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INTRODUCTION: Clinical and genetic studies have implicated lipid dysfunction in Alzheimer Disease (AD) pathogenesis. However, lipid consumption at the individual-level does not vary greatly within most cohorts, and multiple lipids are rarely measured in any one study. METHODS: Mean country-level lipid intakes were compared to Age-Standardized Alzheimer-Disease-Incidence-Rates(ASAIR) in 183 countries across all inhabited continents. Penalized spline regression and multivariable-adjusted linear regression, including a lag between intake and incidence, were used to assess the relationships between five lipid intakes and ASAIR. Validation was conducted using longitudinal within-country changes between 1990 and 2019. RESULTS: Omega6 Polyunsaturated-Fatty-Acid(PUFA) intake exhibited a positive linear relationship with ASAIR(multivariable-adjusted model: ß=2.44; 95%CI: 1.70, 3.19; p=1.38×10 -9 ). ASAIR also increased with saturated-fat, trans-fat, and dietary-cholesterol up to a threshold. The association between Omega6-PUFA and ASAIR was confirmed using longitudinal intake changes. DISCUSSION: Decreasing Omega6-PUFA consumption on the country-level may have substantial benefits in reducing the country-level burden of AD.
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INTRODUCTION: Despite a two-fold risk, individuals of African ancestry have been underrepresented in Alzheimer's disease (AD) genomics efforts. METHODS: Genome-wide association studies (GWAS) of 2,903 AD cases and 6,265 controls of African ancestry. Within-dataset results were meta-analyzed, followed by functional genomics analyses. RESULTS: A novel AD-risk locus was identified in MPDZ on chromosome (chr) 9p23 (rs141610415, MAF = 0.002, P = 3.68×10-9). Two additional novel common and nine rare loci were identified with suggestive associations (P < 9×10-7). Comparison of association and linkage disequilibrium (LD) patterns between datasets with higher and lower degrees of African ancestry showed differential association patterns at chr12q23.2 (ASCL1), suggesting that this association is modulated by regional origin of local African ancestry. DISCUSSION: These analyses identified novel AD-associated loci in individuals of African ancestry and suggest that degree of African ancestry modulates some associations. Increased sample sets covering as much African genetic diversity as possible will be critical to identify additional loci and deconvolute local genetic ancestry effects. HIGHLIGHTS: Genetic ancestry significantly impacts risk of Alzheimer's Disease (AD). Although individuals of African ancestry are twice as likely to develop AD, they are vastly underrepresented in AD genomics studies. The Alzheimer's Disease Genetics Consortium has previously identified 16 common and rare genetic loci associated with AD in African American individuals. The current analyses significantly expand this effort by increasing the sample size and extending ancestral diversity by including populations from continental Africa. Single variant meta-analysis identified a novel genome-wide significant AD-risk locus in individuals of African ancestry at the MPDZ gene, and 11 additional novel loci with suggestive genome-wide significance at P < 9×10-7. Comparison of African American datasets with samples of higher degree of African ancestry demonstrated differing patterns of association and linkage disequilibrium at one of these loci, suggesting that degree and/or geographic origin of African ancestry modulates the effect at this locus. These findings illustrate the importance of increasing number and ancestral diversity of African ancestry samples in AD genomics studies to fully disentangle the genetic architecture underlying AD, and yield more effective ancestry-informed genetic screening tools and therapeutic interventions.
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Alzheimer Disease (AD) is a highly polygenic disease that presents with relatively earlier onset (≤70yo; EOAD) in about 5% of cases. Around 90% of these EOAD cases remain unexplained by pathogenic mutations. Using data from EOAD cases and controls, we performed a genome-wide association study (GWAS) and trans-ancestry meta-analysis on non-Hispanic Whites (NHW, NCase=6,282, NControl=13,386), African Americans (AA NCase=782, NControl=3,663) and East Asians (NCase=375, NControl=838 CO). We identified eight novel significant loci: six in the ancestry-specific analyses and two in the trans-ancestry analysis. By integrating gene-based analysis, eQTL, pQTL and functional annotations, we nominate four novel genes that are involved in microglia activation, glutamate production, and signaling pathways. These results indicate that EOAD, although sharing many genes with LOAD, harbors unique genes and pathways that could be used to create better prediction models or target identification for this type of AD.
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The objective of this study was to investigate attitudes toward brain donation and perceptions of medical research that influence brain donation among African Americans. Cross-sectional surveys were administered to African American community members (nâ=â227). Findings indicate that only 27% of respondents were willing to donate their brain. As medical mistrust was not found to be a significant barrier to research participation, there may be opportunity to increase brain donation by providing information about Alzheimer's disease and brain donation to potential donors and their families so that informed decisions about participating in research can be made.
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Enfermedad de Alzheimer , Negro o Afroamericano , Obtención de Tejidos y Órganos , Humanos , Actitud , Negro o Afroamericano/psicología , Encéfalo , Estudios Transversales , Conocimientos, Actitudes y Práctica en Salud , Encuestas y Cuestionarios , Selección de Paciente , Investigación BiomédicaRESUMEN
There is a paucity of genetic studies of Alzheimer Disease (AD) in individuals of African Ancestry, despite evidence suggesting increased risk of AD in the African American (AA) population. We performed whole-genome sequencing (WGS) and multipoint linkage analyses in 51 multi-generational AA AD families ascertained through the Research in African American Alzheimer Disease Initiative (REAAADI) and the National Institute on Aging Late Onset Alzheimer's disease (NIA-LOAD) Family Based Study. Variants were prioritized on minor allele frequency (<0.01), functional potential of coding and noncoding variants, co-segregation with AD and presence in multi-ancestry ADSP release 3 WGS data. We identified a significant linkage signal on chromosome 5q35 (HLOD=3.3) driven by nine families. Haplotype segregation analysis in the family with highest LOD score identified a 3'UTR variant in INSYN2B with the most functional evidence. Four other linked AA families harbor within-family shared variants located in INSYN2B's promoter or enhancer regions. This AA family-based finding shows the importance of diversifying population-level genetic data to better understand the genetic determinants of AD on a global scale.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/epidemiología , Escala de Lod , Ligamiento Genético/genética , Haplotipos , Cromosomas , Predisposición Genética a la Enfermedad/genéticaRESUMEN
INTRODUCTION: Despite a two-fold increased risk, individuals of African ancestry have been significantly underrepresented in Alzheimer's Disease (AD) genomics efforts. METHODS: GWAS of 2,903 AD cases and 6,265 cognitive controls of African ancestry. Within-dataset results were meta-analyzed, followed by gene-based and pathway analyses, and analysis of RNAseq and whole-genome sequencing data. RESULTS: A novel AD risk locus was identified in MPDZ on chromosome 9p23 (rs141610415, MAF=.002, P =3.68×10 -9 ). Two additional novel common and nine novel rare loci approached genome-wide significance at P <9×10 -7 . Comparison of association and LD patterns between datasets with higher and lower degrees of African ancestry showed differential association patterns at chr12q23.2 ( ASCL1 ), suggesting that the association is modulated by regional origin of local African ancestry. DISCUSSION: Increased sample sizes and sample sets from Africa covering as much African genetic diversity as possible will be critical to identify additional disease-associated loci and improve deconvolution of local genetic ancestry effects.
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INTRODUCTION: Sequencing efforts to identify genetic variants and pathways underlying Alzheimer's disease (AD) have largely focused on late-onset AD although early-onset AD (EOAD), accounting for â¼10% of cases, is largely unexplained by known mutations, resulting in a lack of understanding of its molecular etiology. METHODS: Whole-genome sequencing and harmonization of clinical, neuropathological, and biomarker data of over 5000 EOAD cases of diverse ancestries. RESULTS: A publicly available genomics resource for EOAD with extensive harmonized phenotypes. Primary analysis will (1) identify novel EOAD risk loci and druggable targets; (2) assess local-ancestry effects; (3) create EOAD prediction models; and (4) assess genetic overlap with cardiovascular and other traits. DISCUSSION: This novel resource complements over 50,000 control and late-onset AD samples generated through the Alzheimer's Disease Sequencing Project (ADSP). The harmonized EOAD/ADSP joint call will be available through upcoming ADSP data releases and will allow for additional analyses across the full onset range. HIGHLIGHTS: Sequencing efforts to identify genetic variants and pathways underlying Alzheimer's disease (AD) have largely focused on late-onset AD although early-onset AD (EOAD), accounting for â¼10% of cases, is largely unexplained by known mutations. This results in a significant lack of understanding of the molecular etiology of this devastating form of the disease. The Early-Onset Alzheimer's Disease Whole-genome Sequencing Project is a collaborative initiative to generate a large-scale genomics resource for early-onset Alzheimer's disease with extensive harmonized phenotype data. Primary analyses are designed to (1) identify novel EOAD risk and protective loci and druggable targets; (2) assess local-ancestry effects; (3) create EOAD prediction models; and (4) assess genetic overlap with cardiovascular and other traits. The harmonized genomic and phenotypic data from this initiative will be available through NIAGADS.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/genética , Mutación/genética , Edad de InicioRESUMEN
INTRODUCTION: The underrepresentation of African Americans (AAs) in Alzheimer's disease (AD) research may limit potential benefits from translational applications. This article describes an approach to recruit AA families into an AD genomic study and characteristics of seeds (family connectors) used to overcome recruitment barriers of AA families into AD research. METHODS: A four-step outreach and snowball sampling approach relying on family connectors was used to recruit AA families. Descriptive statistics of a profile survey were gathered to understand the demographic and health characteristics of family connectors. RESULTS: Twenty-five AA families (117 participants) were enrolled in the study via family connectors. Most family connectors self-identified as female (88%), were 60 years of age or older (76%), and attained post-secondary education (77%). DISCUSSION: Community-engaged strategies were essential to recruit AA families. Relationships between study coordinators and family connectors build trust early in the research process among AA families. HIGHLIGHTS: Community events were most effective for recruiting African American families. Family connectors were primarily female, in good health, and highly educated. Systematic efforts by researchers are necessary to "sell" a study to participants.
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Enfermedad de Alzheimer , Femenino , Humanos , Enfermedad de Alzheimer/genética , Negro o Afroamericano , Genómica , Masculino , Persona de Mediana EdadRESUMEN
The risk of Alzheimer disease (AD) increases with age, family history and informative genetic variants. Sadly, there is still no cure or means of prevention. As in other complex diseases, uncovering genetic causes of AD could identify underlying pathological mechanisms and lead to potential treatments. Rare, autosomal dominant forms of AD occur in middle age as a result of highly penetrant genetic mutations, but the most common form of AD occurs later in life. Large-scale, genome-wide analyses indicate that 70 or more genes or loci contribute to AD. One of the major factors limiting progress is that most genetic data have been obtained from non-Hispanic white individuals in Europe and North America, preventing the development of personalized approaches to AD in individuals of other ethnicities. Fortunately, emerging genetic data from other regions - including Africa, Asia, India and South America - are now providing information on the disease from a broader range of ethnicities. Here, we summarize the current knowledge on AD genetics in populations across the world. We predominantly focus on replicated genetic discoveries but also include studies in ethnic groups where replication might not be feasible. We attempt to identify gaps that need to be addressed to achieve a complete picture of the genetic and molecular factors that drive AD in individuals across the globe.
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Enfermedad de Alzheimer , Persona de Mediana Edad , Humanos , Enfermedad de Alzheimer/genética , Estudio de Asociación del Genoma Completo , Predisposición Genética a la Enfermedad/genética , Mutación , EtnicidadRESUMEN
INTRODUCTION: Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. METHODS: A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. RESULTS: 13 variants had p<1×10-7 or p<1×10-5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. DISCUSSION: Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.
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Enfermedad de Alzheimer , Clusterina , Humanos , Clusterina/genética , Colombia , Enfermedad de Alzheimer/diagnóstico , Mutación/genética , Amiloide , Presenilina-1/genética , Edad de InicioRESUMEN
BACKGROUND: This study used admixture mapping to prioritize the genetic regions associated with Alzheimer's disease (AD) in African American (AA) individuals, followed by ancestry-aware regression analysis to fine-map the prioritized regions. METHODS: We analyzed 10,271 individuals from 17 different AA datasets. We performed admixture mapping and meta-analyzed the results. We then used regression analysis, adjusting for local ancestry main effects and interactions with genotype, to refine the regions identified from admixture mapping. Finally, we leveraged in silico annotation and differential gene expression data to prioritize AD-related variants and genes. RESULTS: Admixture mapping identified two genome-wide significant loci on chromosomes 17p13.2 (p = 2.2 × 10-5 ) and 18q21.33 (p = 1.2 × 10-5 ). Our fine mapping of the chromosome 17p13.2 and 18q21.33 regions revealed several interesting genes such as the MINK1, KIF1C, and BCL2. DISCUSSION: Our ancestry-aware regression approach showed that AA individuals have a lower risk of AD if they inherited African ancestry admixture block at the 17p13.2 locus. HIGHLIGHTS: We identified two genome-wide significant admixture mapping signals: on chromosomes 17p13.2 and 18q21.33, which are novel in African American (AA) populations. Our ancestry-aware regression approach showed that AA individuals have a lower risk of Alzheimer's disease (AD) if they inherited African ancestry admixture block at the 17p13.2 locus. We found that the overall proportion of African ancestry does not differ between the cases and controls that suggest African genetic ancestry alone is not likely to explain the AD prevalence difference between AA and non-Hispanic White populations.
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Enfermedad de Alzheimer , Predisposición Genética a la Enfermedad , Humanos , Predisposición Genética a la Enfermedad/genética , Negro o Afroamericano/genética , Enfermedad de Alzheimer/genética , Mapeo Cromosómico/métodos , Genotipo , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple/genética , Cinesinas/genética , Proteínas Serina-Treonina Quinasas/genéticaRESUMEN
African descent populations have a lower Alzheimer disease risk from ApoE ε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE ε4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE ε4 allele and the SNP rs10423769_A allele, (ß = -0.54,SE = 0.12,p-value = 7.50x10-6) in the discovery data set, and replicated this finding in Ibadan (ß = -1.32,SE = 0.52,p-value = 1.15x10-2) and Puerto Rican (ß = -1.27,SE = 0.64,p-value = 4.91x10-2) individuals. The non-Hispanic Whites analyses showed an interaction trending in the "protective" direction but failing to pass a 0.05 significance threshold (ß = -1.51,SE = 0.84,p-value = 7.26x10-2). The presence of the rs10423769_A allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE ε4/ε4 carriers lacking the A allele to 2.1 for ApoE ε4/ε4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. This study identified a new African-ancestry specific locus that reduces the risk effect of ApoE ε4 for developing Alzheimer disease. The mechanism of the interaction with ApoEε4 is not known but suggests a novel mechanism for reducing the risk for ε4 carriers opening the possibility for potential ancestry-specific therapeutic intervention.
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Enfermedad de Alzheimer , Alelos , Enfermedad de Alzheimer/genética , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Genotipo , Humanos , Nigeria , Factores de RiesgoRESUMEN
AIM: We sought to replicate findings from published genome-wide association studies (GWAS), linking specific candidate gene loci with periodontitis-related clinical/microbial traits. MATERIALS AND METHODS: In the published GWAS, a total of 2196 single nucleotide polymorphisms associated with periodontitis-related traits at a p ≤ 5 × 10-6 and mapped to 136 gene loci. The replication cohort included 1124 individuals, 65-98 years old (67% female, 45% Hispanic, 30% Black, 23% White) with available genome-wide genotypes and full-mouth periodontal status. Microbial profiles using checkerboard DNA-DNA hybridization and 16SrRNA sequencing were available from 912 and 739 participants, respectively. RESULTS: Using gene-specific p-values after linkage disequilibrium pruning, the following gene/phenotype associations replicated successfully: CLEC19A with edentulism and %teeth with pocket depth (PD) ≥4 mm; IL37, HPVC1, TRPS1, ABHD12B, LDLRAD4 (C180rF1), TGM3, and GRK5 with %teeth with PD ≥4 mm; DAB2IP with presence of PD ≥6 mm; KIAA1715(LNPK), ROBO2, RAB28, LINC01017, NELL1, LDLRAD4(C18orF1), and CRYBB2P1 with %teeth with clinical attachment level (CAL) ≥3 mm; RUNX2 and LAMA2 with %teeth with CAL ≥5 mm; and KIAA1715(LNPK) with high colonization by Aggregatibacter actinomycetemcomitans. In addition, CLEC19A, IQSEC1, and EMR1 associated with microbial abundance based on checkerboard data, LBP and NCR2 with abundance based on sequencing data, and NCR2 with microbial diversity based on sequencing data. CONCLUSIONS: Several gene loci identified in published GWAS as associated with periodontitis-related phenotypes replicated successfully in an elderly cohort.
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Periodontitis Crónica , Estudio de Asociación del Genoma Completo , Anciano , Envejecimiento , Periodontitis Crónica/genética , ADN , Femenino , Humanos , Interleucina-1 , Masculino , Salud Bucal , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Proteínas Represoras/genética , Transglutaminasas/genética , Washingtón , Proteínas de Unión al GTP rab , Proteínas Activadoras de ras GTPasa/genéticaRESUMEN
INTRODUCTION: There is increasing interest in plasma amyloid beta (Aß) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aß levels may elucidate important biological processes that determine plasma Aß measures. METHODS: We included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aß1-40, Aß1-42 levels and Aß1-42/Aß1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aß deposition and AD risk. RESULTS: Single-variant analysis identified associations with apolipoprotein E (APOE) for Aß1-42 and Aß1-42/Aß1-40 ratio, and BACE1 for Aß1-40. Gene-based analysis of Aß1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aß deposition. DISCUSSION: Identification of variants near/in known major Aß-processing genes strengthens the relevance of plasma-Aß levels as an endophenotype of AD.
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Secretasas de la Proteína Precursora del Amiloide/genética , Precursor de Proteína beta-Amiloide/genética , Amiloide , Apolipoproteínas E/genética , Ácido Aspártico Endopeptidasas/genética , Estudio de Asociación del Genoma Completo , Voluntarios Sanos , Presenilina-2/genética , Enfermedad de Alzheimer/genética , Amiloide/sangre , Amiloide/metabolismo , Encéfalo/metabolismo , Humanos , Tomografía de Emisión de PositronesRESUMEN
INTRODUCTION: There is limited and inconsistent reporting on the association between Life's Simple 7 (LS7) and dementia in the elderly population. METHODS: Based on the Washington Heights-Inwood Columbia Aging Project (WHICAP), LS7 scores were estimated to assess cardiovascular health status. Associations between LS7 scores and incident dementia were investigated by Cox proportional hazards models. RESULTS: Among 1987 subjects, 291 incident cases of dementia were identified over a median follow-up of 5.84 years. Compared with subjects in the poor cardiovascular health group (scores 0 to 5), those in intermediate (6 to 9) and optimal (10 to 14) groups had lower dementia risk, with the hazard ratio (HR; 95% confidence interval) being 0.74 (0.54 to 1.00) and 0.59 (0.38 to 0.91), respectively. These results were significant in apolipoprotein E genotype ε4 (APOE ε4) allele non-carriers but not in carriers. DISCUSSION: Higher LS7 scores are protective for dementia, especially among the APOE ε4 noncarriers.
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Apolipoproteína E4/genética , Demencia/epidemiología , Genotipo , Conducta de Reducción del Riesgo , Anciano , Apolipoproteínas E/genética , Índice de Masa Corporal , Colesterol/sangre , Dieta Saludable , Ejercicio Físico , Femenino , Humanos , Estudios Longitudinales , MasculinoRESUMEN
The genetic admixture of Caribbean Hispanics provides an opportunity to discover novel genetic factors in Alzheimer disease (AD). We sought to identify genetic variants for AD through a family-based design using the Puerto Rican (PR) Alzheimer Disease Initiative (PRADI). Whole-genome sequencing (WGS) and parametric linkage analysis were performed for 100 individuals from 23 multiplex PRADI families. Variants were prioritized by minor allele frequency (<0.01), functional potential [combined annotation dependent depletion score (CADD) >10], and co-segregation with AD. Variants were further ranked using an independent PR case-control WGS dataset (PR10/66). A genome-wide significant linkage peak was found in 9p21 with a heterogeneity logarithm of the odds score (HLOD) >5.1, which overlaps with an AD linkage region from two published independent studies. The region harbors C9orf72, but no expanded repeats were observed in the families. Seven variants prioritized by the PRADI families also displayed evidence for association in the PR10/66 (p < 0.05), including a missense variant in UNC13B. Our study demonstrated the importance of family-based design and WGS in genetic study of AD.
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Enfermedad de Alzheimer/genética , Cromosomas Humanos Par 9/genética , Ligamiento Genético , Variación Genética/genética , Estudio de Asociación del Genoma Completo , Proteína C9orf72/genética , Hispánicos o Latinos/genética , Humanos , Proteínas del Tejido Nervioso/genética , Secuenciación Completa del GenomaRESUMEN
PURPOSE OF REVIEW: Early-onset Alzheimer's disease (EOAD), defined as Alzheimer's disease (AD) occurring before age 65, is significantly less well studied than the late-onset form (LOAD) despite EOAD often presenting with a more aggressive disease progression. The aim of this review is to summarize the current understanding of the etiology of EOAD, their translation into clinical practice, and to suggest steps to be taken to move our understanding forward. RECENT FINDINGS: EOAD cases make up 5-10% of AD cases but only 10-15% of these cases show known mutations in the APP, PSEN1, and PSEN2, which are linked to EOAD. New data suggests that these unexplained cases following a non-Mendelian pattern of inheritance is potentially caused by a mix of common and newly discovered rare variants. However, only a fraction of this genetic variation has been identified to date leaving the molecular mechanisms underlying this type of AD and their association with clinical, biomarker, and neuropathological changes unclear. While great advancements have been made in characterizing EOAD, much work is needed to disentangle the molecular mechanisms underlying this type of AD and to identify putative targets for more precise disease screening, diagnosis, prevention, and treatment.
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Enfermedad de Alzheimer , Edad de Inicio , Anciano , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Humanos , Mutación , Presenilina-1/genética , Presenilina-2/genéticaRESUMEN
Importance: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated. Objective: To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel. Design, Setting, and Participants: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019. Main Outcomes and Measures: Diagnosis of Alzheimer disease. Results: A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain ß-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration. Conclusions and Relevance: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.
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Enfermedad de Alzheimer/genética , Negro o Afroamericano/genética , Predisposición Genética a la Enfermedad/genética , Anciano , Femenino , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Metabolic syndrome (MetS) is associated with dementia, but it is unclear whether MetS is related to Alzheimer's disease (AD). We investigated the association of MetS with brain amyloid, a key AD feature, and neurodegeneration. A community-based sample of 350 middle-aged Hispanics in New York City had cerebral amyloid ß (Aß) burden ascertained with 18F-Florbetaben positron emission tomography. Neurodegeneration was ascertained as cortical thickness in AD signature regions from 3T brain MRI. MetS and its components (glucose, blood pressure, triglycerides, high-density lipoprotein, adiposity) were defined using the National Institutes of Health criteria. Neither the presence of MetS nor the MetS score was associated with Aß or neurodegeneration. Among the MetS components, elevated glucose was associated with lower Aß burden, and this association was not explained by diabetes treatment. Glucose and triglycerides were related to smaller cortical thickness. Our findings suggest that MetS as an arbitrary measure of aggregate metabolic and vascular risk does not capture the risk of AD neuropathology in late middle age and that other approaches to measure the aggregate risk should be examined.
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Péptidos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Síndrome Metabólico/metabolismo , Síndrome Metabólico/patología , Degeneración Nerviosa , Factores de Edad , Enfermedad de Alzheimer/etiología , Compuestos de Anilina , Glucemia/metabolismo , Encéfalo/diagnóstico por imagen , Imagen de Difusión Tensora , Femenino , Hispánicos o Latinos , Humanos , Masculino , Persona de Mediana Edad , New York , Riesgo , Estilbenos , Triglicéridos/metabolismoRESUMEN
There is mounting evidence that only a small fraction of early-onset Alzheimer disease cases (onset <65 years) are explained by known mutations. Even multiplex families with early onset often also have late-onset cases, suggesting that the commonly applied categorization of Alzheimer disease into early- and late-onset forms may not reflect distinct underlying etiology. Nevertheless, this categorization continues to govern today's research and the design of clinical trials. The aim of this review is to evaluate this categorization by providing a comprehensive, critical review of reported clinical, neuropathologic, and genomic characteristics of both onset-based subtypes and explore potential overlap between both categories. The article will lay out the need to comprehensively assess the phenotypic, neuropathologic, and molecular variability in Alzheimer disease and identify factors explaining the observed significant variation in onset age in persons with and without known mutations. The article will critically review ongoing large-scale genomic efforts in Alzheimer disease research (e.g., Alzheimer Disease Sequencing Project, Dominantly Inherited Alzheimer Network, Alzheimer Disease Neuroimaging Initiative) and their shortcomings to disentangle the delineation of unexplained nonmendelian early-onset from late-onset and mendelian forms of Alzheimer disease. In addition, it will outline specific approaches including epigenetic research through which a comprehensive characterization of this delineation can be achieved.