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Genetic association analyses of cognitive performance across multi-ancestry older adults: Application of Tobit models

Producción científica: Article › revisión exhaustiva

Resumen

Background: Previous studies investigating associations between genetic variants and late-onset Alzheimer's disease (LOAD)-related cognitive functions included primarily European-ancestry individuals and utilized linear models on neuropsychological test scores with ceiling effects. Objective: Investigate associations between LOAD-related single nucleotide polymorphisms (SNPs) and neuropsychological test scores by applying the superior approach, Tobit (versus linear) regression models, to identify population-specific SNPs associated with cognitive performance across multiple genetic ancestry groups. Methods: National Alzheimer's Coordinating Center (NACC) Uniform Data Set (UDS) and Alzheimer's Disease Genetics Consortium (ADGC) provided phenotype and genotype data on Alzheimer's Disease Research Center (ADRC) participants, respectively. Using the ADGC genotype data, genetic ancestry groups were identified for ADRC participants, including non-Hispanic White (NHW), African American (AA), Hispanic, and Asian. Tobit and linear models were applied to examine genetic associations of 84 LOAD-related SNPs with cognitive performance at the most recent visit, utilizing the NACC UDS data. Results: Genetic architectures varied across genetic ancestry groups. The Tobit model detected the association of TMEM106B-rs13237518(A) missed by the linear model. APOE-rs429358(C) was negatively associated with global cognitive function across ancestry groups. Subgroup analyses recognized associations among participants with a cognitive status of dementia: ADAMTS1-rs2830489(T) for Asians and SHARPIN-rs34173062(A) for Hispanics. Conclusions: Tobit models demonstrated superior model fit for genetic association analyses of global cognition and language test scores exhibiting ceiling effects.

Idioma originalEnglish
Páginas (desde-hasta)1312-1327
Número de páginas16
PublicaciónJournal of Alzheimer's Disease
Volumen108
N.º3
DOI
EstadoPublished - dic 2025

Nota bibliográfica

Publisher Copyright:
© The Author(s) 2025

Financiación

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by the University of Kentucky Center for Clinical and Translational Science (CCTS) Disparities Researchers Equalizing Access for all coMmunities (DREAM) Scholar Program, the National Institute on Aging (NIA) P01AG078116, RF1AG082339, R01AG082730, R01NS118584, R01AG061111, R01AG072559, U24NS133945, the UK-ADC P30AG072946, the Rush-ADRC P30AG072975, the and Alzheimer's Association and NACC's New Investigator Award Program (NIAP) NIAP24-1276268 () which are awarded each year to promising early-career investigators from across the ADRC Program to support their career development and advance their research on Alzheimer's Disease Related Dementia (ADRD). We are extremely grateful to the research volunteers, clinicians, and staff who made this study possible. The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. We thank Drs. D. Stephen Snyder and Marilyn Miller from NIA who are ex-officio ADGC members. Support was also from the Alzheimer's Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147) and the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program. P.S.G.-H. is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research. Alzheimer's Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council),South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England (HEFCE), Alzheimer's Research Trust (ART), BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following grants: ADGC, U01 AG032984, RC2 AG036528; Samples from the National Cell Repository for Alzheimer's Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764, NIMH MH60451 and by Glaxo Smith Kline. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG041232 to AJM and MJH, The Banner Alzheimer's Foundation, The Johnnie B. Byrd Sr. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was funded by the University of Kentucky Center for Clinical and Translational Science (CCTS) Disparities Researchers Equalizing Access for all coMmunities (DREAM) Scholar Program, the National Institute on Aging (NIA) P01AG078116, RF1AG082339, R01AG082730, R01NS118584, R01AG061111, R01AG072559, U24NS133945, the UK-ADC P30AG072946, the Rush-ADRC P30AG072975, the and Alzheimer's Association and NACC's New Investigator Award Program (NIAP) NIAP24-1276268 ( https://naccdata.org/nacc-productivity/new-investigator-awards ) which are awarded each year to promising early-career investigators from across the ADRC Program to support their career development and advance their research on Alzheimer's Disease Related Dementia (ADRD). The NACC database is funded by NIA/NIH Grant U24 AG072122. NACC data are contributed by the NIA-funded ADRCs: P30 AG062429 (PI James Brewer, MD, PhD), P30 AG066468 (PI Oscar Lopez, MD), P30 AG062421 (PI Bradley Hyman, MD, PhD), P30 AG066509 (PI Thomas Grabowski, MD), P30 AG066514 (PI Mary Sano, PhD), P30 AG066530 (PI Helena Chui, MD), P30 AG066507 (PI Marilyn Albert, PhD), P30 AG066444 (PI David Holtzman, MD), P30 AG066518 (PI Lisa Silbert, MD, MCR), P30 AG066512 (PI Thomas Wisniewski, MD), P30 AG066462 (PI Scott Small, MD), P30 AG072979 (PI David Wolk, MD), P30 AG072972 (PI Charles DeCarli, MD), P30 AG072976 (PI Andrew Saykin, PsyD), P30 AG072975 (PI Julie A. Schneider, MD, MS), P30 AG072978 (PI Ann McKee, MD), P30 AG072977 (PI Robert Vassar, PhD), P30 AG066519 (PI Frank LaFerla, PhD), P30 AG062677 (PI Ronald Petersen, MD, PhD), P30 AG079280 (PI Jessica Langbaum, PhD), P30 AG062422 (PI Gil Rabinovici, MD), P30 AG066511 (PI Allan Levey, MD, PhD), P30 AG072946 (PI Linda Van Eldik, PhD), P30 AG062715 (PI Sanjay Asthana, MD, FRCP), P30 AG072973 (PI Russell Swerdlow, MD), P30 AG066506 (PI Glenn Smith, PhD, ABPP), P30 AG066508 (PI Stephen Strittmatter, MD, PhD), P30 AG066515 (PI Victor Henderson, MD, MS), P30 AG072947 (PI Suzanne Craft, PhD), P30 AG072931 (PI Henry Paulson, MD, PhD), P30 AG066546 (PI Sudha Seshadri, MD), P30 AG086401 (PI Erik Roberson, MD, PhD), P30 AG086404 (PI Gary Rosenberg, MD), P20 AG068082 (PI Angela Jefferson, PhD), P30 AG072958 (PI Heather Whitson, MD), P30 AG072959 (PI James Leverenz, MD).

FinanciadoresNúmero del financiador
Alzheimer's Association
Biomedical Laboratory Research Program
Univ. of Art
North Bristol NHS Trust Research and Innovation Department and DeNDRoN
Internationale Stiching Alzheimer Onderzoek
University of Kentucky, Center for Clinical and Translational Science
Canadian Health Research Institute
Coins for Alzheimer's Research Trust
Netherlands Brain Bank
Hersenstichting Nederland Breinbrekend Werk
Higher Education Funding Council for England
Newcastle Brain Tissue Resource
Wellcome Trust
Institut de Neuropatologia
South West Dementia Brain Bank
National Institutes of Health (NIH)
Newcastle University
Kronos Science
UK Medical Research Council, Engineering and Physical Sciences Research Council
1Florida Alzheimer's Disease Research Center
Stichting Vanderes
NCATS CCTS
BRACE
Hong Kong Arts Development Council
Howard Hughes Medical Institute
US Department of Veterans Affairs Administration
Biomedical Laboratory Research and Development, VA Office of Research and Development
NIA ADRC NACC
Banner Alzheimer's Foundation
MRC London Brain Bank for Neurodegenerative Diseases
NIA/NIH
International Parkinson Fonds
National Alzheimer's Coordinating Center
Universitat de Barcelona
HEFCE
Glaxo Smith Kline
Alzheimer's Disease Related Dementia
Rush-ADRCP30AG072975
ADGCRC2 AG036528, U01 AG032984
NINDS FIRSTNS39764
LAFIIRG-05-14147, IIRG-08-89720
NIMHMH60451
NIAAG041232
NIAPNIAP24-1276268
National Institute on AgingR01AG061111, U24NS133945, R01AG082730, RF1AG082339, R01AG072559, P01AG078116, R01NS118584
UK-ADCP30AG072946
NIHU24 AG072122
National Cell Repository for Alzheimer's DiseaseU24 AG21886

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    ASJC Scopus subject areas

    • General Neuroscience
    • Clinical Psychology
    • Geriatrics and Gerontology
    • Psychiatry and Mental health

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