CoChat
Sign Up
Cited by 54Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsGenetic Associations and Epidemiology

Association and interaction effects of Alzheimer’s disease-associated genes and lifestyle on cognitive aging in older adults in a Taiwanese population

Open access
Lin, Eugene, Tsai, Shih-Jen, Kuo, Po-Hsiu, Liu, Yu-Li, Yang, Albert C., Kao, Chung-Feng·2017·Oncotarget
DOI 10.18632/oncotarget.15269PMC PMC5421828
Open this paper in CoChat — free accountOpen PDF

Abstract

// Eugene Lin 1,2,3,* , Shih-Jen Tsai 4,5,* , Po-Hsiu Kuo 6 , Yu-Li Liu 7 , Albert C. Yang 4,5 and Chung-Feng Kao 8 1 Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan 2 Vita Genomics, Inc., Taipei, Taiwan 3 TickleFish Systems Corporation, Seattle, WA, USA 4 Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan 5 Division of Psychiatry, National Yang-Ming University, Taipei, Taiwan 6 Department of Public Health, Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan 7 Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli County, Taiwan 8 Department of Agronomy, College of Agriculture & Natural Resources, National Chung Hsing University, Taichung, Taiwan * These authors have contributed equally to this work Correspondence to: Eugene Lin, email: // Shih-Jen Tsai, email: // Keywords : Alzheimer’s diseases; cognitive aging; gene-gene and gene-lifestyle interactions; Mini-Mental State Examination; single nucleotide polymorphisms; Gerotarget Received : October 17, 2016 Accepted : January 29, 2017 Published : February 11, 2017 Abstract Genome-wide association studies and meta-analyses implicated that increased risk of developing Alzheimer’s diseases (AD) has been associated with the ABCA7 , APOE , BIN1 , CASS4 , CD2AP , CD33 , CELF1 , CLU , CR1 , DSG2 , EPHA1 , FERMT2 , HLA-DRB1 , HLA-DRB4 , INPP5D , MEF2C , MS4A4A , MS4A4E , MS4A6E , NME8 , PICALM , PLD3 , PTK2B , RIN3 , SLC24A4 , SORL1 , and ZCWPW1 genes. In this study, we assessed whether single nucleotide polymorphisms (SNPs) within these 27 AD-associatedgenes are linked with cognitive aging independently and/or through complex interactions in an older Taiwanese population. We also analyzed the interactions between lifestyle and these genes in influencing cognitive aging. A total of 634 Taiwanese subjects aged over 60 years from the Taiwan Biobank were analyzed. Mini-Mental State Examination (MMSE) scores were performed for all subjects to evaluate cognitive functions. Out of the 588 SNPs tested in this study, only the association between CASS4 -rs911159 and cognitive aging persisted significantly ( P = 2.2 x 10 -5 ) after Bonferroni correction. Our data also showed a nominal association of cognitive aging with the SNPs in six more key AD-associated genes, including EPHA1- rs10952552, FERMT2- rs4901317, MEF2C- rs9293506, PLD3- rs11672825, RIN3- rs1885747, and SLC24A4 -rs67063100 ( P = 0.0018~0.0097). Additionally, we found the interactions among CASS4- rs911159, EPHA- rs10952552, FERMT2- rs4901317, MEF2C- rs9293506, or SLC24A4- rs67063100 on cognitive aging ( P = 0.004~0.035). Moreover, our analysis suggested the interactions of SLC24A4- rs67063100 or MEF2C -rs9293506 with lifestyle such as alcohol consumption, smoking status, physical activity, or social support on cognitive aging ( P = 0.008~0.041). Our study indicates that the AD-associated genes may contribute to the risk of cognitive aging independently as well as through gene-gene and gene-lifestyle interactions.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.18632/oncotarget.15269

Cites

5 of 5 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Focal adhesion signaling has recently been linked to AD through both genetic risk factors and Aβ-associated signaling events.

    “Interestingly, focal adhesion signaling has re­ cently been linked to AD through both genetic risk factors and Aβ-associated signaling events (Grace and Busciglio, 2003; Lambert et al., 2013; Lin et al., 2017; Manocha et al., 2015; Ramos de Matos et al., 2018; Saleh et al., 2022; Schwartzentruber et al., 2021; Wang et al., 2015b)”

    From Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis (2026) · cites this paper as Lin et al., 2017

    The Discussion (page not provided) links CASS4 to focal adhesion integrity and kinase activation, and reports its association with AD risk. It does not establish Aβ-associated focal adhesion signaling events; its discussion of amyloid precursor protein is speculative and does not make that connection. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The SNP rs9293506 within the MEF2C gene has been linked to cognitive aging in Taiwanese populations.

    “In addition to SPI1, the SNPs rs190982 and rs9293506 within the microglial transcription factor gene Myocyte Enhancer Factor 2C (MEF2C) have been linked to Alzheimer's disease risk and cognitive aging in Caucasian [25] and Taiwanese [27] populations, respectively.”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [27]

  • The CASS4 gene locus has consistently been identified in GWAS studies to be associated with an increased risk of developing AD.

    “The CASS4 gene locus has consistently been identified in GWAS studies to be associated with an increased risk of developing AD (Lambert et al., 2013; Lin et al., 2017; Ramos de Matos et al., 2018; Schwartzentruber et al., 2021; Wang et al., 2015b).”

    From Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis (2026) · cites this paper as Lin et al., 2017

  • Mutations in the focal adhesion gene PTK2B have been linked to increased AD risk in GWAS studies.

    “Moreover, mutations in the focal adhesion gene PTK2B , which encodes the protein PYK2 and is a suggested CASS4binding partner (Barrett et al., 2013; Beck et al., 2014), have also been linked to increased AD risk in GWAS studies (Lambert et al., 2013; Lin et al., 2017; Ramos de Matos et al., 2018; Schwartzentruber et al., 2021; Wang et al., 2015b).”

    From Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis (2026) · cites this paper as Lin et al., 2017

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 42

  1. [1]Committee on the Public Health Dimensions of Cognitive Aging Board on Health Sciences Policy Institute of Medicine Blazer DG Yaffe K Liverman CT Cognitive Aging: Progress in Understanding and Opportunities for Action Washington, DC, USA National Academies Press 2015 7 25879131
  2. [2]Katz MJ Lipton RB Hall CB Zimmerman ME Sanders AE Verghese J Dickson DW Derby CA Age-specific and sex-specific prevalence and incidence of mild cognitive impairment, dementia, and Alzheimer dementia in blacks and whites: a report from the Einstein Aging Study Alzheimer Dis Assoc Disord 2012 26 335 43 22156756 PMC3334445
  3. [3]Barnes LL Bennett DA Alzheimer’s disease in African Americans: risk factors and challenges for the future Health Aff (Millwood) 2014 33 580 6 24711318 PMC4084964
  4. [4]Dubois B Feldman HH Jacova C Hampel H Molinuevo JL Blennow K DeKosky ST Gauthier S Selkoe D Bateman R Cappa S Crutch S Engelborghs S Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria Lancet Neurol 2014 13 614 29 24849862
  5. [5]Jack CR Jr Bennett DA Blennow K Carrillo MC Feldman HH Frisoni GB Hampel H Jagust WJ Johnson KA Knopman DS Petersen RC Scheltens P Sperling RA A/T/N: An unbiased descriptive classification scheme for Alzheimer disease biomarkers Neurology 2016 87 539 47 27371494 PMC4970664
  6. [7]Lambert JC Heath S Even G Campion D Sleegers K Hiltunen M Combarros O Zelenika D Bullido MJ Tavernier B Letenneur L Bettens K Berr C Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease Nat Genet 2009 41 1094 9 19734903
  7. [8]Seshadri S Fitzpatrick AL Ikram MA DeStefano AL Gudnason V Boada M Bis JC Smith AV Carassquillo MM Lambert JC Harold D Schrijvers EM Ramirez-Lorca R Genome-wide analysis of genetic loci associated with Alzheimer disease JAMA 2010 303 1832 40 20460622 PMC2989531
  8. [10]Hollingworth P Harold D Sims R Gerrish A Lambert JC Carrasquillo MM Abraham R Hamshere ML Pahwa JS Moskvina V Dowzell K Jones N Stretton A Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease Nat Genet 2011 43 429 35 21460840 PMC3084173
  9. [11]Lambert JC Ibrahim-Verbaas CA Harold D Naj AC Sims R Bellenguez C DeStafano AL Bis JC Beecham GW Grenier-Boley B Russo G Thorton-Wells TA Jones N Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease Nat Genet 2013 45 1452 8 24162737 PMC3896259
  10. [13]Ebbert MT Ridge PG Wilson AR Sharp AR Bailey M Norton MC Tschanz JT Munger RG Corcoran CD Kauwe JS Population-based analysis of Alzheimer’s disease risk alleles implicates genetic interactions Biol Psychiatry 2014 75 732 7 23954108 PMC3867586
  11. [14]Ebbert MT Boehme KL Wadsworth ME Staley LA Alzheimer’s Disease Neuroimaging Initiative Alzheimer’s Disease Genetics Consortium Mukherjee S Crane PK Ridge PG Kauwe JS Interaction between variants in CLU and MS4A4E modulates Alzheimer’s disease risk Alzheimers Dement 2016 12 121 9 26449541 PMC4744542
  12. [15]Chibnik LB Shulman JM Leurgans SE Schneider JA Wilson RS Tran D Aubin C Buchman AS Heward CB Myers AJ Hardy JA Huentelman MJ Corneveaux JJ et al CR1 is associated with amyloid plaque burden and age-related cognitive decline Ann Neurol 2011 69 560 9 21391232 PMC3066288
  13. [16]Nettiksimmons J Tranah G Evans DS Yokoyama JS Yaffe K Gene-based aggregate SNP associations between candidate AD genes and cognitive decline Age (Dordr) 2016 38 41 27005436 PMC5005889
  14. [18]Karch CM Goate AM Alzheimer’s disease risk genes and mechanisms of disease pathogenesis Biol Psychiatry 2015 77 43 51 24951455 PMC4234692
  15. [19]Beecham GW Hamilton K Naj AC Martin ER Huentelman M Myers AJ Corneveaux JJ Hardy J Vonsattel JP Younkin SG Bennett DA De_Jager PL Larson EB et al Genome-wide association meta-analysis of neuropathologic features of Alzheimer’s disease and related dementias PLoS Genet 2014 10 e1004606 25188341 PMC4154667
  16. [20]Ruiz A Heilmann S Becker T Hernández I Wagner H Thelen M Mauleón A Rosende-Roca M Bellenguez C Bis JC Harold D Gerrish A Sims R et al Follow-up of loci from the International Genomics of Alzheimer’s Disease Project identifies TRIP4 as a novel susceptibility gene Transl Psychiatry 2014 4 e358 24495969 PMC3944635
  17. [21]Rosenthal SL Barmada MM Wang X Demirci FY Kamboh MI Connecting the dots: potential of data integration to identify regulatory SNPs in late-onset Alzheimer’s disease GWAS findings PLoS One 2014 9 e95152 24743338 PMC3990600
  18. [22]Wang X Lopez OL Sweet RA Becker JT DeKosky ST Barmada MM Demirci FY Kamboh MI Genetic determinants of disease progression in Alzheimer’s disease J Alzheimers Dis 2015 43 649 55 25114068 PMC4245313
  19. [23]Larsson M Duffy DL Zhu G Liu JZ Macgregor S McRae AF Wright MJ Sturm RA Mackey DA Montgomery GW Martin NG Medland SE GWAS findings for human iris patterns: associations with variants in genes that influence normal neuronal pattern development Am J Hum Genet 2011 89 334 43 21835309 PMC3155193
  20. [25]Akhtar MW Kim MS Adachi M Morris MJ Qi X Richardson JA Bassel-Duby R Olson EN Kavalali ET Monteggia LM In vivo analysis of MEF2 transcription factors in synapse regulation and neuronal survival PLoS One 2012 7 e34863 22496871 PMC3322166
  21. [26]Chapuis J Hansmannel F Gistelinck M Mounier A Van_Cauwenberghe C Kolen KV Geller F Sottejeau Y Harold D Dourlen P Grenier-Boley B Kamatani Y Delepine B et al Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology Mol Psychiatry 2013 18 1225 34 23399914 PMC3807661
  22. [27]Yu L Chibnik LB Srivastava GP Pochet N Yang J Xu J Kozubek J Obholzer N Leurgans SE Schneider JA Meissner A De_Jager PL Bennett DA Association of Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 with pathological diagnosis of Alzheimer disease JAMA Neurol 2015 72 15 24 25365775 PMC4344367
  23. [28]Kajiho H Saito K Tsujita K Kontani K Araki Y Kurosu H Katada T RIN3: a novel Rab5 GEF interacting with amphiphysin II involved in the early endocytic pathway J Cell Sci 2003 116 4159 68 12972505
  24. [29]Lee SH Harold D Nyholt DR ANZGene Consortium International Endogene Consortium Genetic and Environmental Risk for Alzheimer’s disease Consortium Goddard ME Zondervan KT Williams J Montgomery GW Wray NR Visscher PM Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer’s disease, multiple sclerosis and endometriosis Hum Mol Genet 2013 22 832 41 23193196 PMC3554206
  25. [30]Sheehan B Assessment scales in dementia Ther Adv Neurol Disord 2012 5 349 58 23139705 PMC3487532
  26. [31]Rockwood K Fay S Gorman M Carver D Graham JE The clinical meaningfulness of ADAS-Cog changes in Alzheimer’s disease patients treated with donepezil in an open-label trial BMC Neurol 2007 7 26 17760991 PMC2034585
  27. [32]Hsiao TJ Hwang Y Chang HM Lin E Association of the rs6235 variant in the proprotein convertase subtilisin/kexin type 1 (PCSK1) gene with obesity and related traits in a Taiwanese population Gene 2014 533 32 7 24140494
  28. [33]Hsiao TJ Lin E A common rs7903146 variant of the transcription factor 7 like 2 gene is associated with type 2 diabetes mellitus and fasting glucose in a Taiwanese population Diabetes Metab 10.1016/j.diabet.2016.05.003 27286737 · DOI
  29. [34]Hsiao TJ Lin E Evaluation of the glutamine 27 glutamic acid polymorphism in the adrenoceptor beta 2 surface gene on obesity and metabolic phenotypes in Taiwan J Investig Med 2014 62 310 5 24322328
  30. [35]Lane HY Tsai GE Lin E Assessing gene-gene interactions in pharmacogenomics Mol Diagn Ther 2012 16 15 27 22352452
  31. [36]Hsiao TJ Lin E Association of a common rs9939609 variant in the fat mass and obesity-associated (FTO) gene with obesity and metabolic phenotypes in a Taiwanese population: a replication study J Genet 2016 95 595 601 27659330
  32. [37]Hsiao TJ Lin E A validation study of adiponectin rs266729 gene variant with type 2 diabetes, obesity, and metabolic phenotypes in a Taiwanese population Biochem Genet 2016 54 830 841 27388775
  33. [38]Fan CT Lin JC Lee CH Taiwan Biobank: a project aiming to aid Taiwan’s transition into a biomedical island Pharmacogenomics 2008 9 235 46 18370851
  34. [39]Lin E Kuo PH Liu YL Yang AC Kao CF Tsai SJ Association and interaction of APOA5, BUD13, CETP, LIPA and health-related behavior with metabolic syndrome in a Taiwanese population Sci Rep 2016 6 36830 27827461 PMC5101796
  35. [40]Chen CH Yang JH Chiang CW Hsiung CN Wu PE Chang LC Chu HW Chang J Song IW Yang SL Chen YT Liu FT Shen CY Population structure of Han Chinese in the modern Taiwanese population based on 10,000 participants in the Taiwan Biobank project Hum Mol Genet 2016 10 18. [Epub ahead of print]. PMC6078601 27798100
  36. [41]Liou YJ Bai YM Lin E Chen JY Chen TT Hong CJ Tsai SJ Gene-gene interactions of the INSIG1 and INSIG2 in metabolic syndrome in schizophrenic patients treated with atypical antipsychotics Pharmacogenomics J 2012 12 54 61 20877301
  37. [42]Hsiao TJ Lin E The ENPP1 K121Q polymorphism is associated with type 2 diabetes and related metabolic phenotypes in a Taiwanese population Mol Cell Endocrinol 2016 433 20 25 27238374
  38. [43]Felsky D Szeszko P Yu L Honer WG De_Jager PL Schneider JA Malhotra AK Lencz T Ikuta T Pipitone J Chakravarty MM Lobaugh NJ Mulsant BH et al The SORL1 gene and convergent neural risk for Alzheimer’s disease across the human lifespan Mol Psychiatry 2014 19 1125 32 24166411 PMC4004725
  39. [44]Li Y Willer CJ Ding J Scheet P Abecasis GR MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes Genet Epidemiol 2010 34 816 34 21058334 PMC3175618
  40. [45]Hsiao TJ Lin E The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor gamma (PPARG) gene in relation to obesity and metabolic phenotypes in a Taiwanese population Endocrine 2015 48 786 93 25182148
  41. [46]Hsiao TJ Hwang Y Liu CH Chang HM Lin E Association of the C825T polymorphism in the GNB3 gene with obesity and metabolic phenotypes in a Taiwanese population Genes Nutr 2013 8 137 44 22791279 PMC3534990
  42. [47]Lou XY Chen GB Yan L Ma JZ Zhu J Elston RC Li MD A generalized combinatorial approach for detecting gene-by-gene and gene-by-environment interactions with application to nicotine dependence Am J Hum Genet 2007 80 1125 1137 17503330 PMC1867100

Cited by

Sorted by citations

Authors
Lin, E., Tsai, S.-J., Kuo, P.-H., Liu, Y.-L., Yang, A. C., & Kao, C.-F.
Affiliations
  • China Medical University (TW)
  • Taipei Veterans General Hospital (TW)
  • National Taiwan University (TW)
  • National Health Research Institutes (TW)
  • National Chung Hsing University (TW)
Corresponding author
  • Lin, Eugene
  • Tsai, Shih-Jen
ORCID
Venue
Oncotarget
Publisher
Impact Journals, LLC
Published
2017-02-11
Volume
8
Issue
15
Pages
24077-24087
ISSN
1949-2553 (ISSN-L)
DOI
10.18632/oncotarget.15269
PMC
PMC5421828
OpenAlex
W2588990473
Cited by
54
References
5
Citations by year
2026: 4 · 2024: 1 · 2023: 3 · 2022: 5 · 2021: 12 · 2020: 11 · 2019: 9 · 2018: 4 · 2017: 5
FWCI
6.52
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Oncotarget (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Ministry of Science and Technology, Taiwan (V105C-008, VGHUST103-G1-4-1, V105E17-002-MY2-1, 102-2314-B-002-117-MY3)
  • Taipei Veterans General Hospital (V105C-008, V105E17-002-MY2-1, VGHUST103-G1-4-1)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
Alzheimer's disease, cognitive aging, gene-gene interaction, gene-lifestyle interaction, single nucleotide polymorphisms, lifestyle factors, older adults, Taiwanese population
MeSH terms
Cognitive Aging, Age Factors, Aged, Alleles, Alzheimer Disease, Epistasis, Genetic, Female, Humans, Life Style, Male, Middle Aged, Risk Factors, Taiwan, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genetic Association Studies, Gene-Environment Interaction

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review