Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease

The pursuit of susceptibility genes for Alzheimer's disease: progress and prospects

The Genetics of Alzheimer Disease: Back to the Future

Genome-wide association studies have identified numerous Alzheimer's disease (AD) susceptibility loci in European populations. However, the genetic architecture of AD in non-European populations remains underinvestigated. We performed a genetic association study in East Asians (N=8514) to validate known AD loci and identify new susceptibility loci. We identified LILRB2-LILRB5 as an AD susceptibility locus with ethnic-specific effects between Europeans and East Asians. The lead variant, rs587709-T, was associated with decreased AD risk and increased LILRB5 expression in Europeans. Conversely, in East Asians, the same allele was associated with increased AD risk and increased LILRB2 expression. Furthermore, genome-wide analysis identified TTC3 and FAM135A as candidate susceptibility loci for AD or cognition. The results establish LILRB2-LILRB5 as a cross-ancestry AD-associated locus with ethnic-specific genetic mechanisms and reveal new susceptibility loci, extending the understanding of the genetic etiology of AD.

Alzheimer disease (AD) susceptibility genes have been identified on chromosomes 1, 14, 19, and 21, and a recent study has suggested a locus on chromosome 12. To confirm or refute the existence of a familial AD susceptibility locus on chromosome 12 in an independent sample of familial AD cases. Retrospective cohort study. DNA data for 6 chromosome 12 genetic markers were evaluated using parametric lod score and nonparametric linkage methods and linkage heterogeneity tests. The latter include the admixture test of homogeneity in the total group of families and the predivided sample test in families stratified by the presence or absence of an apolipoprotein E (APOE) epsilon4 allele among affected members. Parametric analyses were repeated assuming autosomal dominant inheritance of AD and either age- and sex-dependent penetrance or zero penetrance for the analysis of unaffected relatives. Clinical populations in the continental United States, Canada, Argentina, and Italy. Fifty-three white families composed of multiple members affected with AD, from whom DNA samples were obtained from 173 patients with AD whose conditions were diagnosed using established criteria and from 146 nondemented relatives. Presence of an APOE epsilon4 allele among affected family members. Using parametric methods, no evidence for linkage to the region spanned by the chromosome 12 markers could be detected if familial AD is assumed to arise from the same genetic locus in all 53 families. However, significant evidence for linkage was detected in the presence of locus heterogeneity using the admixture test (odds ratio, 15, 135:1). The estimated proportion of linked families within the 53 families examined varied between 0.40 and 0.65, depending on the genetic model assumed and APOE status. The precise location of the AD gene could not be determined, but includes the entire region suggested previously. Nonparametric linkage analysis confirmed linkage to chromosome 12 with the strongest evidence at D12S96 (P<.001). Our data provide independent confirmation of the existence of an AD susceptibility locus on chromosome 12 and suggest the existence of AD susceptibility genes on other chromosomes. Screening a larger set of families with additional chromosome markers will be necessary for identifying the chromosome 12 AD gene.

Genome-wide Association Analysis Reveals Putative Alzheimer's Disease Susceptibility Loci in Addition to APOE

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.

Chromosome 21 BACE2 haplotype associates with Alzheimer's disease: A two-stage study

In our functional dissection of the CD33 Alzheimer’s disease susceptibility locus, we find that the rs3865444C risk allele is associated with greater cell surface expression of CD33 in monocytes (t50 = 10.06, pjoint=1.3×10–13) of young and older individuals. It is also associated with (1) diminished internalization of Aβ42) (2) accumulation of neuritic amyloid pathology and fibrillar amyloid on in vivo imaging and (3), increased numbers of activated human microglia.

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

Of late-onset Alzheimer's disease patients 50% do not carry an apolipoprotein E epsilon 4 allele, indicating that there must be other genetic or environmental risk factors for the disease. During the past few years, both genetic linkage and candidate gene studies have been undertaken in order to identify novel genetic risk factors for late-onset Alzheimer's disease. Previous genome screens implicated a region of chromosome 12 that contains the genes that encode both alpha(2)-macroglobulin and the low-density lipoprotein receptor-related protein. However, candidate gene studies have produced mixed results with respect to both of these genes. New linkage studies now provide strong evidence for Alzheimer's disease susceptibility loci on chromosomes 9 and 10. The locus on chromosome 10 very probably modifies risk for Alzheimer's disease by modulating beta-amyloid-42 levels.

Recent genome-wide association studies (GWAS) have discovered several Alzheimer disease (AD) susceptibility loci. However, the identified susceptibility loci are substantially inconsistent across GWAS. We aimed to investigate the association of top associated variants in GWAS with AD in Korean population. We selected 86 single-nucleotide polymorphisms (SNPs) selected from 12 genes (ABCA7, APOE, BIN1, CD2AP, CD33, CLU, CR1, EPHA1, LRAT, MS4A6A, PCDH11X, and PICALM) and genotyped in 290 AD cases and 554 unrelated controls from the same region. Three SNPs [rs429358 in APOE: odds ratio (OR)=4.24, 95% confidence interval (CI)=3.01-5.96, P=1.23×10; rs2075650 in APOE: OR=3.57, 95% CI=2.51-5.06, P=1.23×10; and rs677909 in PICALM: OR=0.63, 95% CI=0.49-0.81, P=0.00036, log additive model] were significantly associated with AD susceptibility after correction for multiple testing. Six additional PICALM SNPs, 3 ABCA7 SNPs, and 1 APOE, CD33, and BIN1 SNPs each had significant uncorrected P values. There was no significant association for age at onset of AD. Our results confirm the association of PICALM gene (encoding phosphatidylinositol-binding protein) in addition to APOE gene with AD susceptibility in Korean population but did not show significant associations of other susceptibility loci with AD.

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.

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.

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

While numerous genetic susceptibility loci have been identified for clinical Alzheimer disease (AD), it is important to establish whether these variants are risk factors for the underlying disease pathology, including neuritic plaques. To investigate whether AD susceptibility loci from genome-wide association studies affect neuritic plaque pathology and to additionally identify novel risk loci for this trait. Candidate analysis of single-nucleotide polymorphisms and genome-wide association study in a joint clinicopathologic cohort, including 725 deceased subjects from the Religious Orders Study and the Rush Memory and Aging Project (2 prospective, community-based studies), followed by targeted validation in an independent neuroimaging cohort, including 114 subjects from multiple clinical and research centers. A quantitative measure of neuritic plaque pathologic burden, based on assessments of silver-stained tissue averaged from multiple brain regions. Validation based on β-amyloid load by immunocytochemistry, and replication with fibrillar β-amyloid positron emission tomographic imaging with Pittsburgh Compound B or florbetapir. Besides the previously reported APOE and CR1 loci, we found that the ABCA7 (rs3764650; P = .02) and CD2AP (rs9349407; P = .03) AD susceptibility loci are associated with neuritic plaque burden. In addition, among the top results of our genome-wide association study, we discovered a novel variant near the amyloid precursor protein gene (APP, rs2829887) that is associated with neuritic plaques (P = 3.3 × 10-6). This polymorphism was associated with postmortem β-amyloid load as well as fibrillar β-amyloid in 2 independent cohorts of adults with normal cognition. These findings enhance understanding of AD risk factors by relating validated susceptibility alleles to increased neuritic plaque pathology and implicate common genetic variation at the APP locus in the earliest, presymptomatic stages of AD.