Alzheimer's Disease Susceptibility Loci Research Articles

Genetic insights into the association between inflammatory bowel disease and Alzheimer's disease.

Myeloid cells, including monocytes, macrophages, microglia, dendritic cells and neutrophils are a part of innate immune system, playing a major role in orchestrating innate and adaptive immune responses. Both Alzheimer's disease (AD) and inflammatory bowel disease (IBD) susceptibility loci are enriched for genes expressed in myeloid cells, but it is not clear whether these myeloid risk factors are shared between the two diseases. Leveraging results of genome-wide association studies, we investigated the causal effect of IBD (including ulcerative colitis (UC) and Crohn's disease (CD)) variants on AD and its endophenotypes. Microglia and monocyte expression Quantitative Trait Locus (eQTLs) were used to examine the functional consequences of IBD and AD variants. Our results revealed distinct sets of genes and pathways of AD and IBD susceptibility loci. Specifically, AD loci are enriched for microglial eQTLs, while IBD loci are enriched for monocyte eQTLs. However, we also found that genetically determined IBD is associated with a protective effect against AD (p<0.03). Yet, a genetic propensity for the CD subtype is associated with increased amyloid accumulation (beta=7.14, p-value=0.02) and susceptibility to AD. Susceptibility to UC was associated with increased deposition of TDP-43 (beta=7.58, p-value=6.11×10-4). The relation of these gastrointestinal inflammatory disease to AD is therefore complex; while the different subsets of susceptibility variants preferentially affect different myeloid cell subtypes, there do appear to be certain shared pathways and the possible protective effect of IBD susceptibility on the risk of AD which may provide therapeutic insights.

Identification of 16 novel Alzheimer's disease susceptibility loci using multi-ancestry meta-analyses of clinical Alzheimer's disease and AD-by-proxy cases from four whole genome sequencing datasets.

Alzheimer's disease (AD) is the most prevalent form of dementia. While many AD-associated genetic determinants have been previously identified, few studies have analyzed individuals of non-European ancestry. Here, we describe a multi-ancestry genome-wide association study of clinically-diagnosed AD and AD-by-proxy using whole genome sequencing data from NIAGADS, NIMH, UKB, and All of Us (AoU) consisting of 49,149 cases (12,074 clinically-diagnosed and 37,075 AD-by-proxy) and 383,225 controls. Nearly half of NIAGADS and AoU participants are of non-European ancestry. For clinically-diagnosed AD, we identified 14 new loci - five common (FBN2,/SCL27A6, AC090115.1, DYM, KCNG1/AL121785.1, TIAM1) and nine rare (VWA5B1, RNU6-755P/LMX1A, MOB1A, MORC1-AS1, LINC00989, PDE4D, RNU2-49P/CDO1, NEO1, and SLC35G3/AC022916.1). Meta-analysis of UKB and AoU AD-by-proxy cases yielded two new rare loci (RPL23/LASP1 and CEBPA/ AC008738.6) which were also nominally significant in NIAGADS. In summary, we provide evidence for 16 novel AD loci and advocate for more studies using WGS-based GWAS of diverse cohorts.

Genome-wide association analysis and admixture mapping in a Puerto Rican cohort supports an Alzheimer disease risk locus on chromosome 12.

Hispanic/Latino populations are underrepresented in Alzheimer Disease (AD) genetic studies. Puerto Ricans (PR), a three-way admixed (European, African, and Amerindian) population is the second-largest Hispanic group in the continental US. We aimed to conduct a genome-wide association study (GWAS) and comprehensive analyses to identify novel AD susceptibility loci and characterize known AD genetic risk loci in the PR population. Our study included Whole Genome Sequencing (WGS) and phenotype data from 648 PR individuals (345 AD, 303 cognitively unimpaired). We used a generalized linear-mixed model adjusting for sex, age, population substructure, and genetic relationship matrix. To infer local ancestry, we merged the dataset with the HGDP/1000G reference panel. Subsequently, we conducted univariate admixture mapping (AM) analysis. We identified suggestive signals within the SLC38A1 and SCN8A genes on chromosome 12q13. This region overlaps with an area of linkage of AD in previous studies (12q13) in independent data sets further supporting. Univariate African AM analysis identified one suggestive ancestral block (p = 7.2×10-6) located in the same region. The ancestry-aware approach showed that this region has both European and African ancestral backgrounds and both contributing to the risk in this region. We also replicated 11 different known AD loci -including APOE- identified in mostly European studies, which is likely due to the high European background of the PR population. PR GWAS and AM analysis identified a suggestive AD risk locus on chromosome 12, which includes the SLC38A1 and SCN8A genes. Our findings demonstrate the importance of designing GWAS and ancestry-aware approaches and including underrepresented populations in genetic studies of AD.

Genome-wide meta-analysis identifies ancestry-specific loci for Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurological disease with complex genetic etiology. Yet most known loci have only identified from the late-onset type AD in populations of European ancestry. We performed a two-stage genome-wide association study (GWAS) of AD totaling 6878 Chinese and 63,926 European individuals. In addition to the apolipoprotein E (APOE) locus, our GWAS of two independent Chinese samples uncovered three novel AD susceptibility loci (KIAA2013, SLC52A3, and TCN2) and a novel ancestry-specific variant within EGFR (rs1815157). More replicated variants were observed in the Chinese (31%) than in the European samples (15%). In combining genome-wide associations and functional annotations, EGFR and TCN2 were prioritized as two of the most biologically significant genes. Phenome-wide Mendelian randomization suggests that high mean corpuscular hemoglobin concentration might protect against AD. The current study reveals novel AD susceptibility loci, emphasizes the importance of diverse populations in AD genetic research, and advances our understanding of disease etiology. Loci KIAA2013, SLC52A3, and TCN2 were associated with Alzheimer's disease (AD) in Chinese populations. rs1815157 within the EGFR locus was associated with AD in Chinese populations. The genetic architecture of AD varied between Chinese and European populations. EGFR and TCN2 were prioritized as two of the most biologically significant genes. High mean corpuscular hemoglobin concentrations might have protective effects against AD.

Interpretation of 10years of Alzheimer's disease genetic findings in the perspective of statistical heterogeneity.

Common genetic variants and susceptibility loci associated with Alzheimer's disease (AD) have been discovered through large-scale genome-wide association studies (GWAS), GWAS by proxy (GWAX) and meta-analysis of GWAS and GWAX (GWAS+GWAX). However, due to the very low repeatability of AD susceptibility loci and the low heritability of AD, these AD genetic findings have been questioned. We summarize AD genetic findings from the past 10years and provide a new interpretation of these findings in the context of statistical heterogeneity. We discovered that only 17% of AD risk loci demonstrated reproducibility with a genome-wide significance of P < 5.00E-08 across all AD GWAS and GWAS+GWAX datasets. We highlighted that the AD GWAS+GWAX with the largest sample size failed to identify the most significant signals, the maximum number of genome-wide significant genetic variants or maximum heritability. Additionally, we identified widespread statistical heterogeneity in AD GWAS+GWAX datasets, but not in AD GWAS datasets. We consider that statistical heterogeneity may have attenuated the statistical power in AD GWAS+GWAX and may contribute to explaining the low repeatability (17%) of genome-wide significant AD susceptibility loci and the decreased AD heritability (40-2%) as the sample size increased. Importantly, evidence supports the idea that a decrease in statistical heterogeneity facilitates the identification of genome-wide significant genetic loci and contributes to an increase in AD heritability. Collectively, current AD GWAX and GWAS+GWAX findings should be meticulously assessed and warrant additional investigation, and AD GWAS+GWAX should employ multiple meta-analysis methods, such as random-effects inverse variance-weighted meta-analysis, which is designed specifically for statistical heterogeneity.

A new risk locus on chromosome 1 is suggested by genome‐wide association study in Peruvians for Alzheimer disease

AbstractBackgroundIncreasing ethnic/ancestral diversity in genetic studies is critical for defining the genetic architecture of Alzheimer disease (AD). Amerindian (AI) populations are substantially underrepresented in AD genetic studies. The Peruvian (PE) population, with up to ∼80% of AI ancestry, provides a unique opportunity to assess the role of AI ancestry in AD. We performed the first genome‐wide association study (GWAS) in the PE population to identify novel AD susceptibility loci and characterize known AD genetic risk loci.MethodThe PE dataset includes array‐genotype and phenotype data from 542 individuals (189 cases; 353 controls), imputed to the NHLBI TOPMedv5 haplotype reference panel. We used a generalized linear mixed‐model (SAIGE software) for the GWAS analysis. We analyzed two separate models; the first model accounted for sex, age, and population substructure, while the second model also included the dosage of APOEe4. In both models, we included a genetic relationship matrix as a random effect to account for any potential relatedness. To determine if the associations are specific to specific ancestries, we employed ancestry‐aware approaches using the RFMix software.ResultAPOE was significantly associated with AD with an effect size comparable to that found in non‐Hispanic white (NHW) populations (OR = 3.3(2.2‐4.8),pv = 8.0×10−10). Two additional known AD loci, TREML2 (pv = 0.008) and CLU (pv = 0.012), showed nominal significance Variants at three additional loci reached suggestive significance (pv&lt;1×10−6): NFASC (pv = 9.4×10−8;chromosome 1), STK32A (pv = 9.3×10−7; chromosome 5), and LOC100132830 (pv = 6.7×10−7;chromosome 6). The NFASC locus neared genome‐wide significance in the APOE adjusted model (pv = 6.7×10−8). The haplotypes associated with AD at the NFASC locus were found to be of European origin. Additionally, the STK32A locus was found to have a protective effect specifically among individuals of AI background. We did not observe significant heterogeneity of effect at the APOE and LOC100132830 loci across different ancestral backgrounds.ConclusionPE GWAS identified a novel, promising AD susceptibility locus in the NFASC gene of European origin. We also detected a potential protective effect in the STK32A locus on AI background, emphasizing the importance of incorporating ancestry‐aware approaches in gene discovery in admixed populations.

X chromosome-wide association study of quantitative biomarkers from the Alzheimer's Disease Neuroimaging Initiative study.

Alzheimer's disease (AD) is a complex neurodegenerative disease with high heritability. Compared to autosomes, a higher proportion of disorder-associated genes on X chromosome are expressed in the brain. However, only a few studies focused on the identification of the susceptibility loci for AD on X chromosome. Using the data from the Alzheimer's Disease Neuroimaging Initiative Study, we conducted an X chromosome-wide association study between 16 AD quantitative biomarkers and 19,692 single nucleotide polymorphisms (SNPs) based on both the cross-sectional and longitudinal studies. We identified 15 SNPs statistically significantly associated with different quantitative biomarkers of the AD. For the cross-sectional study, six SNPs (rs5927116, rs4596772, rs5929538, rs2213488, rs5920524, and rs5945306) are located in or near to six genes DMD, TBX22, LOC101928437, TENM1, SPANXN1, and ZFP92, which have been reported to be associated with schizophrenia or neuropsychiatric diseases in literature. For the longitudinal study, four SNPs (rs4829868, rs5931111, rs6540385, and rs763320) are included in or near to two genes RAC1P4 and AFF2, which have been demonstrated to be associated with brain development or intellectual disability in literature, while the functional annotations of other five novel SNPs (rs12157031, rs428303, rs5953487, rs10284107, and rs5955016) have not been found. 15 SNPs were found statistically significantly associated with the quantitative biomarkers of the AD. Follow-up study in molecular genetics is needed to verify whether they are indeed related to AD. The findings in this article expand our understanding of the role of the X chromosome in exploring disease susceptibility, introduce new insights into the molecular genetics behind the AD, and may provide a mechanistic clue to further AD-related studies.

A Comparison of the Various Methods for Selecting Features for Single-Cell RNA Sequencing Data in Alzheimer's Disease.

The high-throughput sequencing method known as RNA-Seq records the whole transcriptome of individual cells. Single-cell RNA sequencing, also known as scRNA-Seq, is widely utilized in the field of biomedical research and has resulted in the generation of huge quantities and types of data. The noise and artifacts that are present in the raw data require extensive cleaning before they can be used. When applied to applications for machine learning or pattern recognition, feature selection methods offer a method to reduce the amount of time spent on calculation while simultaneously improving predictions and offering a better knowledge of the data. The process of discovering biomarkers is analogous to feature selection methods used in machine learning and is especially helpful for applications in the medical field. An attempt is made by a feature selection algorithm to cut down on the total number of features by eliminating those that are unnecessary or redundant while retaining those that are the most helpful.We apply FS algorithms designed for scRNA-Seq to Alzheimer's disease, which is the most prevalent neurodegenerative disease in the western world and causes cognitive and behavioral impairment. AD is clinically and pathologically varied, and genetic studies imply a diversity of biological mechanisms and pathways. Over 20 new Alzheimer's disease susceptibility loci have been discovered through linkage, genome-wide association, and next-generation sequencing (Tosto G, Reitz C, Mol Cell Probes 30:397-403, 2016). In this study, we focus on the performance of three different approaches to marker gene selection methods and compare them using the support vector machine (SVM), k-nearest neighbors' algorithm (k-NN), and linear discriminant analysis (LDA), which are mainly supervised classification algorithms.

The impact of Alzheimer's disease susceptibility loci on lateral ventricular surface morphology in older adults.

The enlargement of ventricular volume is a general trend in the elderly, especially in patients with Alzheimer's disease (AD). Multiple susceptibility loci have been reported to have an increased risk for AD and the morphology of brain structures are affected by the variations in the risk loci. Therefore, we hypothesized that genes contributed significantly to the ventricular surface, and the changes of ventricular surface were associated with the impairment of cognitive functions. After the quality controls (QC) and genotyping, a lateral ventricular segmentation method was employed to obtain the surface features of lateral ventricle. We evaluated the influence of 18 selected AD susceptibility loci on both volume and surface morphology across 410 subjects from Alzheimer's Disease Neuroimaging Initiative (ADNI). Correlations were conducted between radial distance (RD) and Montreal Cognitive Assessment (MoCA) subscales. Only the C allele at the rs744373 loci in BIN1 gene significantly accelerated the atrophy of lateral ventricle, including the anterior horn, body, and temporal horn of left lateral ventricle. No significant effect on lateral ventricle was found at other loci. Our results revealed that most regions of the bilateral ventricular surface were significantly negatively correlated with cognitive scores, particularly in delayed recall. Besides, small areas of surface were negatively correlated with language, orientation, and visuospatial scores. Together, our results indicated that the genetic variation affected the localized areas of lateral ventricular surface, and supported that lateral ventricle was an important brain structure associated with cognition in the elderly.

Assessment of Alzheimer's disease polygenic risk score on longitudinal amyloid accumulation in cognitively intact older adults.

We investigated whether an Alzheimer's disease (AD) polygenic risk score (PRS) could predict longitudinal brain amyloid accumulation in cognitively intact older adults participating in the Flemish Prevent AD Cohort KU Leuven (F-PACK). Previously published data have highlighted associations between AD susceptibility loci and AD-related brain changes. Sixty-one cognitively healthy F-PACK participants (median age: 68 (56-79), 29 females, 29 APOE ε4 carriers) received an [18 F]Flutemetamol-PET scan and structural MRI at baseline and follow-up (average time interval 4.6 years (3.4-8.6)). Amyloid rate of change was defined as absolute change divided by time interval. Participants were genotyped using the Illumina GSA and imputed using the Michigan server and HRC reference panel. Data were quality controlled using PLINK(v1.9, http://pngu.mgh.harvard.edu/purcell/plink/, Purcell et al., 2007) (minor allele frequency >0.01). PRS calculation was performed using PRSice(Choi & O'Reilly, 2019) with the Stage 1 summary statistics (containing SNP p-values and corresponding effect sizes) from the GWAS performed by Kunkle et al.,(2019). European individuals from the 1000 Genomes dataset were used for clumping (N=503). We calculated PRSs at three thresholds for SNP inclusion: pT=0.5(Escott-Price et al., 2015); 1x10-5 ; 5x108 . A Mann-Whitney U-test was used to determine amyloid rate of change differences between APOE ε4 carriers and non-carriers. Linear models were used to assess if the PRS could predict changes in amyloid, with age, sex and the first three principal components from the PRS calculation as covariates, at each of the p-value thresholds for SNP inclusion. APOE ε4 carriers showed a trend towards a significantly higher rate of change than non-carriers (U=459.5, p=0.056). When predicting amyloid rate of change, the linear model outputs were similar when the thresholds for SNP inclusion were pT=1x10-5 and 5x10-8 . Although models did not reach significance, there was a significant effect of PRS on amyloid rate of change: pT=1x10-5 : β=0.0056 (CI: 0.0000785-0.011), p<0.05; pT=5x10-8 : β=0.0054 (CI: 0.000042-0.011), p<0.05. PRS was not a significant predictor for amyloid accumulation when the threshold for SNP inclusion was pT=0.5: β=0.0013 (-0.004-0.007), p>0.05. PRSs calculated with a SNP inclusion threshold of pT=1x10-5 or 5x10-8 explain a small but significant amount of variance in amyloid accumulation in cognitively intact older adults.

Contribution of Alzheimer's disease risk genes in the maintenance of endolysosomal transport regulation.

Alzheimer's disease (AD) is the most common form of dementia of which the incidence increases with age. AD has a strong genetic component, for which further study is essential to identify pathways that can be targeted therapeutically, as no cure is available yet. While most studies have focused over the years on the early onset risk factors (i.e. APP, PSEN1 and PSEN2), those represent only a minor fraction of all cases. GWAS studies have identified ≈30 late-onset AD (LOAD) susceptibility loci that, when functionally clustered, are directly or indirectly linked to cellular trafficking routes and functioning. These include genes linked to cholesterol metabolism, endocytic transport regulation and lysosomal processes. The genetic findings concur with the appearance of endolysosomal abnormalities at preclinical stages, before the appearance of senile plaques and tangles. Using a CRISPR-Cas9 based approach, knock-out (KO) of various risk factors from early (PSEN1) or late (PICALM, PLD3) onset risk factors were realized in fibroblasts and neuronal SH-SY5Y cells. Analysis of the endolysosomal pathway and lysosomal functions were carried out using biochemical assays, lipidomic analysis of isolated organelles, confocal imaging as well as electron microscopy. Both the deficiency of presenilins and late risk factors led to endolysosomal dysfunctions, as characterized by an enlargement of late endosomes/lysosomes that accumulate diverse types of lipids such as cholesterol or glycerophospholipids. Further focusing on PSENs, their depletion led to a delay in the endosomal maturation, resulting in an accumulation of endosomal cargoes and adapters such as the retromer subunit VPS35. Re-expression of either catalytic or inactive PSEN1 was sufficient to correct these aberrant accumulations. Whereas the endolysosomal abnormalities could be connected to the accumulation of APP-CTFs, the nature of γ-secretase-independent contribution remains enigmatic. Activation of recycling significantly alleviated endolysosomal defects observed in PSENdKO cells. Altogether, our results underscore that different upstream mechanisms could lead to similar endolysosomal dysfunctions. Our observations are also shedding light on the potential of modulating/restoring endosomal recycling regulation as a strategy to alleviate observed early endolysosomal dysfunctions at preclinical stages of AD pathogenesis.

Proteomic investigation of the Alzheimer's risk gene MEF2C in microglial like cells

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there are no disease-modifying therapies. Genome-wide association studies and next-generation sequencing have identified over 50 susceptibility loci for AD (1). These include loci containing the transcription factor MEF2C, a master regulator of microglia development and function. In microglia, AD risk single nucleotide polymorphisms (SNPs) are enriched in open chromatin regions that contain DNA binding motifs for MEF2C (2). Disrupted DNA binding due to genetic variation at these sites or altered gene expression in cis may lead to impaired transcriptional control by MEF2C. This implicates the MEF2C transcriptional network as genetic risk mechanism of AD and investigation into the MEF2C interactome in microglia may provide functional and mechanistic insights into the molecular processes involved in AD pathogenesis. To explore this, Co-IP-Mass Spectrometry of endogenous Mef2c has been used to identify its protein isoforms, post-translational modifications, upstream regulators and interacting partners which may be integral to its biological function. The first Co-IP-MS interactome of Mef2c in microglia-like cells will be presented. Protein partners of this AD-relevant transcription factor have been identified. These include a novel interactor Oasl1 which is involved in the innate immune response, the transcriptional repressors Hdac4 and Hdac5, and members of the Hira complex which appear to be holding Mef2c predominantly in a repressed state in basal BV2 cells. The identification of these partners allows for a better understanding of Mef2c regulation and function as a master regulator of microglia and AD risk. This has provided insights into the molecular processes involved in AD, and the pathways through which AD relevant biology is regulated.

Quantitative Genetics Validates Previous Genetic Variants and Identifies Novel Genetic Players Influencing Alzheimer's Disease Cerebrospinal Fluid Biomarkers.

Cerebrospinal fluid (CSF) biomarkers have been extensively investigated in the Alzheimer's disease (AD) field, and are now being applied in clinical practice. CSF amyloid-beta (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect disease pathology, and may be used as quantitative traits for genetic analyses, fostering the identification of new genetic factors and the proposal of novel biological pathways of the disease. In patients, the concentration of CSF Aβ1-42 is decreased due to the accumulation of Aβ1-42 in amyloid plaques in the brain, while t-tau and p-tau levels are increased, indicating the extent of neuronal damage. To better understand the biological mechanisms underlying the regulation of AD biomarkers, and its relation to AD, we examined the association between 36 selected single nucleotide polymorphisms (SNPs) and AD biomarkers Aβ1-42, t-tau, and p-tau in CSF in a cohort of 672 samples (571 AD patients and 101 controls) collected within 10 European consortium centers.Our results highlighted five genes, APOE, LOC100129500, PVRL2, SNAR-I, and TOMM40, previously described as main players in the regulation of CSF biomarkers levels, further reinforcing a role for these in AD pathogenesis. Three new AD susceptibility loci, INPP5D, CD2AP, and CASS4, showed specific association with CSF tau biomarkers. The identification of genes that specifically influence tau biomarkers point out to mechanisms, independent of amyloid processing, but in turn related to tau biology that may open new venues to be explored for AD treatment.

MYELIN BREAKDOWN LEADS TO BIN1 ACCUMULATION IN AMYLOID DEPOSITS

The deposition of amyloid-β (Aβ) peptide in extracellular senile plaques is a hallmark of Alzheimer's disease (AD). Aβ is derived from the cleavage of amyloid precursor protein (APP) by the β- and γ-secretases. It has been proposed as the key trigger in the complex cascade of events which lead to AD. Genome-wide association studies have recently identified BIN1 as a major susceptibility locus for late-onset AD (LOAD) We previously reported a predominant expression of BIN1 in mature oligodendrocytes and the white matter tracts. Interestingly, recent in vitro studies described a role for BIN1 in APP processing by BACE1 and Ab production. However, the role of BIN1 in Ab generation in vivo remains to be reported. In this study, we explored BIN1 localization within the amyloid deposits in different model for Alzheimer disease. We explored the change of solubility properties of BIN1 using sequential detergent extraction. We investigated BIN1 localization within the deposits using confocal and STED microscopy. We confirmed our observations by immunoEM. Here, we report an increase in the levels of insoluble BIN1 in the brains of 5XFAD transgenic mice. We also observe a striking accrual of BIN1 within the amyloid deposits in multiple transgenic models of AD and in the human brain. This aberrant BIN1 localization was distinct from dystrophic neurite accumulation of APP and BACE1. Our immunoEM results suggest that the accumulation of insoluble BIN1 appears along the amyloid processes. We hypothesize that BIN1 insolubility and accumulation is a consequence of myelin destruction and the extracellular release of BIN1. Altogether, our results suggest a reorganization of myelin proteins surrounding the amyloid deposit and the change of BIN1 biophysical properties in relation to Ab accumulation in the brain. Our results bring new evidence of myelin protein reorganization associated with amyloid deposition. This work opens new avenues related to myelin pathology observed in AD.

Alzheimer's genetic risk is reduced in primary age‐related tauopathy: a potential model of resistance?

ObjectiveNearly all adults >50 years of age have evidence for neurofibrillary tau tangles (NFTs) and a significant proportion of individuals additionally develop amyloid plaques (Aβ) consistent with Alzheimer's disease (AD). In an effort to identify the independent genetic risk factors for NFTs and Aβ, we investigated genotypic frequencies of AD susceptibility loci between autopsy‐confirmed AD and primary age‐related tauopathy (PART), a neuropathological condition defined by characteristic neurofibrillary tau tangles (NFTs) with minimal or absent Aβ.MethodsGeneral linear models assessed the odds of AD (N = 1190) relative to PART (N = 376) neuropathologically confirmed cases from two independent series: the Penn Brain Bank (PENN; AD N = 312; PART N = 65) and National Alzheimer's Coordinating Center (NACC; AD N = 878; PART N = 311). We also evaluated the odds of Braak stage NFT burden.ResultsThree genotypes significantly associated with reduced AD risk relative to PART in the PENN (N = 377) and NACC (N = 1189) cohorts including APOE ε4, APOE ε2, and rs6656401 in the CR1 gene. The genotypes rs6733839 in the BIN1 gene and rs28834970 in the PTK2B gene approached significance in the PENN cohort and were significantly associated with reduced AD risk in the NACC cohort. In a combined cohort analysis (N = 1566), APOE ε4 dosage was highly associated with higher Braak stage of NFT burden in Probable PART and AD, but not Definite PART.InterpretationThe presence of genotypic differences between PART and AD suggest that PART can provide a genetic model of NFT risk and potential Aβ resistance to inform disease‐modifying therapies.

Transethnic genome-wide scan identifies novel Alzheimer's disease loci

IntroductionGenetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. MethodsWe conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. ResultsGenome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)–based tests (P < 5 × 10−8) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10−6) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10−6). DiscussionOur findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

Alzheimer's disease risk variants modulate endophenotypes in mild cognitive impairment

IntroductionWe evaluated the effect of Alzheimer's disease (AD) susceptibility loci on endophenotypes closely related with AD pathology in patients with mild cognitive impairment (MCI). MethodsWe selected 1730 MCI patients from four independent data sets. Weighted polygenic risk scores (PGS) were constructed of 18 non-apolipoprotein E (APOE) AD risk variants. In addition, we determined APOE genotype. AD endophenotypes were cognitive decline over time and cerebrospinal fluid (CSF) biomarkers (aβ, tau, ptau). ResultsPGS was modestly associated with cognitive decline over time, as measured by mini-mental state examination (MMSE) (β ± SE:−0.24 ± 0.10; P = .012), and with CSF levels of tau and ptau (tau: 1.38 ± 0.36, P = 1.21 × 10−4; ptau: 1.40 ± 0.36, P = 1.02 × 10−4). DiscussionIn MCI, we observed a joint effect of AD susceptibility loci on nonamyloid endophenotypes, suggesting a link of these genetic loci with neuronal degeneration in general rather than with Alzheimer-related amyloid deposition.

Novel susceptibility loci for Alzheimer's disease.

Late-onset Alzheimer's disease (AD), a highly prevalent neurodegenerative disorder characterized by progressive deterioration in cognition, function and behavior terminating in incapacity and death, is a clinically and pathologically heterogeneous disease with a substantial heritable component. During the past 5 years, the technological developments in next-generation high-throughput genome technologies have led to the identification of more than 20 novel susceptibility loci for AD, and have implicated specific pathways in the disease, in particular intracellular trafficking/endocytosis, inflammation and immune response and lipid metabolism. These observations have significantly advanced our understanding of underlying pathogenic mechanisms and potential therapeutic targets. This review article summarizes these recent advances in AD genomics and discusses the value of identified susceptibility loci for diagnosis and prognosis of AD.

Alzheimer's loci: epigenetic associations and interaction with genetic factors.

ObjectiveWe explore the role of DNA methylation in Alzheimer’s disease (AD). To elucidate where DNA methylation falls along the causal pathway linking risk factors to disease, we examine causal models to assess its role in the pathology of AD.MethodsDNA methylation profiles were generated in 740 brain samples using the Illumina HumanMet450K beadset. We focused our analysis on CpG sites from 11 AD susceptibility gene regions. The primary outcome was a quantitative measure of neuritic amyloid plaque (NP), a key early element of AD pathology. We tested four causal models: (1) independent associations, (2) CpG mediating the association of a variant, (3) reverse causality, and (4) genetic variant by CpG interaction.ResultsSix genes regions (17 CpGs) showed evidence of CpG associations with NP, independent of genetic variation – BIN1 (5), CLU (5), MS4A6A (3), ABCA7 (2), CD2AP (1), and APOE (1). Together they explained 16.8% of the variability in NP. An interaction effect was seen in the CR1 region for two CpGs, cg10021878 (P = 0.01) and cg05922028 (P = 0.001), in relation to NP. In both cases, subjects with the risk allele rs6656401AT/AA display more methylation being associated with more NP burden, whereas subjects with the rs6656401TT protective genotype have an inverse association with more methylation being associated with less NP.InterpretationThese observations suggest that, within known AD susceptibility loci, methylation is related to pathologic processes of AD and may play a largely independent role by influencing gene expression in AD susceptibility loci.

Protein Expression of Alzheimer's disease‐ and Reduced Hippocampal Volume‐ Risk Loci in Human Hippocampus

We examined the protein expression of novel genome‐wide association studies (GWAS) identified risk alleles implicated in Alzheimer's disease (AD) and low hippocampal volume using postmortem hippocampi with no or mild‐to‐moderate AD‐associated pathological changes. We found BIN1, the most significant late‐onset AD susceptibility locus after APOE, expressed in glia of all the examined cases while the punctate signal in neuropil varied substantially. EPHA1, another confirmed AD risk locus, is an ephrin receptor implicated in neuronal apoptosis. We found EphA1 in the neuronal cytoplasm, with a trend of decreasing signal intensity as AD progressed. Methionine sulfoxide reductase B3 (MSRB3) locus, critical for oxidative stress, was identified in GWAS on hippocampal volume. We found MSRB3 signal mostly as cytoplasmic puncta in pyramidal neurons from all of the examined cases, albeit in various amounts. Finally, LEMD3, a possible causal gene at the MSRB3 locus, was expressed in neurons as well as astrocytes. Neuronal expression of LEMD3 may increase with AD progression. Our data provide first insight into the human hippocampal cell type‐ and cell compartment‐specific protein expression of AD‐ and hippocampal volume reduction‐ risk alleles. We are currently examining the correlation of these proteins' expression with the cognitive status reflected in CDR (Clinical Dementia Rating) scores.