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Cited by 13Down syndrome and intellectual disability researchDementia and Cognitive Impairment ResearchAlzheimer's disease research and treatments

Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome

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Gorijala, Priyanka, Aslam, M. Muaaz, Dang, Lam‐Ha T., Xicota, L., Fernandez, Maria V., Sung, Yun Ju, Fan, Kang‐Hsien, Feingold, Eleanor +14 more·2024·Alzheimer's & Dementia
DOI 10.1002/alz.13506PMC PMC10916941
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Abstract

INTRODUCTION: This study aimed to investigate the influence of the overall Alzheimer's disease (AD) genetic architecture on Down syndrome (DS) status, cognitive measures, and cerebrospinal fluid (CSF) biomarkers. METHODS: AD polygenic risk scores (PRS) were tested for association with DS‐related traits. RESULTS: The AD risk PRS was associated with disease status in several cohorts of sporadic late‐ and early‐onset and familial late‐onset AD, but not in familial early‐onset AD or DS. On the other hand, lower DS Mental Status Examination memory scores were associated with higher PRS, independent of intellectual disability and APOE (PRS including APOE , PRS APOE , p = 2.84 × 10 −4 ; PRS excluding APOE , PRS nonAPOE , p = 1.60 × 10 −2 ). PRS APOE exhibited significant associations with Aβ42, tTau, pTau, and Aβ42/40 ratio in DS. DISCUSSION: These data indicate that the AD genetic architecture influences cognitive and CSF phenotypes in DS adults, supporting common pathways that influence memory decline in both traits. Highlights: Examination of the polygenic risk of AD in DS presented here is the first of its kind. AD PRS influences memory aspects in DS individuals, independently of APOE genotype . These results point to an overlap between the genes and pathways that leads to AD and those that influence dementia and memory decline in the DS population. APOE ε4 is linked to DS cognitive decline, expanding cognitive insights in adults.

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  • In DSAD, the effect of APOEε4 genotype on the age of onset of clinical features of disease and AD biomarkers is significant, but relatively modest compared with the effect of the genotype in LOAD, and may be limited to females.

    “Notably, recent work has indicated that in DSAD, the effect of APOEε4 genotype on the age of onset of clinical features of disease and AD biomarkers is significant, but relatively modest compared with the effect of the genotype in LOAD, and may be limited to females [5, 20, 32].”

    From Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome–Alzheimer’s disease (2025) · cites this paper as [20]

    The Results section (page not specified) reports significant associations of APOE ε4 carrier status with several CSF biomarkers in Down syndrome, and the Discussion links APOE ε4 to poorer memory scores. The cited paper does not establish an effect on the age of onset of clinical features or biomarkers, compare the magnitude of an onset effect with LOAD, or report that the effect may be limited to females. (LLM, conf=0.84)

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References 43 · Cited by 13

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  1. [1]Salehi A, Wesson Ashford J, Mufson EJ. Editorial (Thematic issue: the link between alzheimer's disease and Down syndrome. A historical perspective). Curr Alzheimer Res. 2015; 13(1): 2‐ 6. doi: 10.2174/1567205012999151021102914 PMC6368451 26487155 · DOI
  2. [3]Hardy J. The discovery of Alzheimer‐causing mutations in the <scp>APP</scp>gene and the formulation of the “amyloid cascade hypothesis.”. FEBS J. 2017; 284(7): 1040‐ 1044. doi: 10.1111/febs.14004 28054745 · DOI · Paper page
  3. [4]Strydom A, Coppus A, Blesa R, et al. Alzheimer's disease in Down syndrome: an overlooked population for prevention trials. Alzheimer's Dement. 2018; 4(1): 703‐ 713. doi: 10.1016/j.trci.2018.10.006 PMC6296162 30581976 · DOI · Paper page
  4. [5]Patel A, Rees SD, Kelly MA, et al. Association of variants within APOE, SORL1, RUNX1, BACE1 and ALDH18A1 with dementia in Alzheimer's disease in subjects with Down syndrome. Neurosci Lett. 2011; 487(2): 144‐ 148. doi: 10.1016/j.neulet.2010.10.010 20946940 · DOI
  5. [6]Schupf N, Lee JH, Kapell D, et al. Onset of dementia is associated with apolipoprotein E ?4 in Down's syndrome. Ann Neurol. 1996; 40(5): 799‐ 801. doi: 10.1002/ana.410400518 8957023 · DOI
  6. [7]Liu CC, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol. 2013; 9(2): 106‐ 118. doi: 10.1038/nrneurol.2012.263 23296339 PMC3726719 · DOI · Paper page
  7. [8]Wiseman FK, Al‐Janabi T, Hardy J, et al. A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome. Nat Rev Neurosci. 2015; 16(9): 564‐ 574. doi: 10.1038/nrn3983 26243569 PMC4678594 · DOI · Paper page
  8. [9]Sinai A, Mokrysz C, Bernal J, et al. Predictors of age of diagnosis and survival of Alzheimer's disease in Down syndrome. J Alzheimer's Dis. 2017; 61(2): 717‐ 728. doi: 10.3233/JAD-170624 PMC6004911 29226868 · DOI
  9. [10]Hithersay R, Startin CM, Hamburg S, et al. Association of dementia with mortality among adults with Down syndrome older than 35 years. JAMA Neurol. 2019; 76(2): 152. doi: 10.1001/jamaneurol.2018.3616 30452522 PMC6439956 · DOI · Paper page
  10. [11]Deb S, Braganza J, Norton N, et al. APOE ε4 influences the manifestation of Alzheimer's disease in adults with down's syndrome. The British Journal of Psychiatry. 2000; 176(5): 468‐ 472. doi: 10.1192/bjp.176.5.468 10912224 · DOI · Paper page
  11. [12]Prasher VP, Sajith SG, Rees SD, et al. Significant effect of APOE epsilon 4 genotype on the risk of dementia in Alzheimer's disease and mortality in persons with Down syndrome. Int J Geriatr Psychiatry. 2008; 23(11): 1134‐ 1140. doi: 10.1002/gps.2039 18464295 PMC2714805 · DOI
  12. [13]Hyman BT, West HL, Rebeck GW, et al. Quantitative analysis of senile plaques in Alzheimer disease: observation of log‐normal size distribution and molecular epidemiology of differences associated with apolipoprotein E genotype and trisomy 21 (Down syndrome). Proc Natl Acad Sci. 1995; 92(8): 3586‐ 3590. doi: 10.1073/pnas.92.8.3586 7724603 PMC42212 · DOI · Paper page
  13. [14]Esralew L, Janicki MP, Keller SM. National Task Group Early Detection Screen for Dementia (NTG‐EDSD). Neuropsychological Assessments of Dementia in Down Syndrome and Intellectual Disabilities. Springer International Publishing; 2018: 197‐ 213. doi: 10.1007/978-3-319-61720-6_11 · DOI
  14. [16]Deb S, Hare M, Prior L, Bhaumik S. Dementia screening questionnaire for individuals with intellectual disabilities. The British Journal of Psychiatry. 2007; 190(5): 440‐ 444. doi: 10.1192/bjp.bp.106.024984 17470960 · DOI
  15. [17]Krinsky‐McHale SJ, Zigman WB, Lee JH, et al. Promising outcome measures of early Alzheimer's dementia in adults with Down syndrome. Alzheimer's Dement (Amst). 2020; 12(1): e12044. doi: 10.1002/dad2.12044 32647741 PMC7335903 · DOI
  16. [18]Trevino CE, Holleman AM, Corbitt H, et al. Identifying genetic factors that contribute to the increased risk of congenital heart defects in infants with Down syndrome. Sci Rep. 2020; 10(1): 18051. doi: 10.1038/s41598-020-74650-4 33093519 PMC7582922 · DOI
  17. [19]Cruchaga C, Del‐Aguila JL, Saef B, et al. Polygenic risk score of sporadic late‐onset Alzheimer's disease reveals a shared architecture with the familial and early‐onset forms. Alzheimer's Dement. 2018; 14(2): 205‐ 214. doi: 10.1016/j.jalz.2017.08.013 28943286 PMC5803427 · DOI · Paper page
  18. [20]Bellenguez C, Küçükali F, Jansen IE, et al. New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022; 54(4): 412‐ 436. doi: 10.1038/s41588-022-01024-z 35379992 PMC9005347 · DOI · Paper page
  19. [26]Handen BL, Lott IT, Christian BT, et al. The Alzheimer's biomarker consortium‐Down syndrome: rationale and methodology. Alzheimer's Dement. 2020; 12(1). doi: 10.1002/dad2.12065 PMC7396809 32775597 · DOI
  20. [27]Yang C, Farias FHG, Ibanez L, et al. Genomic atlas of the proteome from brain, CSF and plasma prioritizes proteins implicated in neurological disorders. Nat Neurosci. 2021; 24(9): 1302‐ 1312. doi: 10.1038/s41593-021-00886-6 34239129 PMC8521603 · DOI · Paper page
  21. [28]Yang C, Fagan AM, Perrin RJ, Rhinn H, Harari O, Cruchaga C. Mendelian randomization and genetic colocalization infer the effects of the multi‐tissue proteome on 211 complex disease‐related phenotypes. Genome Med. 2022; 14(1): 140. doi: 10.1186/s13073-022-01140-9 36510323 PMC9746220 · DOI · Paper page
  22. [30]Timsina J, Ali M, Do A, Wang L, Sung YJ, Cruchaga C. Harmonization of CSF and imaging biomarkers for Alzheimer's disease biomarkers: need and practical applications for genetics studies and preclinical classification. bioRxiv. 2023. doi: 10.1101/2023.05.24.542118. Published online May 24. PMC12661535 38072165 · DOI
  23. [31]Taliun D, Harris DN, Kessler MD, et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed program. Nature. 2021; 590(7845): 290‐ 299. doi: 10.1038/s41586-021-03205-y 33568819 PMC7875770 · DOI · Paper page
  24. [32]Lee JH. Analyses of the National Institute on Aging late‐onset Alzheimer's disease family study. Arch Neurol. 2008; 65(11): 1518. doi: 10.1001/archneur.65.11.1518 19001172 PMC2694670 · DOI
  25. [33]Choi SW, Mak TSH, O'Reilly PF. Tutorial: a guide to performing polygenic risk score analyses. Nat Protoc. 2020; 15(9): 2759‐ 2772. doi: 10.1038/s41596-020-0353-1 32709988 PMC7612115 · DOI
  26. [35]Phillips B, Western D, Wang L, et al. Proteome wide association studies of LRRK2 variants identify novel causal and druggable proteins for Parkinson's disease. NPJ Parkinsons Dis. 2023; 9(1): 107. doi: 10.1038/s41531-023-00555-4 37422510 PMC10329646 · DOI
  27. [36]Silverman W, Krinsky‐McHale SJ, Lai F, et al. Evaluation of the National Task Group‐Early Detection Screen for Dementia: sensitivity to ‘mild cognitive impairment’ in adults with Down syndrome. J Appl Res Intellect Disabil. 2021; 34(3): 905‐ 915. doi: 10.1111/jar.12849 33314467 PMC8356176 · DOI
  28. [37]Koehl L, Harp J, Van Pelt KL, Head E, Schmitt FA. Longitudinal assessment of dementia measures in Down syndrome. Alzheimer's Dement. 2020; 12(1). doi: 10.1002/dad2.12075 PMC7666427 33225040 · DOI
  29. [38]Robin X, Turck N, Hainard A, et al. pROC: an open‐source package for R and S+ to analyze and compare ROC curves. BMC Bioinformatics. 2011; 12(1): 77. doi: 10.1186/1471-2105-12-77 21414208 PMC3068975 · DOI · Paper page
  30. [40]Deming Y, Li Z, Kapoor M, et al. Genome‐wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers. Acta Neuropathol. 2017; 133(5): 839‐ 856. doi: 10.1007/s00401-017-1685-y 28247064 PMC5613285 · DOI · Paper page
  31. [41]D'Souza H, Mason L, Mok KY, et al. Differential associations of apolipoprotein E ε4 genotype with attentional abilities across the life span of individuals with Down syndrome. JAMA Netw Open. 2020; 3(9): e2018221. doi: 10.1001/jamanetworkopen.2020.18221 32986108 PMC7522696 · DOI
  32. [43]Forte GI, Piccione M, Scola L, et al. Apolipoprotein E genotypic frequencies among Down syndrome patients imply early unsuccessful aging for ApoE4 carriers. Rejuvenation Res. 2007; 10(3): 293‐ 300. doi: 10.1089/rej.2006.0525 17559337 · DOI
  33. [45]Prasher VP, Farrer MJ, Kessling AM, et al. Molecular mapping of alzheimer‐type dementia in Down's syndrome. Ann Neurol. 1998; 43(3): 380‐ 383. doi: 10.1002/ana.410430316 9506555 · DOI · Paper page
  34. [48]De Strooper B, Karran E. The cellular phase of Alzheimer's disease. Cell. 2016; 164(4): 603‐ 615. doi: 10.1016/j.cell.2015.12.056 26871627 · DOI · Paper page

Authors
Gorijala, P., Aslam, M. M., Dang, L. T., Xicota, L., Fernandez, M. V., Sung, Y. J., Fan, K., Feingold, E., Surace, E. I., Chhatwal, J. P., Hom, C. L., Dominantly Inherited Alzheimer Network (DIAN), T. A. D. N. I. (., the NIA‐LOAD family study, F. T. A. B. C. S. (. I., Hartley, S. L., Hassenstab, J., Perrin, R. J., Mapstone, M., Zaman, S. H., Ances, B. M., Kamboh, M. I., Lee, J. H., & Cruchaga, C.
Affiliations
  • Washington University in St. Louis (US)
  • University of Pittsburgh (US)
  • Columbia University Irving Medical Center (US)
  • Department of Psychiatry Washington University School of Medicine St. Louis Missouri USA
  • Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
  • Harvard University (US)
  • University of California, Irvine (US)
  • University of Wisconsin–Madison (US)
Corresponding author
Cruchaga, Carlos
ORCID
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2023-10-19
Volume
20
Issue
2
Pages
1038-1049
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
DOI
10.1002/alz.13506
PMC
PMC10916941
OpenAlex
W4387764774
Cited by
13
References
43
Citations by year
2026: 4 · 2025: 7 · 2024: 1 · 2023: 1
FWCI
3.32
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
Funders
  • National Institutes of Health (U01 AG024904, P01AG003991, RF1AG053303, RF1AG058501, U01AG058922, RF1AG074007, R01AG064877)
  • Chan Zuckerberg Initiative
  • Michael J. Fox Foundation for Parkinson's Research (LI‐W81XWH2010849)
  • National Institute on Aging
  • Alzheimer's Association (SG‐20‐690363‐DIAN)
  • Deutsches Zentrum für Neurodegenerative Erkrankungen
  • Japan Agency for Medical Research and Development
  • Korea Health Industry Development Institute
  • Alzheimer's Disease Neuroimaging Initiative (U01 AG024904, W81XWH‐12‐2‐0012)
  • National Institute of Biomedical Imaging and Bioengineering
  • National Center for Advancing Translational Sciences (UL1 TR001873, UL1 TR002373, UL1 TR001414, UL1 TR001857, UL1 TR002345)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development
Topics
  • 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
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
Alzheimer's disease, Down syndrome
MeSH terms
Genetic Risk Score, Adult, Alzheimer Disease, Apolipoproteins E, Cognition, Down Syndrome, Humans, Memory Disorders, Phenotype, Biomarkers, Amyloid beta-Peptides, Cognitive Dysfunction

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