Polymorphisms in BACE2 may affect the age of onset Alzheimer's dementia in Down syndrome
Open accessAbstract
It is known that Alzheimer's disease (AD) presents at an early age in people with Down syndrome (DS). The trisomy 21 in DS provides an opportunity to study the effect of duplicated genes in AD. APP and BACE2 are 2 genes located in chromosome 21 and related to AD. We looked into our cohort of 67 DS cases with dementia for the effect of BACE2 variants in age of onset of dementia. Of the 83 single-nucleotide polymorphisms (SNPs), 6 were associated with age of onset and another 8 SNPs were borderline associated. Our finding also replicated a previous study showing association of rs2252576 with AD.
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.
Integrity signals
Registry
Cites
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.
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?
Many additional genes on HSA21 modulate processes that could contribute to AD pathology in DS.
“However, many additional genes on HSA21 modulate processes that could contribute to AD pathology in DS.14,15,16”
From Interferon signaling modulates Down syndrome-associated Alzheimer’s disease pathology in a mouse model (2025) · cites this paper as [15]
The Introduction identifies APP and BACE2 as chromosome 21 genes related to AD, and the Discussion proposes that BACE2 may influence dementia pathogenesis in people with trisomy 21. This supports an additional gene beyond APP, but the paper does not establish that many additional HSA21 genes modulate relevant processes. (LLM, conf=0.86)
Experimental — accuracy not yet measured
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
Naj, A. C., Jun, G., Beecham, G. W., Wang, L.-S., Vardarajan, B. N., Buros, J., Gallins, P. J., Buxbaum, J. D., Jarvik, G. P., Crane, P. K., et al. (2011) · Nature Genetics · doi:10.1038/ng.801 · Cited by 1,901 · see citing works
Self-citationGene expression profiling in the adult Down syndrome brain
Lockstone, H. E., Harris, L. W., Swatton, J. E., Wayland, M. T., Holland, A. J., & Bahn, S. (2007) · Genomics · doi:10.1016/j.ygeno.2007.08.005 · Cited by 240 · see citing works
Flagged first, then by citations
Research works printed but not linked: 14
- Abdul-Hay S.O. Sahara T. McBride M. Kang D. Leissring M.A. Identification of BACE2 as an avid β-amyloid-degrading protease Mol. Neurodegener. 7 2012 46 22986058 PMC3470943
- Cheon M.S. Dierssen M. Kim S.H. Lubec G. Protein expression of BACE1, BACE2 and APP in Down syndrome brains Amino Acids 35 2008 339 343 18163181
- Hanney M. Prasher V. Williams N. Jones E.L. Aarsland D. Corbett A. Lawrence D. Yu L.M. Tyrer S. Francis P.T. Johnson T. Bullock R. Ballard C. Memantine for dementia in adults older than 40 years with Down's syndrome (MEADOWS): a randomised, double-blind, placebo-controlled trial Lancet 379 2012 528 536 22236802
- Holler C.J. Webb R.L. Laux A.L. Beckett T.L. Niedowicz D.M. Ahmed R.R. Liu Y. Simmons C.R. Dowling A.L. Spinelli A. Khurgel M. Estus S. Head E. Hersh L.B. Murphy M.P. BACE2 expression increases in human neurodegenerative disease Am. J. Pathol. 180 2012 337 350 22074738 PMC3338345
- Hollingworth P. Harold D. Sims R. Gerrish A. Lambert J.C. Carrasquillo M.M. Abraham R. Hamshere M.L. Pahwa J.S. Moskvina V. Dowzell K. Jones N. Stretton A. Thomas C. Richards A. Ivanov D. Widdowson C. Chapman J. Lovestone S. Powell J. Proitsi P. Lupton M.K. Brayne C. Rubinsztein D.C. Gill M. Lawlor B. Lynch A. Brown K.S. Passmore P.A. Craig D. McGuinness B. Todd S. Holmes C. Mann D. Smith A.D. Beaumont H. Warden D. Wilcock G. Love S. Kehoe P.G. Hooper N.M. Vardy E.R. Hardy J. Mead S. Fox N.C. Rossor M. Collinge J. Maier W. Jessen F. Rüther E. Schürmann B. Heun R. Kölsch H. van den Bussche H. Heuser I. Kornhuber J. Wiltfang J. Dichgans M. Frölich L. Hampel H. Gallacher J. Hüll M. Rujescu D. Giegling I. Goate A.M. Kauwe J.S. Cruchaga C. Nowotny P. Morris J.C. Mayo K. Sleegers K. Bettens K. Engelborghs S. De Deyn P.P. Van Broeckhoven C. Livingston G. Bass N.J. Gurling H. McQuillin A. Gwilliam R. Deloukas P. Al-Chalabi A. Shaw C.E. Tsolaki M. Singleton A.B. Guerreiro R. Mühleisen T.W. Nöthen M.M. Moebus S. Jöckel K.H. Klopp N. Wichmann H.E. Pankratz V.S. Sando S.B. Aasly J.O. Barcikowska M. Wszolek Z.K. Dickson D.W. Graff-Radford N.R. Petersen R.C. Alzheimer's Disease Neuroimaging Initiative van Duijn C.M. Breteler M.M. Ikram M.A. DeStefano A.L. Fitzpatrick A.L. Lopez O. Launer L.J. Seshadri S. CHARGE consortium Berr C. Campion D. Epelbaum J. Dartigues J.F. Tzourio C. Alpérovitch A. Lathrop M. EADI1 consortium Feulner T.M. Friedrich P. Riehle C. Krawczak M. Schreiber S. Mayhaus M. Nicolhaus S. Wagenpfeil S. Steinberg S. Stefansson H. Stefansson K. Snaedal J. Björnsson S. Jonsson P.V. Chouraki V. Genier-Boley B. Hiltunen M. Soininen H. Combarros O. Zelenika D. Delepine M. Bullido M.J. Pasquier F. Mateo I. Frank-Garcia A. Porcellini E. Hanon O. Coto E. Alvarez V. Bosco P. Siciliano G. Mancuso M. Panza F. Solfrizzi V. Nacmias B. Sorbi S. Bossù P. Piccardi P. Arosio B. Annoni G. Seripa D. Pilotto A. Scarpini E. Galimberti D. Brice A. Hannequin D. Licastro F. Jones L. Holmans P.A. Jonsson T. Riemenschneider M. Morgan K. Younkin S.G. Owen M.J. O'Donovan M. Amouyel P. Williams J. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease Nat. Genet. 43 2011 429 435 21460840 PMC3084173
- Jones E.L. Mok K. Hanney M. Harold D. Sims R. Williams J. Ballard C. Evidence that PICALM affects age at onset of Alzheimer's dementia in Down syndrome Neurobiol. Aging 34 2013 2441.e1 2441.e5 23601808 PMC3898582
- Lambert J.C. Ibrahim-Verbaas C.A. Harold D. Naj A.C. Sims R. Bellenguez C. Jun G. Destefano A.L. Bis J.C. Beecham G.W. Grenier-Boley B. Russo G. Thornton-Wells T.A. Jones N. Smith A.V. Chouraki V. Thomas C. Ikram M.A. Zelenika D. Vardarajan B.N. Kamatani Y. Lin C.F. Gerrish A. Schmidt H. Kunkle B. Dunstan M.L. Ruiz A. Bihoreau M.T. Choi S.H. Reitz C. Pasquier F. Hollingworth P. Ramirez A. Hanon O. Fitzpatrick A.L. Buxbaum J.D. Campion D. Crane P.K. Baldwin C. Becker T. Gudnason V. Cruchaga C. Craig D. Amin N. Berr C. Lopez O.L. De Jager P.L. Deramecourt V. Johnston J.A. Evans D. Lovestone S. Letenneur L. Moron F.J. Rubinsztein D.C. Eiriksdottir G. Sleegers K. Goate A.M. Fievet N. Huentelman M.J. Gill M. Brown K. Kamboh M.I. Keller L. Barberger-Gateau P. McGuinness B. Larson E.B. Green R. Myers A.J. Dufouil C. Todd S. Wallon D. Love S. Rogaeva E. Gallacher J. St George-Hyslop P. Clarimon J. Lleo A. Bayer A. Tsuang D.W. Yu L. Tsolaki M. Bossu P. Spalletta G. Proitsi P. Collinge J. Sorbi S. Sanchez-Garcia F. Fox N.C. Hardy J. Naranjo M.C. Bosco P. Clarke R. Brayne C. Galimberti D. Mancuso M. Matthews F. Moebus S. Mecocci P. Del Zompo M. Maier W. Hampel H. Pilotto A. Bullido M. Panza F. Caffarra P. Nacmias B. Gilbert J.R. Mayhaus M. Lannfelt L. Hakonarson H. Pichler S. Carrasquillo M.M. Ingelsson M. Beekly D. Alvarez V. Zou F. Valladares O. Younkin S.G. Coto E. Hamilton-Nelson K.L. Gu W. Razquin C. Pastor P. Mateo I. Owen M.J. Faber K.M. Jonsson P.V. Combarros O. O'Donovan M.C. Cantwell L.B. Soininen H. Blacker D. Mead S. Mosley T.H. Jr. Bennett D.A. Harris T.B. Fratiglioni L. Holmes C. de Bruijn R.F. Passmore P. Montine T.J. Bettens K. Rotter J.I. Brice A. Morgan K. Foroud T.M. Kukull W.A. Hannequin D. Powell J.F. Nalls M.A. Ritchie K. Lunetta K.L. Kauwe J.S. Boerwinkle E. Riemenschneider M. Boada M. Hiltunen M. Martin E.R. Schmidt R. Rujescu D. Wang L.S. Dartigues J.F. Mayeux R. Tzourio C. Hofman A. Nothen M.M. Graff C. Psaty B.M. Jones L. Haines J.L. Holmans P.A. Lathrop M. Pericak-Vance M.A. Launer L.J. Farrer L.A. van Duijn C.M. Van Broeckhoven C. Moskvina V. Seshadri S. Williams J. Schellenberg G.D. Amouyel P. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease Nat. Genet. 2013 PMC3896259 24162737
- Mann D.M. Royston M.C. Ravindra C.R. Some morphometric observations on the brains of patients with Down's syndrome: their relationship to age and dementia J. Neurol. Sci. 99 1990 153 164 2150858
- Margallo-Lana M.L. Moore P.B. Kay D.W. Perry R.H. Reid B.E. Berney T.P. Tyrer S.P. Fifteen-year follow-up of 92 hospitalized adults with Down's syndrome: incidence of cognitive decline, its relationship to age and neuropathology J. Intellect. Disabil. Res. 51 Pt. 6 2007 463 477 17493029
- Murray C.J. Richards M.A. Newton J.N. Fenton K.A. Anderson H.R. Atkinson C. Bennett D. Bernabe E. Blencowe H. Bourne R. Braithwaite T. Brayne C. Bruce N.G. Brugha T.S. Burney P. Dherani M. Dolk H. Edmond K. Ezzati M. Flaxman A.D. Fleming T.D. Freedman G. Gunnell D. Hay R.J. Hutchings S.J. Ohno S.L. Lozano R. Lyons R.A. Marcenes W. Naghavi M. Newton C.R. Pearce N. Pope D. Rushton L. Salomon J.A. Shibuya K. Vos T. Wang H. Williams H.C. Woolf A.D. Lopez A.D. Davis A. UK health performance: findings of the Global Burden of Disease Study 2010 Lancet 381 2013 997 1020 23668584
- Myllykangas L. Wavrant-De Vrieze F. Polvikoski T. Notkola I.L. Sulkava R. Niinisto L. Edland S.D. Arepalli S. Adighibe O. Compton D. Hardy J. Haltia M. Tienari P.J. Chromosome 21 BACE2 haplotype associates with Alzheimer's disease: a two-stage study J. Neurol. Sci. 236 2005 17 24 16023140
- Purcell S. Neale B. Todd-Brown K. Thomas L. Ferreira M.A. Bender D. Maller J. Sklar P. de Bakker P.I. Daly M.J. Sham P.C. PLINK: a tool set for whole-genome association and population-based linkage analyses Am. J. Hum. Genet. 81 2007 559 575 17701901 PMC1950838
- Sun X. He G. Song W. BACE2, as a novel APP theta-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome Faseb J. 20 2006 1369 1376 16816112
- Yu Y. Jia J. Lack of association between the polymorphisms of beta-site APP-cleaving enzyme 2 (BACE2) 5′-flanking region and sporadic Alzheimer's disease Brain Res. 1257 2009 10 15 19124009
Cited by
Sorted by citations
Wiseman, F. K., Pulford, L. J., Barkus, C., Liao, F., Portelius, E., Webb, R., Chávez-Gutiérrez, L., Cleverley, K., Noy, S., Sheppard, O., et al. (2018) · Brain · doi:10.1093/brain/awy159 · Cited by 133 · see citing works
Self-citationAlić, I., Goh, P. A., Murray, A., Portelius, E., Gkanatsiou, E., Gough, G., Mok, K. Y., Koschut, D., Brunmeir, R., Yeap, Y. J., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-020-0806-5 · Cited by 123 · see citing works
Self-citationZheng, Q., Li, G., Wang, S., Zhou, Y., Liu, K., Gao, Y., Zhou, Y., Zheng, L., Zhu, L., Deng, Q., et al. (2021) · Science Advances · doi:10.1126/sciadv.abe1340 · Cited by 85 · see citing works
Zheng, Q., Song, B., Li, G., Cai, F., Wu, M., Zhao, Y., Jiang, L., Guo, T., Shen, M., Hou, H., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci152170 · Cited by 73 · see citing works
Araya, P., Niemeyer, B., Schade, K., Dunn, L. N., Waugh, K., Busquet, N., Brindley, C., Brown, C., Winkler, C., Lyford, H. R., et al. (2025) · iScience · doi:10.1016/j.isci.2025.113130 · Cited by 7 · see citing works
- Authors
- Mok, K. Y., Jones, E. L., Hanney, M., Harold, D., Sims, R., Williams, J., Ballard, C., & Hardy, J.
- Affiliations
- National Hospital for Neurology and Neurosurgery (GB)
- King's College London (GB)
- Northgate Hospital (GB)
- Cardiff University (GB)
- Corresponding author
- Mok, Kin Y.
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 35
- Issue
- 6
- Pages
- 1513.e1-1513.e5
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC3969241
- OpenAlex
- W1988112256
- Cited by
- 48
- References
- 2
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 3 · 2023: 1 · 2022: 4 · 2021: 7 · 2020: 8 · 2019: 5 · 2018: 3 · 2017: 5 · 2016: 2 · 2015: 3 · 2014: 3
- FWCI
- 2.89
- Type
- journal article
- Language
- en
- Update notices
- Open access
- hybrid
- doi.org
- Locations
- Neurobiology of Aging (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, other-oa)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Funders
- National Institute for Health Research Mental Health Biomedical Research Centre at South London
- Maudsley National Health Service Foundation Trust
- King's College London
- Medical Research Council
- Wellcome Trust Strategic Grant Award
- Wellcome Trust Down Syndrome initiative
- The Henry Smith Charity
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- BACE2, Down syndrome, Alzheimer's disease, age of onset, single nucleotide polymorphisms, duplicate genes, APP, genetic association
- MeSH terms
- Aged, Alleles, Alzheimer Disease, Chromosomes, Human, Pair 21, Down Syndrome, Female, Humans, Male, Middle Aged, Cohort Studies, Aspartic Acid Endopeptidases, Age of Onset, Polymorphism, Single Nucleotide, Amyloid Precursor Protein Secretases, Genetic Association Studies
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
