Genomic, physiological, and environmental predictors of AD risk, resilience and resistance
AD 风险、复原力和抵抗力的基因组、生理学和环境预测因素
基本信息
- 批准号:10047358
- 负责人:
- 金额:$ 37.05万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-15 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AgeAlzheimer&aposs DiseaseAlzheimer&aposs Disease PathwayAlzheimer&aposs disease riskAmyloid beta-ProteinBlood GlucoseBlood PressureBlood VesselsBrainChronicClinicalCognitionCognitiveCognitive agingCommunitiesDataData SetDatabasesDementiaDiagnosisDiseaseEarly DiagnosisEducationElderlyEnvironmentFramingham Heart StudyFutureGenerationsGenesGeneticGenetic MarkersGenomicsGenotypeGoalsHealthIL6 geneImpaired cognitionIndividualInflammationInflammatoryInvestigationLife StyleLinkLipidsMRI ScansMagnetic Resonance ImagingMeasuresMetabolicModelingMonitorNerve DegenerationNeuropsychologyOnset of illnessOutcomeParticipantPathologyPhenotypePhysiologicalPlasmaPrevention therapyProcessRandomizedResistanceResourcesRiskRisk FactorsStructureSymptomsTNF geneTestingTimeVariantapolipoprotein E-4basecardiovascular risk factorcigarette smokingcognitive abilitycohortcomorbiditydigitaleffective therapyendophenotypegenome wide association studyhigh riskin vivoindexinginflammatory markerinsightmethylomemiddle agemodel buildingneuropathologynovelpersonalized medicinepleiotropismpredictive modelingprognosticprospectiveresilienceresponsesecondary analysissexstatisticstau Proteinstraittranscriptomevascular risk factorwhole genome
项目摘要
The lack of an effective treatment for Alzheimer's disease (AD) has led to a call to detect the disease earlier in
its course. However, AD's insidious onset that can span many years, adds complexity to making an early
diagnosis. It is widely accepted that even among individuals with well-documented AD risk factors (e.g., age,
sex, low education, APOE ε4, high cardiovascular risk, high plasma Aβ40/42 ratio, tau pathology), diagnosis is not
inevitable. By way of its longstanding investigation of cognitive aging and dementia/AD, the Framingham Heart
Study (FHS) has amassed arguably one of richest databases acquired from a community-based cohort. Across
its multi- generational cohorts, participants have undergone up to 7 decades of regular health examinations that
document many co-morbid features linked to future risk of late life cognitive decline and dementia. Because AD-
related processes are likely initiated many years before onset of disease symptoms, one primary objective of
this project is to better elucidate mid-life vascular and inflammatory traits that are associated with AD risk.
Additional unique goals of this project are to leverage this unprecedented resource to identify factors associated
with longitudinal trajectories of cognitive decline, with longitudinal trajectories of neurodegeneration as measured
by MRI, and with resilience to developing cognitive decline. To achieve these goals, we will first apply prediction
modeling approaches to identify measured and derived traits associated with AD and related endophenotypes.
From the extensive list of demographic, lifestyle, vascular/metabolic, plasma and omics measures (including
whole genome, transcriptome, and methylome) already captured as part of the FHS, we will use traditional model
building (guided by a priori determined AD pathways) and data driven approaches to identify traits associated
with (a) MCI, dementia and AD, (b) longitudinal trajectories of cognitive decline, (c) longitudinal trajectories of
structural MRI indices, and (d) AD-related neuropathological indices. We will perform pleiotropy GWAS to identify
shared genetic underpinnings of significantly correlated traits in initial analyses and test whether using digital
neuropsychological phenotypes strengthen findings. Next, using the same database of previously measured
traits, we will apply prediction modeling approaches to identify measured and derived traits associated with
cognitive resistance, as defined by lack of conversion to dementia. Finally, we will identify vascular and
inflammatory moderators of genetic influences by performing Mendelian randomization to assess the causal
relationship between vascular risk factors (e.g., blood glucose, lipid fractions, blood pressure, BMI, cigarette
smoking) and inflammatory markers (e.g., CRP, IL-β, TNFα, IL6) and AD using existing GWAS summary
statistics. For vascular and inflammatory risk factors with significant causal effects, we will assess gene ˣ
environment interactions with variants in targeted genes previously implicated in AD. The novel factors identified
in this project will inform AD prognostication as well as provide insight into disease mechanisms and new targets
for prevention and therapy, heralding a personalized medicine approach to AD.
由于阿尔茨海默病(AD)缺乏有效的治疗方法,人们呼吁尽早发现这种疾病
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Lindsay A. Farrer其他文献
Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer’s disease
- DOI:
10.1186/s13059-025-03564-z - 发表时间:
2025-07-17 - 期刊:
- 影响因子:9.400
- 作者:
Farid Rajabli;Penelope Benchek;Giuseppe Tosto;Nicholas Kushch;Jin Sha;Katrina Bazemore;Congcong Zhu;Wan-Ping Lee;Jacob Haut;Kara L. Hamilton-Nelson;Nicholas R. Wheeler;Yi Zhao;John J. Farrell;Michelle A. Grunin;Yuk Yee Leung;Pavel P. Kuksa;Donghe Li;Eder Lucio da Fonseca;Jesse B. Mez;Ellen L. Palmer;Jagan Pillai;Richard M. Sherva;Yeunjoo E. Song;Xiaoling Zhang;Takeshi Ikeuchi;Taha Iqbal;Omkar Pathak;Otto Valladares;Dolly Reyes-Dumeyer;Amanda B. Kuzma;Erin Abner;Larry D. Adams;Perrie M. Adams;Alyssa Aguirre;Marilyn S. Albert;Roger L. Albin;Mariet Allen;Lisa Alvarez;Liana G. Apostolova;Steven E. Arnold;Sanjay Asthana;Craig S. Atwood;Sanford Auerbach;Gayle Ayres;Clinton T. Baldwin;Robert C. Barber;Lisa L. Barnes;Sandra Barral;Thomas G. Beach;James T. Becker;Gary W. Beecham;Duane Beekly;Bruno A. Benitez;David Bennett;John Bertelson;Thomas D. Bird;Deborah Blacker;Bradley F. Boeve;James D. Bowen;Adam Boxer;James Brewer;James R. Burke;Jeffrey M. Burns;Joseph D. Buxbaum;Nigel J. Cairns;Laura B. Cantwell;Chuanhai Cao;Christopher S. Carlson;Cynthia M. Carlsson;Regina M. Carney;Minerva M. Carrasquillo;Scott Chasse;Marie-Francoise Chesselet;Nathaniel A. Chin;Helena C. Chui;Jaeyoon Chung;Suzanne Craft;Paul K. Crane;David H. Cribbs;Elizabeth A. Crocco;Carlos Cruchaga;Michael L. Cuccaro;Munro Cullum;Eveleen Darby;Barbara Davis;Philip L. De Jager;Charles DeCarli;John DeToledo;Malcolm Dick;Dennis W. Dickson;Beth A. Dombroski;Rachelle S. Doody;Ranjan Duara;NIlüfer Ertekin-Taner;Denis A. Evans;Kelley M. Faber;Thomas J. Fairchild;Kenneth B. Fallon;David W. Fardo;Martin R. Farlow;Victoria Fernandez-Hernandez;Steven Ferris;Robert P. Friedland;Tatiana M. Foroud;Matthew P. Frosch;Brian Fulton-Howard;Douglas R. Galasko;Adriana Gamboa;Marla Gearing;Daniel H. Geschwind;Bernardino Ghetti;John R. Gilbert;Rodney C.P. Go;Alison M. Goate;Thomas J. Grabowski;Neill R. Graff-Radford;Robert C. Green;John H. Growdon;Hakon Hakonarson;James Hall;Ronald L. Hamilton;Oscar Harari;John Hardy;Lindy E. Harrell;Elizabeth Head;Victor W. Henderson;Michelle Hernandez;Timothy Hohman;Lawrence S. Honig;Ryan M. Huebinger;Matthew J. Huentelman;Christine M. Hulette;Bradley T. Hyman;Linda S. Hynan;Laura Ibanez;Gail P. Jarvik;Suman Jayadev;Lee-Way Jin;Kim Johnson;Leigh Johnson;M. Ilyas Kamboh;Anna M. Karydas;Mindy J. Katz;John S. Kauwe;Jeffrey A. Kaye;C. Dirk Keene;Aisha Khaleeq;Masataka Kikuchi;Ronald Kim;Janice Knebl;Neil W. Kowall;Joel H. Kramer;Walter A. Kukull;Frank M. LaFerla;James J. Lah;Eric B. Larson;Alan Lerner;James B. Leverenz;Allan I. Levey;Andrew P. Lieberman;Richard B. Lipton;Mark Logue;Oscar L. Lopez;Kathryn L. Lunetta;Constantine G. Lyketsos;Douglas Mains;Flanagan E. Margaret;Daniel C. Marson;Eden RR. Martin;Frank Martiniuk;Deborah C. Mash;Eliezer Masliah;Paul Massman;Arjun Masurkar;Wayne C. McCormick;Susan M. McCurry;Andrew N. McDavid;Stefan McDonough;Ann C. McKee;Marsel Mesulam;Bruce L. Miller;Carol A. Miller;Joshua W. Miller;Thomas J. Montine;Edwin S. Monuki;John C. Morris;Shubhabrata Mukherjee;Amanda J. Myers;Trung Nguyen;Thomas Obisesan;Sid O’Bryant;John M. Olichney;Marcia Ory;Raymond Palmer;Joseph E. Parisi;Henry L. Paulson;Valory Pavlik;David Paydarfar;Victoria Perez;Elaine Peskind;Ronald C. Petersen;Helen Petrovitch;Aimee Pierce;Marsha Polk;Wayne W. Poon;Huntington Potter;Liming Qu;Mary Quiceno;Joseph F. Quinn;Ashok Raj;Murray Raskind;Eric M. Reiman;Barry Reisberg;Joan S. Reisch;John M. Ringman;Erik D. Roberson;Monica Rodriguear;Ekaterina Rogaeva;Howard J. Rosen;Roger N. Rosenberg;Donald R. Royall;Marwan Sabbagh;A. Dessa Sadovnick;Mark A. Sager;Mary Sano;Andrew J. Saykin;Julie A. Schneider;Lon S. Schneider;William W. Seeley;Susan H. Slifer;Scott Small;Amanda G. Smith;Janet P. Smith;Joshua A. Sonnen;Salvatore Spina;Peter St George-Hyslop;Takiyah D. Starks;Robert A. Stern;Alan B. Stevens;Stephen M. Strittmatter;David Sultzer;Russell H. Swerdlow;Rudolph E. Tanzi;Jeffrey L. Tilson;John Q. Trojanowski;Juan C. Troncoso;Magda Tsolaki;Debby W. Tsuang;Vivianna M. Van Deerlin;Linda J. van Eldik;Jeffery M. Vance;Badri N. Vardarajan;Robert Vassar;Harry V. Vinters;Jean-Paul Vonsattel;Sandra Weintraub;Kathleen A. Welsh-Bohmer;Patrice L. Whitehead;Ellen M. Wijsman;Kirk C. Wilhelmsen;Benjamin Williams;Jennifer Williamson;Henrik Wilms;Thomas S. Wingo;Thomas Wisniewski;Randall L. Woltjer;Martin Woon;Clinton B. Wright;Chuang-Kuo Wu;Steven G. Younkin;Chang-En Yu;Lei Yu;Xiongwei Zhu;Brian W. Kunkle;William S. Bush;Akinori Miyashita;Goldie S. Byrd;Li-San Wang;Lindsay A. Farrer;Jonathan L. Haines;Richard Mayeux;Margaret A. Pericak-Vance;Gerard D. Schellenberg;Gyungah R. Jun;Christiane Reitz;Adam C. Naj - 通讯作者:
Adam C. Naj
Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer’s disease
外显子组测序确定了 ATP8B4 和 ABCA1 中的罕见破坏性变异作为阿尔茨海默病的危险因素
- DOI:
10.1038/s41588-022-01208-7 - 发表时间:
2022-11-21 - 期刊:
- 影响因子:29.000
- 作者:
Henne Holstege;Marc Hulsman;Camille Charbonnier;Benjamin Grenier-Boley;Olivier Quenez;Detelina Grozeva;Jeroen G. J. van Rooij;Rebecca Sims;Shahzad Ahmad;Najaf Amin;Penny J. Norsworthy;Oriol Dols-Icardo;Holger Hummerich;Amit Kawalia;Philippe Amouyel;Gary W. Beecham;Claudine Berr;Joshua C. Bis;Anne Boland;Paola Boss√π;Femke Bouwman;Jose Bras;Dominique Campion;J. Nicholas Cochran;Antonio Daniele;Jean-Fran√ßois Dartigues;St√©phanie Debette;Jean-Fran√ßois Deleuze;Nicola Denning;Anita L. DeStefano;Lindsay A. Farrer;Maria Victoria Fern√°ndez;Nick C. Fox;Daniela Galimberti;Emmanuelle Genin;Johan J. P. Gille;Yann Le Guen;Rita Guerreiro;Jonathan L. Haines;Clive Holmes;M. Arfan Ikram;M. Kamran Ikram;Iris E. Jansen;Robert Kraaij;Marc Lathrop;Afina W. Lemstra;Alberto Lle√≥;Lauren Luckcuck;Marcel M. A. M. Mannens;Rachel Marshall;Eden R. Martin;Carlo Masullo;Richard Mayeux;Patrizia Mecocci;Alun Meggy;Merel O. Mol;Kevin Morgan;Richard M. Myers;Benedetta Nacmias;Adam C. Naj;Valerio Napolioni;Florence Pasquier;Pau Pastor;Margaret A. Pericak-Vance;Rachel Raybould;Richard Redon;Marcel J. T. Reinders;Anne-Claire Richard;Steffi G. Riedel-Heller;Fernando Rivadeneira;St√©phane Rousseau;Natalie S. Ryan;Salha Saad;Pascual Sanchez-Juan;Gerard D. Schellenberg;Philip Scheltens;Jonathan M. Schott;Davide Seripa;Sudha Seshadri;Daoud Sie;Erik A. Sistermans;Sandro Sorbi;Resie van Spaendonk;Gianfranco Spalletta;Niccolo‚Äô Tesi;Betty Tijms;Andr√© G. Uitterlinden;Sven J. van der Lee;Pieter Jelle Visser;Michael Wagner;David Wallon;Li-San Wang;Aline Zarea;Jordi Clarimon;John C. van Swieten;Michael D. Greicius;Jennifer S. Yokoyama;Carlos Cruchaga;John Hardy;Alfredo Ramirez;Simon Mead;Wiesje M. van der Flier;Cornelia M. van Duijn;Julie Williams;Ga√´l Nicolas;C√©line Bellenguez;Jean-Charles Lambert - 通讯作者:
Jean-Charles Lambert
Linkage of polymorphic congenital cataract to the gamma-crystallin gene locus on human chromosome 2q33-35.
多态性先天性白内障与人类染色体 2q33-35 上 γ-晶状体蛋白基因座的连锁。
- DOI:
10.1093/hmg/5.5.699 - 发表时间:
1996 - 期刊:
- 影响因子:3.5
- 作者:
E. Rogaev;E. Rogaev;E. Rogaeva;Galina Korovaitseva;Lindsay A. Farrer;Alexander N. Petrin;Sergey A. Keryanov;Shirine Turaeva;Ilya Chumakov;P. S. George;E. K. Ginter - 通讯作者:
E. K. Ginter
Identification of functional variants from whole-exome sequencing, combined with neuroimaging genetics
通过全外显子组测序结合神经影像遗传学鉴定功能变异
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:11
- 作者:
K. Nho;Jason J. Corneveaux;Sungeun Kim;Hai Lin;S. Risacher;L. Shen;S. Swaminathan;V. Ramanan;Yunlong Liu;T. Foroud;M. Inlow;A. Siniard;Rebecca Reiman;P. Aisen;Ronald C. Petersen;Robert C. Green;C. Jack;Michael W. Weiner;C. Baldwin;K. Lunetta;Lindsay A. Farrer;S. Furney;Simon Lovestone;Andrew Simmons;Patrizia Mecocci;Bruno Vellas;Magda Tsolaki;I. Kloszewska;H. Soininen;B. McDonald;M. Farlow;B. Ghetti;M. Huentelman;A. Saykin - 通讯作者:
A. Saykin
Multiple QTLs influencing triglyceride and HDL and total cholesterol levels identified in families with atherogenic dyslipidemia
- DOI:
10.1194/jlr.m500137-jlr200 - 发表时间:
2005-10-01 - 期刊:
- 影响因子:
- 作者:
Yi Yu;Diego F. Wyszynski;Dawn M. Waterworth;Steven D. Wilton;Philip J. Barter;Y. Antero Kesäniemi;Robert W. Mahley;Ruth McPherson;Gérard Waeber;Thomas P. Bersot;Qianli Ma;Sanjay S. Sharma;Douglas S. Montgomery;Lefkos T. Middleton;Scott S. Sundseth;Vincent Mooser;Scott M. Grundy;Lindsay A. Farrer - 通讯作者:
Lindsay A. Farrer
Lindsay A. Farrer的其他文献
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{{ truncateString('Lindsay A. Farrer', 18)}}的其他基金
Genetic Studies of Alzheimer's Disease in Jewish and Arab Populations
犹太人和阿拉伯人群阿尔茨海默病的遗传学研究
- 批准号:
10639024 - 财政年份:2023
- 资助金额:
$ 37.05万 - 项目类别:
Genomic, physiological, and environmental predictors of AD risk, resilience and resistance
AD 风险、复原力和抵抗力的基因组、生理学和环境预测因子
- 批准号:
10670338 - 财政年份:2020
- 资助金额:
$ 37.05万 - 项目类别:
Genomic, physiological, and environmental predictors of AD risk, resilience and resistance
AD 风险、复原力和抵抗力的基因组、生理学和环境预测因素
- 批准号:
10256773 - 财政年份:2020
- 资助金额:
$ 37.05万 - 项目类别: