Evidence map›Paper›PMID 35120553›Full record

ArticleAlzheimer's research & therapy2022

Challenges at the APOE locus: a robust quality control approach for accurate APOE genotyping.

Michael E Belloy, Sarah J Eger, Yann Le Guen, Vincent Damotte, Shahzad Ahmad, M Arfan Ikram, Alfredo Ramirez, Anthoula C Tsolaki, Giacomina Rossi, Iris E Jansen and 19 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Alzheimer's research & therapy, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
15citing papers in PubMed, 1 pooled it
3.2field-weighted citation impact, top 8% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

15 citing papers in PubMed, 1 synthesis or guideline pooled it, 19 citations in OpenAlex.

  1. Pooled it
  2. Article
  3. Article
  4. Article
  5. Article
  6. Article
  7. Article
  8. Review
  9. Impact of APOE4-related dementia risk in underrepresented groups from the All of Us research program.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
    Article
  10. Alzheimer's Disease Sequencing Project release 4 whole genome sequencing dataset.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
    Article
  11. Alzheimer's Disease Sequencing Project Release 4 Whole Genome Sequencing Dataset.medRxiv : the preprint server for health sciences · 2024
    Article
  12. Article
  13. Article
  14. Article
  15. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

29 authors at 19 institutions in 13 countries.

Michael E BelloyDepartment of Neurology and Neurological Sciences - Greicius lab, Stanford University, 290 Jane Stanford Way, Stanford, CA, 94304, USA. mbelloy@stanford.edu.ORCID 0000-0001-7748-9033
Sarah J EgerDepartment of Neurology and Neurological Sciences - Greicius lab, Stanford University, 290 Jane Stanford Way, Stanford, CA, 94304, USA.
Yann Le GuenDepartment of Neurology and Neurological Sciences - Greicius lab, Stanford University, 290 Jane Stanford Way, Stanford, CA, 94304, USA.
Vincent DamotteUniv. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.
Shahzad AhmadDepartment of Epidemiology, ErasmusMC, Rotterdam, The Netherlands.
M Arfan IkramDepartment of Epidemiology, ErasmusMC, Rotterdam, The Netherlands.
Alfredo RamirezDivision of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Anthoula C Tsolaki1st Department of Neurology, AHEPA Hospital, Aristotle University of Thessaloniki, Athens, Greece.
Giacomina RossiUnit of Neurology V and Neuropathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Iris E JansenAlzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
Itziar de RojasResearch Center and Memory Clinic, ACE Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain.
Kayenat ParveenDivision of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Kristel SleegersComplex Genetics of Alzheimer's Disease Group, Center for Molecular Neurology, VIB, Antwerp, Belgium.
Martin IngelssonDepartment of Public Health and Carins Sciences/Geriatrics, Uppsala University, Uppsala, Sweden.
Mikko HiltunenInstitute of Biomedicine, University of Eastern Finland, Yliopistonranta 1E, 70211, Kuopio, Finland.
Najaf AminDepartment of Epidemiology, ErasmusMC, Rotterdam, The Netherlands.
Ole AndreassenNORMENT Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
Pascual Sánchez-JuanCIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain.
Patrick KehoeTranslational Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Philippe AmouyelUniv. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.
Rebecca SimsDivision of Psychological Medicine and Clinical Neuroscience, School of Medicine, Cardiff University, Wales, UK.
Ruth Frikke-SchmidtDepartment of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
Wiesje M van der FlierAlzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
Jean-Charles LambertUniv. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, France.
European Alzheimer & Dementia BioBank (EADB)
Zihuai HeDepartment of Neurology and Neurological Sciences - Greicius lab, Stanford University, 290 Jane Stanford Way, Stanford, CA, 94304, USA.
Summer S HanQuantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, CA, 94304, USA.
Valerio NapolioniSchool of Biosciences and Veterinary Medicine, University of Camerino, 62032, Camerino, Italy.
Michael D GreiciusDepartment of Neurology and Neurological Sciences - Greicius lab, Stanford University, 290 Jane Stanford Way, Stanford, CA, 94304, USA.
Stanford Medicine · USInserm · FRAmsterdam Neuroscience · NLErasmus MC · NLUniversità di Camerino · ITUniversity of Cologne · DEAristotle University of Thessaloniki · GRCardiff University · GBFondazione IRCCS Istituto Neurologico Carlo Besta · ITInstituto de Salud Carlos III · ESLeiden University · NLOslo University Hospital · NOStanford University · USUniversidad de Cantabria · ESUniversity of Antwerp · BEUniversity of Bristol · GBUniversity of Copenhagen · DKUniversity of Eastern Finland · FIUppsala University · SE

Funding

Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6M
Large Scale Genome SequencingU54HG003079 · NHGRI · WASHINGTON UNIVERSITY · PI DUTCHER, SUSAN K · 2004 to 2016
$445.7M
The Human Genome Sequencing CenterU54HG003273 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI GIBBS, RICHARD A · 2004 to 2015
$341.3M
Project 1U19AG024904 · NIA · NORTHERN CALIFORNIA INSTITUTE/RES/EDU · PI Paul S. Aisen · 2016 to 2026
$226.7M
Alzheimer's Disease Neuroimaging Initiative - SupplementU01AG024904 · NIA · NORTHERN CALIFORNIA INSTITUTE RES &EDUC · PI WEINER, MICHAEL W · 2004 to 2015
$121.0M
National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)U24AG021886 · NIA · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI TATIANA M. FOROUD · 2002 to 2026
$119.8M
TRIAL OF VALPROATE TO ATTENUATE THE PROGRESSION OF ADU01AG010483 · NIA · UNIVERSITY OF ROCHESTER · PI AISEN, PAUL S. · 1991 to 2012
$116.2M
VCID and Stroke in a Bi-racial National CohortU01NS041588 · NINDS · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI CUSHMAN, MARY, HOWARD, GEORGE · 2002 to 2022
$96.0M
NATIONAL ALZHEIMERS COORDINATING CENTER (NACC)U01AG016976 · NIA · UNIVERSITY OF WASHINGTON · PI KUKULL, WALTER ANTHONY · 1999 to 2020
$72.8M
Smartphone-Based "Burst" Cognitive AssessmentsP01AG003991 · NIA · WASHINGTON UNIVERSITY · PI JOHN MORRIS · 1985 to 2026
$69.5M
TDP-43 Loss-of-Function: Biology to BiomarkersP01AG019724 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Jennifer Merrilees · 2002 to 2026
$67.2M
ARIC Neurocognitive Study (ARIC-NCS) Renewal 2023-2028U01HL096812 · NHLBI · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · PI JOSEF CORESH, THOMAS H MOSLEY · 2010 to 2026
$65.7M
Austrian Science Fund FWF I 904Medical Research Council MR/K013041/1Medical Research Council MR/L023784/1Medical Research Council MR/L501517/1NCI NIH HHS R01 CA129769NCRR NIH HHS KL2 RR024151NCRR NIH HHS UL1 RR029893NHGRI NIH HHS RC2 HG005605NHGRI NIH HHS U01 HG004610NHGRI NIH HHS U01 HG006375NHGRI NIH HHS U01 HG008657NHGRI NIH HHS U54 HG003067NHGRI NIH HHS U54 HG003079NHGRI NIH HHS U54 HG003273NHLBI NIH HHS HHSN268200800007CNHLBI NIH HHS HHSN268201100005CNHLBI NIH HHS HHSN268201100005GNHLBI NIH HHS HHSN268201100005INHLBI NIH HHS HHSN268201100006CNHLBI NIH HHS HHSN268201100007CNHLBI NIH HHS HHSN268201100007INHLBI NIH HHS HHSN268201100008CNHLBI NIH HHS HHSN268201100008INHLBI NIH HHS HHSN268201100009CNHLBI NIH HHS HHSN268201100009INHLBI NIH HHS HHSN268201100010CNHLBI NIH HHS HHSN268201100011CNHLBI NIH HHS HHSN268201100011INHLBI NIH HHS HHSN268201100012CNHLBI NIH HHS HHSN268201200036CNHLBI NIH HHS HHSN268201500001CNHLBI NIH HHS HHSN268201500001INHLBI NIH HHS N01 HC025195NHLBI NIH HHS N01 HC055222NHLBI NIH HHS N01 HC085079NHLBI NIH HHS N01 HC085080NHLBI NIH HHS N01 HC085081NHLBI NIH HHS N01 HC085082NHLBI NIH HHS N01 HC085083NHLBI NIH HHS N01 HC085086NHLBI NIH HHS R01 HL070825NHLBI NIH HHS R01 HL105756NHLBI NIH HHS RC2 HL102419NHLBI NIH HHS U01 HL080295NHLBI NIH HHS U01 HL096812NHLBI NIH HHS U01 HL096814NHLBI NIH HHS U01 HL096899NHLBI NIH HHS U01 HL096902NHLBI NIH HHS U01 HL096917NHLBI NIH HHS U01 HL130114NIA NIH HHS K23 AG030944NIA NIH HHS P01 AG002219NIA NIH HHS P01 AG003991NIA NIH HHS P01 AG010491NIA NIH HHS P01 AG019724NIA NIH HHS P01 AG026276NIA NIH HHS P30 AG008017NIA NIH HHS P30 AG008051NIA NIH HHS P30 AG010124NIA NIH HHS P30 AG010129NIA NIH HHS P30 AG010133NIA NIH HHS P30 AG010161NIA NIH HHS P30 AG012300NIA NIH HHS P30 AG013846NIA NIH HHS P30 AG013854NIA NIH HHS P30 AG019610NIA NIH HHS P30 AG028377NIA NIH HHS P30 AG028383NIA NIH HHS P30 AG035982NIA NIH HHS P30 AG049638NIA NIH HHS P30 AG053760NIA NIH HHS P30 AG062421NIA NIH HHS P30 AG062422NIA NIH HHS P30 AG062428NIA NIH HHS P30 AG062429NIA NIH HHS P30 AG062715NIA NIH HHS P30 AG066444NIA NIH HHS P30 AG072947NIA NIH HHS P50 AG005128NIA NIH HHS P50 AG005131NIA NIH HHS P50 AG005133NIA NIH HHS P50 AG005134NIA NIH HHS P50 AG005136NIA NIH HHS P50 AG005138NIA NIH HHS P50 AG005142NIA NIH HHS P50 AG005144NIA NIH HHS P50 AG005146NIA NIH HHS P50 AG005681NIA NIH HHS P50 AG008012NIA NIH HHS P50 AG008702NIA NIH HHS P50 AG016570NIA NIH HHS P50 AG016573NIA NIH HHS P50 AG016574NIA NIH HHS P50 AG016582NIA NIH HHS P50 AG023501NIA NIH HHS P50 AG025688NIA NIH HHS P50 AG033514NIA NIH HHS P50 AG047266NIA NIH HHS P50 AG047270NIA NIH HHS P50 AG047366NIA NIH HHS R01 AG009029NIA NIH HHS R01 AG009956NIA NIH HHS R01 AG011101NIA NIH HHS R01 AG011380NIA NIH HHS R01 AG012101NIA NIH HHS R01 AG013616NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG015928NIA NIH HHS R01 AG017173NIA NIH HHS R01 AG017917NIA NIH HHS R01 AG017919NIA NIH HHS R01 AG018016NIA NIH HHS R01 AG019085NIA NIH HHS R01 AG019757NIA NIH HHS R01 AG020098NIA NIH HHS R01 AG020688NIA NIH HHS R01 AG021136NIA NIH HHS R01 AG021547NIA NIH HHS R01 AG022018NIA NIH HHS R01 AG022374NIA NIH HHS R01 AG023629NIA NIH HHS R01 AG025259NIA NIH HHS R01 AG026390NIA NIH HHS R01 AG026916NIA NIH HHS R01 AG027944NIA NIH HHS R01 AG028786NIA NIH HHS R01 AG030146NIA NIH HHS R01 AG030653NIA NIH HHS R01 AG031272NIA NIH HHS R01 AG031581NIA NIH HHS R01 AG032990NIA NIH HHS R01 AG033040NIA NIH HHS R01 AG033193NIA NIH HHS R01 AG035137NIA NIH HHS R01 AG036836NIA NIH HHS R01 AG037212NIA NIH HHS R01 AG037985NIA NIH HHS R01 AG041232NIA NIH HHS R01 AG041718NIA NIH HHS R01 AG041797NIA NIH HHS R01 AG042437NIA NIH HHS R01 AG048927NIA NIH HHS R01 AG049607NIA NIH HHS R01 AG054076NIA NIH HHS R01 AG060747NIA NIH HHS R01 AG066206NIA NIH HHS R37 AG015473NIA NIH HHS R56 AG051876NIA NIH HHS RC2 AG036502NIA NIH HHS RC2 AG036528NIA NIH HHS RC2 AG036650NIA NIH HHS RC4 AG039085NIA NIH HHS RF1 AG015473NIA NIH HHS RF1 AG051504NIA NIH HHS RF1 AG054023NIA NIH HHS RF1 AG054052NIA NIH HHS RF1 AG054074NIA NIH HHS RF1 AG058066NIA NIH HHS RF1 AG058267NIA NIH HHS U01 AG006781NIA NIH HHS U01 AG010483NIA NIH HHS U01 AG016976NIA NIH HHS U01 AG024904NIA NIH HHS U01 AG032984NIA NIH HHS U01 AG046139NIA NIH HHS U01 AG046152NIA NIH HHS U01 AG049505NIA NIH HHS U01 AG049506NIA NIH HHS U01 AG049507NIA NIH HHS U01 AG049508NIA NIH HHS U01 AG052409NIA NIH HHS U01 AG052410NIA NIH HHS U01 AG052411NIA NIH HHS U01 AG057659NIA NIH HHS U01 AG062602NIA NIH HHS U19 AG024904NIA NIH HHS U24 AG021886NIA NIH HHS U24 AG026395NIA NIH HHS U24 AG041689NIA NIH HHS UF1 AG047133NIDDK NIH HHS U01 DK066134NIMHD NIH HHS P20 MD000546NIMH NIH HHS P50 MH060451NIMH NIH HHS R01 MH080295NINDS NIH HHS P01 NS026630NINDS NIH HHS P50 NS039764NINDS NIH HHS P50 NS071674NINDS NIH HHS R01 NS017950NINDS NIH HHS R01 NS029993NINDS NIH HHS R01 NS059873NINDS NIH HHS R01 NS069719NINDS NIH HHS R01 NS080820NINDS NIH HHS U01 NS041588Wellcome Trust
6 · The paper itself

Abstract

backgroundGenetic variants within the APOE locus may modulate Alzheimer's disease (AD) risk independently or in conjunction with APOE*2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of APOE pathophysiology and provide critical guidance for AD therapies aimed at APOE. The APOE locus however remains relatively poorly understood in AD, owing to multiple challenges that include its complex linkage structure and uncertainty in APOE*2/3/4 genotype quality. Here, we present a novel APOE*2/3/4 filtering approach and showcase its relevance on AD risk association analyses for the rs439401 variant, which is located 1801 base pairs downstream of APOE and has been associated with a potential regulatory effect on APOE.

methodsWe used thirty-two AD-related cohorts, with genetic data from various high-density single-nucleotide polymorphism microarrays, whole-genome sequencing, and whole-exome sequencing. Study participants were filtered to be ages 60 and older, non-Hispanic, of European ancestry, and diagnosed as cognitively normal or AD (n = 65,701). Primary analyses investigated AD risk in APOE*4/4 carriers. Additional supporting analyses were performed in APOE*3/4 and 3/3 strata. Outcomes were compared under two different APOE*2/3/4 filtering approaches.

resultsUsing more conventional APOE*2/3/4 filtering criteria (approach 1), we showed that, when in-phase with APOE*4, rs439401 was variably associated with protective effects on AD case-control status. However, when applying a novel filter that increases the certainty of the APOE*2/3/4 genotypes by applying more stringent criteria for concordance between the provided APOE genotype and imputed APOE genotype (approach 2), we observed that all significant effects were lost.

conclusionsWe showed that careful consideration of APOE genotype and appropriate sample filtering were crucial to robustly interrogate the role of the APOE locus on AD risk. Our study presents a novel APOE filtering approach and provides important guidelines for research into the APOE locus, as well as for elucidating genetic interaction effects with APOE*2/3/4.

Indexed as

Alzheimer DiseaseApolipoproteins EApolipoprotein E4Genetic Predisposition to DiseaseGenotypeHumansMiddle AgedQuality ControlApolipoprotein E4Apolipoproteins EAlzheimer’s disease (AD)Apolipoprotein E (APOE)GeneticsHaplotypesNovel approachesrs439401

Identifiers

PMID35120553
PMCPMC8815198
OpenAlexW4220762197

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.