Risk Of Late-onset Alzheimer's Disease Research Articles

Atypical Localization and Dissociation between Glucose Uptake and Amyloid Deposition in Cognitively Normal APOE*E4 Homozygotic Elders Compared with Patients with Late-Onset Alzheimer's Disease.

Alzheimer's disease (AD) progresses insidiously over decades. Therefore, study of preclinical AD is critical to identify early pathophysiological changes as potential targets for prevention or treatment. The brain processes at the preclinical stage remain minimally understood. Aside from age, the E4 allele of APOE flags a group at particularly high risk of late-onset AD (LOAD). Studies of these individuals could provide insights about the ontogenesis of AD offering clues for novel treatment strategies. To this end, cognitively normal, APOE*E4 homozygotes from the Alzheimer's Diseases Neuroimaging Research Initiative database (ADNI-LONI) provided fluorodeoxyglucose and amyloid (florbetapir) PET scans (n = 8 and 7, respectively; mean age 76 years). Their scans were compared to those of matched cognitively normal elders who were not E4 carriers. There was dissociation in the distribution between glucose uptake and amyloid deposition in the homozygotes. Peak hypometabolism localized bilaterally along the medial temporal cortex. In contrast, peak amyloid deposition localized principally to the putamen, a finding also seen in preclinical carriers of autosomal dominant AD mutations and preclinical AD associated with Down syndrome. Additional regions of amyloid deposition in homozygotes were medial prefrontal cortices including the anterior cingulate, middle and inferior frontal cortices, and middle and inferior occipital cortices. These findings contrast with those reported for LOAD. These data begin to characterize elders with normal cognition despite high AD risk in comparison to the known phenotypes of patients with LOAD.

Lack of association between triggering receptor expressed on myeloid cells 2 polymorphism rs75932628 and late-onset Alzheimer's disease in a Chinese Han population.

Recently, several studies have investigated the association between the rare mutation of triggering receptor expressed on myeloid cells 2 (TREM2) gene (rs75932628-T) and the risk of late-onset Alzheimer’s disease (LOAD), but they did not draw the same conclusion. Our aim was to investigate the link between the TREM2 polymorphism and LOAD in the Chinese Han population. We examined 786 patients and 803 controls in this study. The rs75932628 polymorphism was evaluated using high-resolution melting analysis and direct sequencing. rs75932628-T (predicted to cause an R47H substitution) was absent in our cohort. We did not find an association between the rs75932628 single nucleotide polymorphism of TREM2 and LOAD in this study. Thus, rs75932628 is unlikely to be related to LOAD in the Chinese Han population.

Risk of Late-Onset Alzheimer's Disease by Plasma Cholesterol: Rational In Silico Drug Investigation of Pyrrole-Based HMG-CoA Reductase Inhibitors.

Alzheimer's disease (AD), a worldwide renowned progressive neurodegenerative disorder, is the most common cause of dementia. There are several studies on the important role of cholesterol metabolism in AD pathogenesis, which indicated that the high concentrations of serum cholesterol increase the risk of AD. Biosynthesis of the plasma cholesterol and other isoprenoids is catalyzed by 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) through the conversion of HMG-CoA to mevalonic acid in mevalonate pathway. Normally, the high level of plasma cholesterol is downregulated by HGMCR inhibition as the result of degradation of LDL, but in abnormal conditions, for example, high blood glucose, the HMGCR over activated resulting in uncontrolled blood cholesterol. Selective HMGCR inhibitor drugs such as statins, which increase the catabolism of plasma LDL and reduce the plasma concentration of cholesterol, have been investigated as a possible treatment for AD. In the present study, we have identified the binding modes of 22 various derivatives of 3-sulfamoylpyrroles 16, prepared via a [3 + 2] cycloaddition of a münchnone with a sulfonamide-substituted alkyne, by using efficient biocomputational tools. Out of 22, 5 ligands, with code numbers 5b, 5c, 5d, 5i, and 5j, possessed most absorption, distribution, metabolism, and excretion (ADME) and toxicity profiles in acceptable ranges. Among ligands, 5j (sodium (3R,5R)-7-(3-(N,N-dimethylsulfamoyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrol-1-yl)-3,5-dihydroxyheptanoate) could inhibit HMGCR enzyme in inhibitory binding site with affinity value -12.17 kcal/mol and binding energy -94.10 kcal/mol through 5 hydrogen bonds. It showed the best ADME and toxicity profiling and higher affinity values than other potent candidate and market drugs such as atorvastatin and rosuvastatin. Therefore, it is suggested for further in vivo investigation, the druggability of 5j and its cholesterol regulatory impact on AD.

Association of glutathione S-transferases M1, P1 and T1 variations and risk of late-onset Alzheimer’s disease

Objective: Late-onset Alzheimer’s disease (AD) is a genetically heterogeneous neurodegenerative disorder. Associations of the glutathione S-transferases (GSTs) polymorphisms with the risk factors for AD have not been definitely confirmed. We investigated the association of GSTM1 and GSTT1 null deletion and GSTP1 313 A/G polymorphisms and the risk of AD in an Iranian population.Methods: The case group consisted of 280 individuals with AD and the control group included 168 age-matched healthy individuals. The genotyping of the GSTP1 polymorphism was determined by PCR-RFLP and the GSTM1 and GSTT1 deletions were done by multiplex PCR method.Results: The GSTP1 AG genotype was significantly lower (p = 0.005; OR = 0.57, 95% CI: 0.38–0.84) in the patients (41.1%) than the control group (56.5%). The GSTM1 null genotype was significantly higher (p < 0.001) in the patients (40.5%) than the control group (15.8%). The GSTT1 null genotype was significantly higher (p < 0.038) in the patients (31.2%) than the control group (21.5%). The patients homozygous for the GSTM1 and GSTT1 null alleles showed a 3.5 and 1.5-fold increased risk of AD, respectively. There were interaction between GSTP1 AG genotype and absence of APOE e4 allele (p = 0.001), as well as presence of APOE ε4 and GSTM1 null genotype (p < 0.0001).Conclusion: These findings suggested that GSTM1 and GSTT1 null deletions may be associated with susceptibility to AD and people with APOE e4 and GSTM1 null deletion have a higher increased risk for Late-onset AD in Iranian population.

Methionine Sulfoxide Reductase-B3 (MsrB3) Protein Associates with Synaptic Vesicles and its Expression Changes in the Hippocampi of Alzheimer's Disease Patients.

Genome-wide association studies (GWAS) identified susceptibility loci associated with decreased hippocampal volume, and found hippocampal subfield-specific effects at MSRB3 (methionine sulfoxide reductase-B3). The MSRB3 locus was also linked to increased risk for late onset Alzheimer's disease (AD). In this study, we uncovered novel sites of MsrB3 expression in CA pyramidal layer and arteriolar walls by using automated immunohistochemistry on hippocampal sections from 23 individuals accompanied by neuropathology reports and clinical dementia rating scores. Controls, cognitively intact subjects with no hippocampal neurofibrillary tangles, exhibited MsrB3 signal as distinct but rare puncta in CA1 pyramidal neuronal somata. In CA3, however, MsrB3-immunoreactivity was strongest in the neuropil of the pyramidal layer. These patterns were replicated in rodent hippocampi where ultrastructural and immunohistofluorescence analysis revealed MsrB3 signal associated with synaptic vesicles and colocalized with mossy fiber terminals. In AD subjects, the number of CA1 pyramidal neurons with frequent, rather than rare, MsrB3-immunoreactive somatic puncta increased in comparison to controls. This change in CA1 phenotype correlated with the occurrence of AD pathological hallmarks. Moreover, the intensity of MsrB3 signal in the neuropil of CA3 pyramidal layer correlated with the signal pattern in neurons of CA1 pyramidal layer that was characteristic of cognitively intact individuals. Finally, MsrB3 signal in the arteriolar walls in the hippocampal white matter decreased in AD patients. This characterization of GWAS-implicated MSRB3 protein expression in human hippocampus suggests that patterns of neuronal and vascular MsrB3 protein expression reflect or underlie pathology associated with AD.

EMERGING CSF BIOMARKERS AS PREDICTORS OF ALZHEIMER DISEASE DEMENTIA

Cerebrospinal fluid (CSF) biomarkers have shown great promise in identifying individuals with both preclinical Alzheimer disease (AD) and symptomatic AD. The best established CSF biomarkers for AD are the concentrations of amyloid-β 42 (Aβ42), tau, and phosphotau181 (ptau). Several emerging CSF biomarkers for AD are also under investigation: the pre-synaptic protein synaptosomal-associated protein-25 (SNAP-25), the post-synaptic calmodulin binding protein neurogranin, and the neuronal calcium sensor visinin-like protein 1 (VILIP-1). These markers may reflect different processes in the AD pathological cascade than Aβ42, tau and ptau. We measured CSF SNAP-25, neurogranin and VILIP-1 levels in a Washington University cohort of 264 individuals at risk for late onset AD who were cognitively normal at their baseline CSF collection. The cohort has a mean age of 63 ± 9 years at baseline and has been followed an average of 7 ± 3 years. 42 individuals developed cognitive impairment (progressor group) and 222 individuals remained cognitively normal (stable group). As expected, individuals who developed cognitive impairment had significantly lower baseline levels of CSF Aβ42 and significantly higher baseline levels of tau and ptau. Additionally, individuals who developed cognitive impairment had higher baseline levels of neurogranin (P<0.01) and VILIP-1 (p<0.05). Baseline SNAP-25 levels were not different between the progressor and cognitively stable groups.

AD FAMILY HISTORY MODULATES EFFECTS OF TOMM40 ‘523’ POLY-T ON MTL ATROPHY AND HYPOMETABOLISM IN PRECLINICAL AND AD COHORTS

There is tremendous interest in finding novel genetic risk factors for Alzheimer's disease (AD) among individuals lacking the Apolipoprotein E ε4 allele (non-APOE4's). Translocase of Outer Mitochondrial Membrane-kD40 (TOMM40), which affects mitochondrial function, is a gene with strong linkage disequilibrium to APOE. A TOMM40 variable poly-T length polymorphism at rs10524523 within intron 6 may increase risk for late onset AD. Few studies have examined how a “very long” (VL) versus “short” (S) poly-T length is related to neural outcomes. Furthermore, we found recently that AD family history (FH) changes the association between VL poly-T length and cognitive decline in cognitively normal middle-aged and aged adults across the AD spectrum. Thus, we examined TOMM40 poly-T genotype, FH, and their interaction on changes in medial temporal lobe (MTL) gray matter (GM) and glucose metabolism across time. Longitudinal linear mixed modeling assessed FH and TOMM40 main effects and interactions, among non-APOE4's, for subsets of 913 middle-aged subjects from the Wisconsin Registry for Alzheimer's Prevention (WRAP) over 7–10 years and 334 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) over 3 years. FreeSurfer was used to derive mean MTL volume and cortical thickness (CT). Arterial spin labeling (ASL) in WRAP and fluorodeoxyglucose Positron Emission Tomography (FDG-PET) in ADNI were used to gauge MTL glucose metabolism. Significant TOMM40 x FH interactions indicated that TOMM40 VL's who were FH- and FH+ respectively showed robust step-wise protective or detrimental effects for GM, ASL, and FDG-PET. Figure 1 and Figure 2 illustrate this association in MTL volume for WRAP and MTL CT for ADNI. Figure 3 illustrates this association for MTL versus global cerebral blood flow in WRAP, with comparable associations seen for FDG-PET in ADNI.

PHOSPHOLIPASE D3 CONTRIBUTES TO ALZHEIMER’S DISEASE RISK VIA DISRUPTION OF Aβ CLEARANCE THROUGH THE LYSOSOME

Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) in the brain. We recently identified coding variants in the phospholipase D3 (PLD3) gene that double the risk for late onset AD. While the normal function of PLD3 is poorly understood, PLD3 is highly expressed in neurons and in brain regions most susceptible to amyloid pathology. We examined the impact of PLD3 risk variants on PLD3 and Aβ metabolism using CRISPR/Cas9 in induced pluripotent stem cells (iPSC). We then modeled the PLD3 expression patterns observed in AD brains in immortalized cell and AD mouse models. Lysosomal function was assessed in human brain tissue. PLD3 A442A disrupts a splicing enhancer binding site and reduces PLD3 splicing in human brains. Differentiation of PLD3 A442A and isogenic control iPSCs into cortical neurons produced cells that were morphologically similar. At the molecular level, PLD3 A442A neurons displayed a similar defect in PLD3 splicing as was observed in human brains and a significant increase in Aβ42/Aβ40 compared with isogenic control lines. Thus, PLD3 A442A is sufficient to alter PLD3 splicing and Aβ metabolism. PLD3 expression was significantly lower in AD brains compared with controls, and PLD3 expression was highly correlated with expression of lysosomal genes. Thus, we sought to determine whether PLD3 contributes to Aβ accumulation in AD via disrupted Aβ metabolism. We found that overexpression of PLD3 in immortalized cells decreased Aβ levels while shRNA silencing of PLD3 increased Aβ levels. In an AD mouse model, overexpression of PLD3 in hippocampal neurons produced decreased interstitial fluid (ISF) Aβ levels and accelerated Aβ turnover. Conversely, PLD3 silencing increased ISF Aβ and reduced Aβ turnover. Thus, reduced turnover of ISF Aβ may lead to Aβ accumulation. To begin to determine whether PLD3 influences Aβ turnover via the lysosome, we isolated lysosomal fractions from human AD and control brains. PLD3 was enriched in lysosomal subfractions and PLD3 distribution in these subfractions was altered in AD. Furthermore, PLD3 stability in the lysosomal fractions was disrupted in AD brains. These findings demonstrate that PLD3 may contribute to AD risk via altered Aβ clearance through the lysosome.

WHOLE GENOME SEQUENCING IN HEALTHY ELDERLY APOE ε4 SUBJECTS IDENTIFIES PROTECTIVE GAIN OF FUNCTION MUTATIONS IN ALZHEIMER’S DISEASE

To identify protective genetic factors that can modify or reduce the effect of APOEε4 on the risk for late-onset Alzheimer's disease (LOAD) by whole genome sequencing (WGS) of elderly and healthy APOE ε44, ε34 and ε24 samples. We conducted WGS on 77 APOE ε4 homozygous and 123 heterozygous elderly healthy individuals. These samples were chosen from Caribbean Hispanic (CH) families with two of more LOAD affected samples (with or without APOEε4) and at least one unaffected APOEε44 individual. Further, we required that the unaffected APOEε4 homozygotes be two or more years older than the average age of onset within their families. Variants from WGS were called using the BWA-ATLAS pipeline and annotated using ANNOVAR. Novel or rare coding mutations segregating exclusively in ε4 unaffected subjects are being genotyped in additional family subjects and 1500 elderly ε4 carriers from the same ancestral background. We identified four genes with novel/rare (<1% in public databases) stop loss (gain of function) variants that were observed in multiple unaffected APOEε44 individuals and were absent in all affected individuals. In particular, a stop loss mutation (chr11:31811484 A/T) in PAX6 was found in two ε4 homozygote and one heterozygote control and is absent in ExAC database. Interestingly, no stop loss mutations were observed in PAX6 in the ExAC database. In addition, 263 loss of function mutations were observed to be segregating in APOE ε44 individuals. UNC5B, DNAH7 and RGPD4 carry multiple loss of function mutations in segregating with ε4 status. WGS in healthy elderly APOE ε4 carriers from CH families multiply affected by LOAD revealed a PAX6 gain of function variant segregating with APOE ε4 carriers in a large family. PAX6 is key regulatory gene for eye, brain, and pancreas development and is a transcriptional activator and repressor. Prioritized loss and gain of function mutations are being genotyped in a larger cohort of ε4 carriers to establish population frequencies. Identifying functional sequence variants in LOAD will facilitate the creation of tractable models for investigation of disease related mechanisms and potential therapies.

SORL1 Variants Show Different Association with Early-Onset and Late-Onset Alzheimer's Disease Risk.

A recent study sequenced the full coding region of SORL1 in 1,255 early-onset Alzheimer's disease (EOAD) cases and 1,938 control individuals, and investigated the contribution of genetic variability in SORL1 to EOAD risk in a European cohort. This study identified six common variants and five low frequency variants in the SORL1 coding sequence. However, none of these 11 variants was significantly associated with EOAD risk after adjusting for multiple testing. We consider whether these 11 SORL1 variants identified in European EOAD contribute to late-onset Alzheimer's disease (LOAD) risk in individuals of European ancestry. Here, we investigated these 11 SORL1 variants identified in European EOAD and LOAD risk in individuals of European ancestry using a large-scale LOAD GWAS. Our results indicate that three genetic variants rs2070045, rs2276412, and rs17125548 as well as their tagged genetic variants contribute to LOAD risk in European population. We further investigate whether these variants could affect SORL1 expression using multiple expression quantitative trait loci (eQTLs) datasets. Our findings suggest that three genetic variants rs2070045, rs1699102, and rs3824968 could significantly regulate SORL1 expression in human brain tissues. We believe that our findings further provide important supplementary information about the involvement of the SORL1 variants in LOAD risk.

The Association of MME microRNA Binding Site Polymorphism with the Risk of Late Onset Alzheimer's Disease in Northern Han Chinese.

Although β-amyloid (Aβ) degradation has been normally implicated in the pathogenesis of late-onset Alzheimer's disease (LOAD) through cellular biological studies, the genetic studies linking Aβ degradation and LOAD are still scarce. Neprilysin (NEP), one of the most crucial Aβ-degrading enzymes in AD, is the metalloendopeptidase which particularly participates in the monomeric Aβ species degradation. MicroRNAs (miRNAs) exert post-transcriptional dysregulation and their target sequence on the 3' untranslated regions (3'UTR) may be regulated by single nucleotide polymorphisms (SNPs). To investigate the potential risk of common locus within NEP gene (MME) with LOAD in Northern Han Chinese population. We screened a locus (rs6665) in 3' UTR of NEP gene (MME) which sequence was specially regulated by miRNA-187, and further investigated its possible association with LOAD onset in a large case-control study (984 LOAD patients and 1354 healthy controls) in Northern Han Chinese. The distribution of rs6665 genotype (P=0.003) and allele A/C (P=0.001) showed significant difference between LOAD and controls (Odds Ratio (OR) =1.255, 95% Confidence Interval (CI) =1.102-1.429). After adjusting for age, gender and Apolipoprotein (ApoE) ε4 status, the minor C allele of rs6665 showed significant association with LOAD in all three genotypic models (Dominant: P=0.003, OR=1.291, 95%CI=1.092-1.526; Recessive: P=0.030, OR =1.425, 95%CI =1.035- 1.961; Additive: P=0.001, OR=1.249,95%CI=1.093-1.427). After stratifying by ApoE ε4 status, rs6665 polymorphism was found to elevate the LOAD risk in ApoE ε4 carriers (P=0.002, OR=1.846, 95%CI=1.264-2.697). Our study firstly confirmed the association of MME miRNA binding site polymorphism with the risk of LOAD. However, the association results warrant further validation.

Whole transcriptome profiling of the human hippocampus suggests an involvement of the KIBRA rs17070145 polymorphism in differential activation of the MAPK signaling pathway

The rs17070145-T variant of the WWC1 gene, coding for the KIBRA protein, has been associated with both increased episodic memory performance and lowered risk for late onset Alzheimer's disease, although the mechanism behind this protective effect has not been completely elucidated. To achieve a better understanding of the pathways modulated by rs17070145 and its associated functional variant(s), we used laser capture microdissection (LCM) and RNA-sequencing to investigate the effect of rs17070145 genotypes on whole transcriptome expression in the human hippocampus (HP) of 22 neuropathologically normal individuals, with a specific focus on the dentate gyrus (DG) and at the pyramidal cells (PC) of CA1 and CA3 sub-regions. Differential expression analysis of RNA-seq data within the HP based on the rs17070145 genotype revealed an overexpression of genes involved in the MAPK signaling pathway, potentially driven by the T/T genotype. The most important contribution comes from genes dysregulated within the DG region. Other genes significantly dysregulated, and not involved in the MAPK pathway (Adj P < 0.01 and Fold Change > |1.00|) were: RSPO4 (HP); ARC, DUSP5, DNAJB5, EGR4, PPP1R15A, WBP11P1, EGR1, GADD45B (DG); CH25H, HSPA1A, HSPA1B, TNFSF9, and NPAS4 (PC). Several evidences suggested that the MAPK signaling pathway is linked with memory and learning processes. In non-neuronal cells, the KIBRA protein is phosphorylated by ERK1/2 (involved in the MAPK signaling) in cells as well as in vitro. Several of the other dysregulated genes are involved in memory and learning processes, as well as in Alzheimer's Disease. In conclusion, our results suggest that the effect of the WWC1 rs17070145 polymorphism on memory performance and Alzheimer's disease might be due to a differential regulation of the MAPK signaling, a key pathway involved in memory and learning processes.

Identification of biological pathways to Alzheimer's disease using polygenic scores

IntroductionSingle nucleotide polymorphisms (SNPs) contribute small increases in risk for late-onset Alzheimer's disease (LOAD). LOAD SNPs cluster around genes with similar biological functions (pathways). Polygenic risk scores (PRS) aggregate the effect of SNPs genome-wide. However, this approach has not been widely used for SNPs within specific pathways.ObjectivesWe investigated whether pathway-specific PRS were significant predictors of LOAD case/control status.MethodsWe mapped SNPs to genes within 8 pathways implicated in LOAD. For our polygenic analysis, the discovery sample comprised 13,831 LOAD cases and 29,877 controls. LOAD risk alleles for SNPs in our 8 pathways were identified at a P-value threshold of 0.5. Pathway-specific PRS were calculated in a target sample of 3332 cases and 9832 controls. The genetic data were pruned with R2 &gt; 0.2 while retaining the SNPs most significantly associated with AD. We tested whether pathway-specific PRS were associated with LOAD using logistic regression, adjusting for age, sex, country, and principal components. We report the proportion of variance in liability explained by each pathway.ResultsThe most strongly associated pathways were the immune response (NSNPs = 9304, = 5.63 × 10−19, R2 = 0.04) and hemostasis (NSNPs = 7832, P = 5.47 × 10−7, R2 = 0.015). Regulation of endocytosis, hematopoietic cell lineage, cholesterol transport, clathrin and protein folding were also significantly associated but accounted for less than 1% of the variance. With APOE excluded, all pathways remained significant except proteasome-ubiquitin activity and protein folding.ConclusionsGenetic risk for LOAD can be split into contributions from different biological pathways. These offer a means to explore disease mechanisms and to stratify patients.Disclosure of interestThe authors have not supplied their declaration of competing interest.

The Methylenetetrahydrofolate Reductase C677T Polymorphism and Risk for Late-Onset Alzheimer's disease: Further Evidence in an Italian Multicenter Study.

A functional polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, namely C677T (rs1801133), results in increased Hcy levels and has been associated with risk of late-onset Alzheimer's disease (LOAD). Many investigators reported association between rs1801133 and LOAD risk in Asian populations and in carriers of the apolipoprotein E (APOE) ɛ4 allele, but recent meta-analyses suggest a contribution also in other populations, including Caucasians and/or northern Africans. To further address this issue, we performed a relatively large case-control study, including 581 LOAD patients and 468 matched controls of Italian origin. APOE data were available for a subgroup of almost 600 subjects. Genotyping for rs1801133 was performed with PCR-RFLP techniques. In the total population, the MTHFR 677T allele (OR = 1.20; 95% CI = 1.01-1.43) and carriers of the MTHFR 677T allele (CT+TT versus CC: OR = 1.34; 95% CI = 1.03-1.73) resulted in increased LOAD risk. Similarly, in APOEɛ4 carriers, we observed an increased frequency of MTHFR 677CT carriers (CT versus CC: OR = 2.82; 95% CI = 1.25-6.32). Very interestingly, also in non-APOEɛ4 carriers, both MTHFR 677T allele (OR = 1.38; 95% CI = 1.03-1.85) and MTHFR 677TT genotype (OR = 2.08; 95% CI = 1.11-3.90) were associated with LOAD. All these associations survived after corrections for age, gender, and multiple testing. The present results suggest that the MTHFR C677T polymorphism is likely a LOAD risk factor in our cohort, either in APOEɛ4 or in non-APOEɛ4 carriers.

Strong Association of Lipid Metabolism Related MicroRNA Binding Sites Polymorphisms with the Risk of Late Onset Alzheimer's Disease.

Although altered lipid metabolism has been extensively implicated in the pathogenesis of late onset Alzheimer's disease (LOAD) through cell biological and epidemiological studies, genetic studies linking lipid metabolism and LOAD are still not well understood. MicroRNAs (miRNAs) exert posttranscriptional down-regulation and their target sequence on the 3' untranslated regions (3'UTR) may be altered by single nucleotide polymorphisms (SNPs). We therefore explore whether the six loci in Clusterin gene (CLU) (rs9331949), Lipoprotein lipase gene (LPL) (rs1059507, rs3200218, rs3208305, rs3735964) and Low-density lipoprotein receptor related protein 6 (LRP6) (rs2160525) could modulate LOAD risk through the alteration of miRNA binding sites. We performed a case-control study of 2338 unrelated subjects (984 cases and 1354 age- and gender-matched controls) in the Northern Han Chinese. We found that the minor C allele in rs9331949 significantly increased the risk of LOAD (P<0.001, OR=1.31, 95% CI=1.14-1.51), even after adjusting for multiple testing. Logistic analysis identified the rs9331949 polymorphism was still strongly associated with LOAD, even in Apolipoprotein E (APOE) ε4 allele noncarrier subgroups. However, the other five loci were not significantly associated with LOAD after Bonferroni adjustment. In conclusion, we have identified that the locus (rs9331949) located in the binding site of 3' UTR of CLU has a strong association with LOAD rather than loci in LPL and LRP6. However, additional independent replication is required for further validation.

Microglia express ABI3 in the brains of Alzheimer's disease and Nasu-Hakola disease.

Nasu-Hakola disease (NHD) is a rare autosomal recessive leukoencephalopathy caused by a loss-of-function mutation of either TYROBP (DAP12) or TREM2 expressed in microglia. A rare variant of the TREM2 gene encoding p.Arg47His causes a 3-fold increase in the risk for late-onset Alzheimer's disease (LOAD). A recent study demonstrated that a rare coding variant p.Ser209Phe in the ABI family member 3 (ABI3) gene, a regulator of actin cytoskeleton organization, confers risk of developing of LOAD, although the pattern of ABI3 expression in AD and NHD brains with relevance to microglial pathology remains to be characterized. We investigated the cell type-specific expression of ABI3 in the brains derived from four non-neurological controls (NC), ten AD and five NHD cases by immunohistochemistry. We identified an intense ABI3 immunoreactivity chiefly on a subset of microglia with ramified or amoeboid morphology located in the grey matter and the white matter of the frontal cortex and the hippocampus of NC, AD, and NHD cases. The immunolabeled area of ABI3-positive microglia was not significantly different among NC, AD, and NHD cases due to great variability from case to case. The clusters of ABI3-immunoreactive microglia were found exclusively in AD brains and they were associated with amyloid plaques. Although these observations do not actively support the view that ABI3-immunoreactive microglia play a central role in the development of leukoencephalopathy in NHD brains and the neurodegeneration in AD brains, the intense expression of ABI3 on microglia might regulate their migration under conditions of health and disease in the central nervous system (CNS).

Bin1 and CD2AP polarise the endocytic generation of beta-amyloid.

The mechanisms driving pathological beta-amyloid (Aβ) generation in late-onset Alzheimer's disease (AD) are unclear. Two late-onset AD risk factors, Bin1 and CD2AP, are regulators of endocytic trafficking, but it is unclear how their endocytic function regulates Aβ generation in neurons. We identify a novel neuron-specific polarisation of Aβ generation controlled by Bin1 and CD2AP We discover that Bin1 and CD2AP control Aβ generation in axonal and dendritic early endosomes, respectively. Both Bin1 loss of function and CD2AP loss of function raise Aβ generation by increasing APP and BACE1 convergence in early endosomes, however via distinct sorting events. When Bin1 levels are reduced, BACE1 is trapped in tubules of early endosomes and fails to recycle in axons. When CD2AP levels are reduced, APP is trapped at the limiting membrane of early endosomes and fails to be sorted for degradation in dendrites. Hence, Bin1 and CD2AP keep APP and BACE1 apart in early endosomes by distinct mechanisms in axon and dendrites. Individuals carrying variants of either factor would slowly accumulate Aβ in neurons increasing the risk for late-onset AD.

SORL1 rs1699102 polymorphism modulates age-related cognitive decline and gray matter volume reduction in non-demented individuals.

SORL1 rs1699102 is associated with the risk of late-onset Alzheimer's disease. However, the effects of this single nucleotide polymorphism on cognition and brain structure during normal aging are unclear. This study aimed to examine the effects of the rs1699102 polymorphism on age-related cognitive decline and cortical gray matter reduction in the Chinese Han population. A total of 780 non-demented adults completed a battery of neuropsychological tests. High-resolution T1-weighted structural magnetic resonance imaging data from 89 of these subjects were also collected using a Siemens Trio 3.0 Tesla scanner. The T allele carriers displayed an accelerated age-related change in episodic memory and processing speed tests relative to the CC genotype. A similar pattern was observed in the age-related gray matter volume (GMV) reduction of the right middle temporal pole. The GMV in this region was significantly positively correlated with the episodic memory scores. The SORL1 gene rs1699102 polymorphism has been found to be associated with age-related cognitive decline and GMV reduction of the right middle temporal pole in older adults. These findings elucidate how the SORL1 variants shape the neural system to modulate age-related cognitive decline and support the hypothesis that SORL1 may represent a candidate gene for late-onset Alzheimer's disease.

The Role of Cardiovascular Risk Factors and Stroke in Familial Alzheimer Disease.

The contribution of cardiovascular disease (CV) and cerebrovascular disease to the risk for late-onset Alzheimer disease (LOAD) has been long debated. Investigations have shown that antecedent CV risk factors increase the risk for LOAD, although other investigations have failed to validate this association. To study the contribution of CV risk factors (type 2 diabetes, hypertension, and heart disease) and the history of stroke to LOAD in a data set of large families multiply affected by LOAD. The National Institute on Aging Late-Onset Alzheimer Disease/National Cell Repository for Alzheimer Disease family study (hereinafter referred to as NIA-LOAD study) is a longitudinal study of families with multiple members affected with LOAD. A multiethnic community-based longitudinal study (Washington Heights-Inwood Columbia Aging Project [WHICAP]) was used to replicate findings. The 6553 participants in the NIA-LOAD study were recruited from 23 US Alzheimer disease centers with ongoing data collection since 2003; the 5972 WHICAP participants were recruited at Columbia University with ongoing data collection since 1992. Data analysis was performed from 2003 to 2015. Generalized mixed logistic regression models tested the association of CV risk factors (primary association) with LOAD. History of stroke was used for the secondary association. A secondary model adjusted for the presence of an apolipoprotein E (APOE) ε4 allele. A genetic risk score, based on common variants associated with LOAD, was used to account for LOAD genetic risk beyond the APOE ε4 effect. Mediation analyses evaluated stroke as a mediating factor between the primary association and LOAD. A total of 6553 NIA-LOAD participants were included in the analyses (4044 women [61.7%]; 2509 men [38.3%]; mean [SD] age, 77.0 [9] years), with 5972 individuals from the WHICAP study included in the replication sample (4072 women [68.2%]; 1900 men [31.8%]; mean [SD] age, 76.5 [7.0] years). Hypertension was associated with decreased LOAD risk (odds ratio [OR], 0.63; 95% CI, 0.55-0.72); type 2 diabetes and heart disease were not. History of stroke conferred greater than 2-fold increased risk for LOAD (OR, 2.23; 95% CI, 1.75-2.83). Adjustment for APOE ε4 did not alter results. The genetic risk score was associated with LOAD (OR, 2.85; 95% CI, 2.05-3.97) but did not change the independent association of LOAD with hypertension or stroke. In the WHICAP sample, hypertension was not associated with LOAD (OR, 0.99; 95% CI, 0.88-1.11), whereas history of stroke increased the risk for LOAD (OR, 1.96; 95% CI, 1.56-2.46). The effect of hypertension on LOAD risk was also mediated by stroke in the NIA-LOAD and the WHICAP samples. In familial and sporadic LOAD, a history of stroke was significantly associated with increased disease risk and mediated the association between selected CV risk factors and LOAD, which appears to be independent of the LOAD-related genetic background.

Integration of transcriptomic and genomic data suggests candidate mechanisms for APOE4-mediated pathogenic action in Alzheimer's disease.

Among the genetic factors known to increase the risk of late onset Alzheimer’s diseases (AD), the presence of the apolipoproteine e4 (APOE4) allele has been recognized as the one with the strongest effect. However, despite decades of research, the pathogenic role of APOE4 in Alzheimer’s disease has not been clearly elucidated yet. In order to investigate the pathogenic action of APOE4, we applied a systems biology approach to the analysis of transcriptomic and genomic data of APOE44 vs. APOE33 allele carriers affected by Alzheimer’s disease. Network analysis combined with a novel technique for biomarker computation allowed the identification of an alteration in aging-associated processes such as inflammation, oxidative stress and metabolic pathways, indicating that APOE4 possibly accelerates pathological processes physiologically induced by aging. Subsequent integration with genomic data indicates that the Notch pathway could be the nodal molecular mechanism altered in APOE44 allele carriers with Alzheimer’s disease. Interestingly, PSEN1 and APP, genes whose mutation are known to be linked to early onset Alzheimer’s disease, are closely linked to this pathway. In conclusion, APOE4 role on inflammation and oxidation through the Notch signaling pathway could be crucial in elucidating the risk factors of Alzheimer’s disease.