulating the activity or expression level of autophagy-related proteins and genes. On the one hand, statins can induce autophagy through Sirtuin1 (SIRT1), P21, nuclear P53 and adenylate activated protein kinase (AMPK). On the other hand, statins inhibit the mevalonate metabolism pathway, thereby interfering with the prenylation of small GTPases, leading to autophagy dysfunction. Statins can also reduce the levels of LAMP2 and dynein, destroying autophagy. In this review, we focused on the role of autophagy in AD and the autophagy mechanism of statins in the potential treatment of AD.

Crry silencing alleviates Alzheimer's disease injury by regulating neuroinflammatory cytokines and the complement system.

Complement component (3b/4b) receptor 1 (CR1) expression is positively related to the abundance of phosphorylated microtubule-associated protein tau (tau), and CR1 expression is associated with susceptibility to Alzheimer's disease. However, the exact role of CR1 in tau protein-associated neurodegenerative diseases is unknown. In this study, we show that the mouse Cr1-related protein Y (Crry) gene, Crry, is localized to microglia. We also found that Crry protein expression in the hippocampus and cortex was significantly elevated in P301S mice (a mouse model widely used for investigating tau pathology) compared with that in wild-type mice. Tau protein phosphorylation (at serine 202, threonine 205, threonine 231, and serine 262) and expression of the major tau kinases glycogen synthase kinase-3 beta and cyclin-dependent-like kinase 5 were greater in P301S mice than in wild-type mice. Crry silencing by lentivirus-transfected short hairpin RNA led to greatly reduced tau phosphorylation and glycogen synthase kinase-3 beta and cyclin-dependent-like kinase 5 activity. Crry silencing reduced neuronal apoptosis and rescued cognitive impairment of P301S mice. Crry silencing also reduced the levels of the neuroinflammatory factors interleukin-1 beta, tumor necrosis factor alpha, and interleukin-6 and the complement components complement 3 and complement component 3b. Our results suggest that Crry silencing in the P301S mouse model reduces tau protein phosphorylation by reducing the levels of neuroinflammation and complement components, thereby improving cognitive function.

Explore the role of CR1 genetic variants in late-onset Alzheimer's disease susceptibility.

BACKGROUND: Complement component (3b/4b) receptor 1 (CR1) is an interesting candidate gene which has a close connection with Alzheimer's disease, and its polymorphisms have been reported to link to the late-onset Alzheimer's disease (LOAD) susceptibility. However, the findings of these related studies are inconsistent. Objective To explore the effect of CR1 genetic variants in LOAD susceptibility. MethodsWe searched relevant studies for the period up to 1 November 2020. And odds ratios (ORs) and their 95% confidence intervals (CIs) were utilized to assess the strength of the association. In addition, we carried out a case-control association study to assess their genetic association. RESULTS: Finally, a total of 30 articles with 30108 LOAD cases and 37895 controls were included. Significant allele frequency between LOAD patients and controls was observed in rs3818361 and rs6656401 (rs3818361, T vs. C: OR,1.18; 95% CI, 1.13-1.23; rs6656401, A vs. G: OR, 1.23; 95% CI, 1.10-1.36). Moreover, these results remain significant in subgroup of rs3818361 in Asia or America (OR,1.26; 95% CI,1.06-1.45; OR, 1.18; 95% CI, 1.13-1.24, respectively) and rs6656401 in Europe (OR = 1.26; 95% CI, 1.09-1.42). In addition, the two single nucleotide polymorphisms were proved to significantly increase LOAD risk in the overall population under the dominant model (OR = 1.12; 95% CI, 1.02-1.21; OR = 1.18, 95% CI, 1.15-1.22, respectively). Our case-control study showed that the distribution of rs6656401 genotype was significant (P = 0.000; OR, 6.889; 95% CI, 2.709-17.520), suggesting the A allele of rs6656401 is the risk allele. CONCLUSION: These available data indicate that rs6656401 in CR1 is significant to increase LOAD risk.

Analysis of Serum miRNAs in Alzheimer's Disease.

This paper was aimed to analyze the microRNA (miRNA) signatures in Alzheimer disease (AD) and find the significant expressions of miRNAs, their target genes, the functional enrichment analysis of the confirmed genes, and potential drug treatment. The miRNA expression information of the gene expression profile data was downloaded from the Gene Expression Omnibus database. The total data sample size is 1309, including 1021 AD samples and 288 normal samples. A total of 21 differentially expressed miRNAs were obtained, of which 16 (hsa-miR-6761-3p, hsa-miR-6747-3p, hsa-miR-6875-3p, hsa-miR-6754-3p, hsa-miR-6736-3p, hsa-miR-6762-3p, hsa-miR-6787-3p, hsa-miR-208a-5p, hsa-miR-6740-3p, hsa-miR-6778-3p, hsa-miR-595, hsa-miR-6753-3p, hsa-miR-4747-3p, hsa-miR-3646, hsa-miR-6716-3p and hsa-miR-4435) were up-regulated and 5 (hsa-miR-125a-3p, hsa-miR-22-3p, hsa-miR-24-3p, hsa-miR-6131 and hsa-miR-125b-1-3p) were down-regulated in AD. A total of 6 miRNAs (hsa-miR-595, hsa-miR-3646, hsa-miR-4435 hsa-miR-125a-3p, hsa-miR-22-3p and hsa-miR-24-3p) and 78 miRNA-disease-related gene sub-networks were predicted, and 116 ceRNA regulatory relationship pairs, and the ceRNA regulatory network were obtained. The results of enrichment analysis suggested that the main target pathways of several miRNAs differentially expressed in AD were mitogen-activated protein kinase signal pathway. According to the prediction results of Drug-Gene Interaction database 2.0, we obtained 53 pairs of drug-gene interaction, including 7 genes (PTGS2, EGFR, CALM1, PDE4D, FGFR2, HMGCR, cdk6) and 53 drugs. We hope our results are helpful to find a viable way to prevent, delay the onset, diagnose, and treat AD.

Impacts of CR1 genetic variants on cerebrospinal fluid and neuroimaging biomarkers in alzheimer's disease.

BACKGROUND: The complement component (3b/4b) receptor 1 gene (CR1) gene has been proved to affect the susceptibility of Alzheimer's disease (AD) in different ethnic and districts groups. However, the effect of CR1 genetic variants on amyloid ß (Aß) metabolism of AD human is still unclear. Hence, the aim of this study was to investigate genetic influences of CR1 gene on Aß metabolism. METHODS: All data of AD patients and normal controls (NC) were obtained from alzheimer's disease neuroimaging initiative database (ADNI) database. In order to assess the effect of each single nucleotide polymorphism (SNP) of CR1 on Aß metabolism, the PLINK software was used to conduct the quality control procedures to enroll appropriate SNPs. Moreover, the correlation between CR1 genotypes and Aß metabolism in all participants were estimated with multiple linear regression models. RESULTS: After quality control procedures, a total of 329 samples and 83 SNPs were enrolled in our study. Moreover, our results identified five SNPs (rs10494884, rs11118322, rs1323721, rs17259045 and rs41308433), which were linked to Aß accumulation in brain. In further analyses, rs17259045 was found to decrease Aß accumulation among AD patients. Additionally, our study revealed the genetic variants in rs12567945 could increase CSF Aß42 in NC population. CONCLUSIONS: Our study had revealed several novel SNPs in CR1 genes which might be involved in the progression of AD via regulating Aß accumulation. These findings will provide a new basis for the diagnosis and treatment AD.

Overview the effect of statin therapy on dementia risk, cognitive changes and its pathologic change: a systematic review and meta-analysis.

BACKGROUND: Many studies have reported on the role of statin therapy in dementia, but its efficacy remains controversial. We aimed to search for reliable and meaningful articles to assess the efficacy of statin therapy for dementia risk, cognitive items, and pathologic markers. METHODS: Related literature for this study was published in the period from January 1, 1987 to January 1, 2018. Odds ratio (OR) and 95% confidence interval (95% CI) estimates were pooled in either fixed or random effects models. RESULTS: A total of 23 relevant studies were included after the application of the search strategy. The pooled results showed that statin therapy would downregulate dementia risk according to an analysis of 1,314,431 dementia patients and 1,836,539 healthy controls (OR: 0.64, 95% CI: 0.50, 0.81). In addition, specific changes in mini-mental state examination (MMSE) score were observed in individuals with dementia with statin therapy (OR: 0.46, 95% CI: 0.17, 0.74). However, the results of this meta-analysis showed that statin therapy did not significantly modify the Alzheimer's Disease Assessment Scale (ADAS-cog) score (OR: -0.26, 95% CI: -1.13, 0.62). No significant association was found between statin therapy and activities of daily living performance (OR: -0.69, 95% CI: -4.12, 2.74). When investigating pathological markers, our results indicated a significant influence of statin therapy on plasma amyloid ß40 (Aß40) (OR: 9.27, 95% CI: 0.71, 17.84), plasma Aß42 (OR: 2.60, 95% CI: 1.07, 4.13), plasma low-density lipoprotein (LDL) cholesterol (OR: -16.95, 95% CI: -25.54, -8.37), plasma lathosterol (OR: -0.11, 95% CI: -0.14, -0.07), plasma 24s-hydroxycholesterol (OR: -10.41, 95% CI: -15.57, -5.25), and cerebrospinal fluid (CSF) lathosterol (OR: -0.07, 95% CI: -0.12, -0.01). CONCLUSIONS: The available data indicate that statin therapy may reduce dementia risk, altering cognitive items and pathologic markers.

A Missense Variant in TREML2 Reduces Risk of Alzheimer's Disease in a Han Chinese Population.

Recently, Benitez and colleagues re-analyzed whole-exome sequencing data and revealed that a coding missense variant (rs3747742-C) in triggering receptor expressed on myeloid cells-like 2 (TREML2) gene reduced late-onset Alzheimer's disease (LOAD) risk in Caucasians. To date, no study was carried out to test this association in other ethnic groups and populations, including Han Chinese. Therefore, the aim of the current study was to validate the relation between rs3747742 and LOAD susceptibility in a large Han Chinese population including 992 LOAD patients and 1358 healthy controls. In the total sample, the minor (C) allele of rs3747742 was associated with a reduced LOAD risk under the recessive genetic model after Bonferroni correction (odds ratio (OR) = 0.713; 95 % confidence interval (CI): 0.546-0.932; P = 0.013, Bonferroni-corrected P = 0.039). Interestingly, after stratifying data according to apolipoprotein E (APOE) ε4 status, we revealed that this protection only exists in APOE ε4 carriers (recessive genetic model, OR = 0.448; 95 % CI: 0.262-0.765; P = 0.003, Bonferroni-corrected P = 0.009) in our cohort. Taken together, our findings support rs3747742-C as a protective factor for LOAD, especially in APOE ε4 carriers.

Association of Parkinson's Disease GWAS-Linked Loci with Alzheimer's Disease in Han Chinese.

Alzheimer's disease (AD) and Parkinson's disease (PD) have overlapping pathological mechanisms and genetic background, suggesting it would be meaningful to replicate PD-related genetic variants in AD population to identify new loci of AD. Here, in order to discover potential AD-related loci, we investigated the association between late-onset AD (LOAD) susceptibility and nine single-nucleotide polymorphisms (SNPs) (rs11724635 of BST1, rs12637471 of MCCC1, rs15553999 of TMEM229, rs17649553 of MAPT, rs34311866 of TMEM175-GAK-DGKQ, rs356182 of SNCA, rs6430538 of ACMSD-TMEM163, rs76904798 of LRRK2 and rs823118 of RAB7L1-NUCKS1) which were reported to have genome-wide significant associations with PD risk in a recent Genome Wide Association Study performed among white population. We included 2350 samples comprising with 992 sporadic LOAD patients and 1358 gender- and age-matched control subjects who were unrelated northern Han Chinese residents. Finally, among these included genetic variants, only rs76904798 of LRRK2 was proved to significantly reduce LOAD risk in a multivariate analysis in a dominant model after adjusting for age, sex, and apolipoprotein E (APOE) ε4 status (OR = 0.616; 95 % CI 0.446-0.849; Bonferroni corrected P = 0.027). In addition, when these data were stratified by APOE ε4 status, rs76904798 was still evident among subjects without APOE ε4 allele. Our results first time indicated rs76904798 of LRRK2 is also a common risk genetic variant for LOAD susceptibility in a northern Han Chinese people.

Effect of CR1 Genetic Variants on Cerebrospinal Fluid and Neuroimaging Biomarkers in Healthy, Mild Cognitive Impairment and Alzheimer's Disease Cohorts.

The complement component (3b/4b) receptor 1 gene (CR1) is considered as one of the most important genetic susceptibility loci in Alzheimer's disease (AD). However, to date, few studies were performed to discover the possible effect of CR1 genetic variants on AD pathology in the brain. Here, we evaluated the potential role of CR1 common variants in AD-related pathology by assessing neuroimaging biomarkers and cerebrospinal fluid (CSF) proteins. Finally, a total of 812 subjects from the Alzheimer's disease Neuroimaging Initiative database and eight single nucleotide polymorphisms (SNPs) after quality control procedures are enrolled in our analysis. After applied to multiple linear regression models, significant associations were proved to exist between rs4844609 and amyloid deposition in cingulated, frontal, parietal, and temporal on florbetapir 18F amyloid positron emission tomography. In the analysis of the impacts of CR1 genetic variants on brain structures, three SNPs (rs12034383, rs3737002, and rs6691117) were significantly linked to the changes in volume of middle temporal. In addition, rs10779339 showed a negative connection with the cerebral metabolism rate of glucose in the right temporal on 18F-fluorodeoxyglucose PET imaging. However, no significant statistical findings were detected between CR1 genetic variants and CSF proteins (amyloid ß, total-tau, and p-tau) at baseline diagnose or in the follow-up study of 2 years. The results of our study indicated that CR1 plays a vital role in AD pathology mainly by influencing Aß deposition, brain structure, and glucose metabolism during AD progression.

Cerebral Microinfarcts and Dementia: A Systematic Review and Metaanalysis.

OBJECTIVE: To systematically review the relationship between the cerebral microinfarcts and dementia. METHODS: We conducted a systematic review and meta-analyses using the MEDLINE, EMBASE，the Cochrane library, and BIOSIS preview for studies published in the period from January 1st, 1997 to April 1st, 2014. We also searched the reference lists of relevant studies and review articles. Studies had to be controlled, with participants divided into a dementia group and a control group. Experimental participants included must be demented individuals with dementia syndromes (dementia overall, AD, and vascular dementia (VaD)). Outcome measures should include the presence of microinfarcts lesions. The effect size was estimated as odds ratio (OR) with 95% confidence intervals (CIs). Heterogeneity was assessed using Cochran's Q-test and I2-statistic. RESULTS: We pooled data from 12 studies, including 2181 people. Cerebral microinfarcts were significantly associated with dementia in random effects model [the odds ratios (OR) 2.15, 95% confidence interval (95% CI) 1.46-3.15, P=0.0008]. There was no evidence of an association between the microinfarcts and Alzheimer's disease (AD) in random effects model (OR 2.81, 95% CI 0.94-8.42, P=0.06). CONCLUSION: These results suggest that cerebral microinfarcts are significantly associated with dementia. Whether cerebral microinfarcts are associated with AD needs to be further investigated.

TREM2 Overexpression has No Improvement on Neuropathology and Cognitive Impairment in Aging APPswe/PS1dE9 Mice.

Previously, we showed that overexpression of triggering receptor expressed on myeloid cells 2 (TREM2), a microglia-specific immune receptor, in the brain of a middle-aged (7 months old) APPswe/PS1dE9 mice could ameliorate Alzheimer's disease (AD)-related neuropathology by enhancement of microglial amyloid-ß (Aß) phagocytosis. Since AD is an age-related neurodegenerative disorder, it is critical to assess the efficacy of TREM2 overexpression in aging animals with an advanced disease stage. In vivo, we employed a lentiviral strategy to overexpress TREM2 in the brain of aging (18 months old) APPswe/PS1dE9 mice, and observed its efficacy on AD-related neuropathology and cognitive functions. Afterwards, we directly isolated microglia from middle-aged and aging APPswe/PS1dE9 mice and determined effects of TREM2 overexpression on microglial Aß phagocytosis and Aß-binding receptors expression in vitro. In aging APPswe/PS1dE9 mice, TREM2 overexpression has no beneficial effect on AD-related neuropathology and spatial cognitive functions. Of note, in vitro experiments showed a significant reduction of Aß phagocytosis in microglia from aging APPswe/PS1dE9 mice, possibly attributing to the declined expression of Aß-binding receptors. Meanwhile, this phagocytic deficit in microglia from aging APPswe/PS1dE9 mice cannot be rescued by TREM2 overexpression. Taken together, our study shows that TREM2 overexpression fails to provide neuroprotection in aging APPswe/PS1dE9 mice, possibly attributing to deficits in microglial Aß phagocytosis at the late-stage of disease progression. These findings indicate that TREM2-mediated protection in AD is at least partially dependent on the reservation of microglial phagocytic functions, emphasizing the importance of early therapeutic interventions for this devastating disease.

GWAS-Linked Loci and Neuroimaging Measures in Alzheimer's Disease.

Recently, 19 susceptibility loci for Alzheimer's disease (AD) had been identified through AD genome-wide association studies (GWAS) meta-analysis. However, how they influence the pathogenesis of AD still remains largely unknown. We studied those loci with six MRI measures, abnormal glucose metabolism, and ß-amyloid (Aß) deposition on neuroimaging in a large cohort from Alzheimer's Disease Neuroimaging Initiative (ADNI) database in order to provide clues of the mechanisms through which these genetic variants might be acting. As a result, single nucleotide polymorphisms (SNPs) at rs983392 within MS4A6A and rs11218343 within SOLR1 were both associated with the percentage of increase in the volume of left inferior temporal regions in the follow-up study. Meanwhile, rs11218343 at SORL1 and rs6733839 at BIN1 was associated with rate of volume change of left parahippocampal and right inferior parietal, respectively. Moreover, rs6656401 at CR1 and rs983392 at MS4A6A were both associated with smaller volume of right middle temporal at baseline. However, in addition to the APOE locus, we did not detect any influence on glucose metabolism and Aß deposition. APOE ε4 allele was associated with almost all measures. Altogether, five loci (rs6656401 at CR1, rs983392within MS4A6A, rs11218343 at SORL1, rs6733839 at BIN1, and APOE ε4) have been detected to be associated with one or a few established AD-related neuroimaging measures.

TREM1 facilitates microglial phagocytosis of amyloid beta.

As the most common type of neurodegenerative disease, Alzheimer's disease (AD) is characterized by the accumulation of amyloid-ß peptide (Aß) within the brain. Triggering receptor expressed on myeloid cells (TREM) 1 is an immune receptor expressed by mononuclear phagocytes including monocytes and microglia, coupling with TYRO protein tyrosine kinase binding protein to regulate immune reactions. Emerging evidence indicates that rs6910730G, an intronic variant of TREM1, is associated with an increased Aß neuropathology in the brains of elderly subjects, but the underlying mechanisms remain unclear. Here, using two independent cohorts of healthy individuals, we provided evidence that rs6910730G reduced the ability of human monocytes for Aß phagocytosis, and this reduction was likely attributed to a decreased monocytic TREM1 expression. By knockdown and overexpression of Trem1 in mouse primary microglia, we showed that TREM1 facilitated microglial phagocytosis of Aß. In support of this finding, knockdown of Trem1 in the brains of APP/PSEN1 mice increased Aß1-42 levels and total amyloid burden, whereas selective overexpression of Trem1 on microglia or activation of Trem1 signaling by an agonistic antibody ameliorated Aß neuropathology and rescued AD-related spatial cognitive impairments. Altogether, these findings uncover the role of TREM1 in microglial Aß clearance, and establish TREM1 as a potential therapeutic target for AD.

Lack of Association Between SLC24A4 Polymorphism and Late-onset Alzheimer's Disease in Han Chinese.

Recently, a single nucleotide polymorphism rs10498633 on solute carrier family 24 member 4 (SLC24A4) was revealed to be closely related to the risk of late-onset Alzheimer`s disease (LOAD) in a large genome-wide association study containing 74046 individuals in Caucasians. However, no study was performed to validate this relation in other ethnic populations, including Han Chinese. Therefore, we recruited 992 LOAD patients and 1358 age- and sex- matched healthy controls to validate the association between rs10498633 and LOAD susceptibility in Han Chinese. In our total sample, no significant difference was observed between the minor (T) allele of rs10498633 and LOAD risk under a dominant genetic model (OR=0.903, 95% CI: 0.738-1.104, P=0.320). In addition, no significant relation was noted between rs10498633 and LOAD risk in neither apolipoprotein E (APOE) ε4 carriers nor non-carriers after adjusting for age and gender. Therefore, our findings indicate that rs10498633 may not play a major role in LOAD susceptibility in Han Chinese.

Effect of CLU genetic variants on cerebrospinal fluid and neuroimaging markers in healthy, mild cognitive impairment and Alzheimer's disease cohorts.

The Clusterin (CLU) gene, also known as apolipoprotein J (ApoJ), is currently the third most associated late-onset Alzheimer's disease (LOAD) risk gene. However, little was known about the possible effect of CLU genetic variants on AD pathology in brain. Here, we evaluated the interaction between 7 CLU SNPs (covering 95% of genetic variations) and the role of CLU in ß-amyloid (Aß) deposition, AD-related structure atrophy, abnormal glucose metabolism on neuroimaging and CSF markers to clarify the possible approach by that CLU impacts AD. Finally, four loci (rs11136000, rs1532278, rs2279590, rs7982) showed significant associations with the Aß deposition at the baseline level while genotypes of rs9331888 (P = 0.042) increased Aß deposition. Besides, rs9331888 was significantly associated with baseline volume of left hippocampus (P = 0.014). We then further validated the association with Aß deposition in the AD, mild cognitive impairment (MCI), normal control (NC) sub-groups. The results in sub-groups confirmed the association between CLU genotypes and Aß deposition further. Our findings revealed that CLU genotypes could probably modulate the cerebral the Aß loads on imaging and volume of hippocampus. These findings raise the possibility that the biological effects of CLU may be relatively confined to neuroimaging trait and hence may offer clues to AD.

A rare coding variant in TREM2 increases risk for Alzheimer's disease in Han Chinese.

Two recent studies have identified that a rare coding variant (p.R47H) in exon 2 of triggering receptor expressed on myeloid cells 2 (TREM2) gene is associated with Alzheimer's disease (AD) susceptibility in Caucasians. This association was not successfully replicated in Han Chinese, where this variant was rare or even absent. Previously, we resequenced TREM2 exon 2 to investigate whether additional rare variants conferred risk to AD in our cohort. Although several new variants had been identified, none of them was significantly associated with disease susceptibility. Here, to test whether TREM2 is truly a susceptibility gene of AD in Han Chinese, we extend our previous study by sequencing the other four exons of TREM2 in 988 AD patients and 1,354 healthy controls. We provided the first evidence that a rare coding variant (p.H157Y) in TREM2 exon 3 conferred a considerable risk of AD in our cohort (Pcorrected = 0.02, odds ratio = 11.01, 95% confidence interval: 1.38-88.05). This finding indicates that rare coding variants of TREM2 may play an important role in AD in Han Chinese.

The impact of PICALM genetic variations on reserve capacity of posterior cingulate in AD continuum.

Phosphatidylinositolbinding clathrin assembly protein (PICALM) gene is one novel genetic player associated with late-onset Alzheimer's disease (LOAD), based on recent genome wide association studies (GWAS). However, how it affects AD occurrence is still unknown. Brain reserve hypothesis highlights the tolerant capacities of brain as a passive means to fight against neurodegenerations. Here, we took the baseline volume and/or thickness of LOAD-associated brain regions as proxies of brain reserve capacities and investigated whether PICALM genetic variations can influence the baseline reserve capacities and the longitudinal atrophy rate of these specific regions using data from Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. In mixed population, we found that brain region significantly affected by PICALM genetic variations was majorly restricted to posterior cingulate. In sub-population analysis, we found that one PICALM variation (C allele of rs642949) was associated with larger baseline thickness of posterior cingulate in health. We found seven variations in health and two variations (rs543293 and rs592297) in individuals with mild cognitive impairment were associated with slower atrophy rate of posterior cingulate. Our study provided preliminary evidences supporting that PICALM variations render protections by facilitating reserve capacities of posterior cingulate in non-demented elderly.