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Cited by 73Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchGenetic Associations and Epidemiology

Genomics and Functional Genomics of Alzheimer's Disease

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Kamboh, M. Ilyas·2022·Neurotherapeutics
DOI 10.1007/s13311-021-01152-0PMC PMC9130391
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Abstract

Alzheimer's disease (AD) is a complex and multifactorial neurodegenerative disease. Due to its long clinical course and lack of an effective treatment, AD has become a major public health problem in the USA and worldwide. Due to variation in age-at-onset, AD is classified into early-onset (< 60 years) and late-onset (≥ 60 years) forms with early-onset accounting for only 5-10% of all cases. With the exception of a small number of early-onset cases that are afflicted because of high penetrant single gene mutations in APP, PSEN1, and PSEN2 genes, AD is genetically heterogeneous, especially the late-onset form having a polygenic or oligogenic risk inheritance. Since the identification of APOE as the most significant risk factor for late-onset AD in 1993, the path to the discovery of additional AD risk genes had been arduous until 2009 when the use of large genome-wide association studies opened up the discovery gateways that led the identification of ~ 95 additional risk loci from 2009 to early 2022. This article reviews the history of AD genetics followed by the potential molecular pathways and recent application of functional genomics methods to identify the causal AD gene(s) among the many genes that reside within a single locus. The ultimate goal of integrating genomics and functional genomics is to discover novel pathways underlying the AD pathobiology in order to identify drug targets for the therapeutic treatment of this heterogeneous disorder.

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  • In addition to the established and opposite associations of APOE*4 and APOE*2 with both AD risk and ApoE level, multiple additional independent AD-associated SNPs reported in the APOE region and reported SNPs in some known non-APOE AD loci are also associated with plasma ApoE level.

    “We show here that in addition to the established and opposite associations of APOE*4 and APOE*2 with both AD risk and ApoE level, multiple additional independent AD-associated SNPs reported in the APOE region [23] as well as reported SNPs in some known non-APOE AD loci [5], are also associated with plasma ApoE level.”

    From Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer’s disease risk (2023) · cites this paper as [5]

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  1. [2]Alzheimer’s disease facts and figures Alzheimers Dement 2021 17 327 406 10.1002/alz.12328 33756057 · DOI
  2. [4]Chene G Beiser A Au R Preis SR Wolf PA Dufouil C Seshadri S Gender and incidence of dementia in the Framingham Heart Study from mid-adult life Alzheimers Dement 2015 11 310 320 10.1016/j.jalz.2013.10.005 24418058 PMC4092061 · DOI · Paper page
  3. [5]Gatz M Reynolds CA Fratiglioni L Johansson B Mortimer JA Berg S Role of genes and environments for explaining Alzheimer disease Arch Gen Psychiatry 2006 63 168 174 10.1001/archpsyc.63.2.168 16461860 · DOI · Paper page
  4. [8]Bertram L McQueen MB Mullin K Blacker D Tanzi RE Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database Nat Genet 2007 39 17 23 10.1038/ng1934 17192785 · DOI · Paper page
  5. [9]Ridge PG Hoyt KB Boehme K Mukherjee S Crane PK Haines JL Assessment of the genetic variance of late-onset Alzheimer’s disease Neurobiol Aging 2016 200 e13 e20 PMC4948179 27036079
  6. [10]Lee S, Harold D, Nyholt DR, ANZGene Consortium, International Endogene Consortium, Genetic and Environmental Risk for Alzheimer’s disease Consortium, et al. Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer’s disease, multiple sclerosis and endometriosis. Hum Mol Genet 2013; 22: 832–841. PMC3554206 23193196
  7. [11]Brainstorm Consortium et al. Analysis of shared heritability in common disorders of the brain. Science 2018; 360: eaap8757. PMC6097237 29930110
  8. [12]Bateman RJ Xiong C Benzinger TL Fagan AM Goate A Fox NC Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med, 367:795–804 Erratum. In: N Engl J Med 2012 2012 367 780 PMC3474597 22784036
  9. [13]Gordan BA Blazey TM Su Y Hari-Raj A Dincer A Flores S Spatial patterns of neuroimaging biomarker change in individuals from families with autosomal dominant Alzheimer’s disease: a longitudinal study Lancet Neurol 2018 17 241 250 10.1016/S1474-4422(18)30028-0 29397305 PMC5816717 · DOI · Paper page
  10. [15]Zhu XC Tan L Wang HF Jiang T Cao L Wang C Rate of early onset Alzheimer’s disease: a systematic review and meta-analysis Ann Transl Med 2015 3 38 25815299 PMC4356853
  11. [17]Jarmolowicz AI Chen HY Panegyres PK The patterns of inheritance in early-onset dementia: Alzheimer’s disease and frontotemporal dementia Am J Alzheimers Dis Other Demen 2015 30 299 306 10.1177/1533317514545825 25147204 PMC10852564 · DOI
  12. [18]De Strooper, B. Vassar R, Golde T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol 2010; 6:99–107. PMC2879045 20139999
  13. [19]Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science 2019; 363:eaaw0930 30630874
  14. [20]Xia W γ-Secretase and its modulators: Twenty years and beyond Neurosci Lett 2019 701 162 169 10.1016/j.neulet.2019.02.011 30763650 PMC7008970 · DOI · Paper page
  15. [21]Shah S Lee SF Tabuchi K Hao YH Yu C LaPlant Q Nicastrin functions as a gamma-secretase substrate receptor Cell 2005 122 435 447 10.1016/j.cell.2005.05.022 16096062 · DOI
  16. [22]Wong E, Frost GR, Li YM. γ-secretase modulatory proteins: The guiding hand behind the running scissors Front Aging Neurosci. 2020; 12:614690. PMC7738330 33343338
  17. [23]Hoogmartens J, Cacace R, Van Broeckhoven C. Insight into the genetic etiology of Alzheimer’s disease: A comprehensive review of the role of rare variants. Alzheimers Dement (Amst). 2021; 13:e12155. PMC7896636 33665345
  18. [26]Sun L Zhou R Shi Y Analysis of 138 PSEN1 pathogenic mutations in the presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase Proc Natl Acad Sci USA 2017 114 E476 E485 27930341 PMC5278480
  19. [27]Pottier C Hannequin D Coutant S Rovelet-Lecrux A Wallon D Rousseau S High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early onset Alzheimer disease Mol Psychiatry 2012 17 875 879 10.1038/mp.2012.15 22472873 · DOI · Paper page
  20. [28]Nicolas G Charbonnier C Wallon D Quenez O Bellenguez C Grenier-Boley B SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease Mol Psychiatry 2016 21 831 836 10.1038/mp.2015.121 26303663 · DOI · Paper page
  21. [29]Kim M Suh J Romano D Truong MH Mullin K Hooli B Potential late-onset Alzheimer disease associated mutations in the ADAM10 gene attenuate alpha-secretase activity Hum Mol Genet 2009 18 3987 3996 10.1093/hmg/ddp323 19608551 PMC2748890 · DOI · Paper page
  22. [33]Bamne MN Demirci FY Berman S Snitz BE Rosenthal SL Wang X Investigation of an amyloid precursor protein protective mutation (A673T) in a North American case-control sample of late-onset Alzheimer’s disease Neurobiol Aging 2014 35 1779.e1715 1779.e1716 10.1016/j.neurobiolaging.2014.01.020 PMC4009010 24529499 · DOI
  23. [34]Wang LS Naj AC Graham RR Crane PK Kunkle BW Cruchaga C Rarity of the Alzheimer disease-protective APP A673T variant in the United States JAMA Neurol 2015 72 209 216 10.1001/jamaneurol.2014.2157 25531812 PMC4324097 · DOI
  24. [35]Xia Q Yang X Shi J Liu Z Peng Y Wang W The Protective A673T mutation of amyloid precursor protein (APP) in Alzheimer’s disease Mol Neurobiol 2021 58 4038 4050 10.1007/s12035-021-02385-y 33914267 · DOI
  25. [36]Kero M Paetau A Polvikoski T Tanskanen M Sulkava R Jansson L Amyloid precursor protein (APP) A673T mutation in the elderly Finnish population Neurobiol Aging 2013 34 1518.e1511 1518.e1513 10.1016/j.neurobiolaging.2012.09.017 23102935 · DOI · Paper page
  26. [37]Kamboh MI Apolipoprotein E polymorphism and susceptibility to Alzheimer’s diseases Hum Biol 1995 67 195 215 7729825
  27. [39]Seripa D Matera MG Daniele A Bizzarro A Rinaldi M Gravina C The missing ApoE allele Ann Hm Genet 2007 71 496 500 10.1111/j.1469-1809.2006.00344.x 17244188 · DOI
  28. [40]Mahley RW Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders J Mol Med (Berl) 2016 94 739 746 10.1007/s00109-016-1427-y 27277824 PMC4921111 · DOI · Paper page
  29. [42]Yamazaki Y, Zhao N, Caulfied TR, Liu C-C, Bu G. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol 2019; 15:501–518. PMC7055192 31367008
  30. [45]Chen Y Strickland MR Soranno A Holtzman DM Apolipoprotein E: Structural insights and links to Alzheimer disease pathogenesis Neuron 2021 109 205 221 10.1016/j.neuron.2020.10.008 33176118 PMC7931158 · DOI · Paper page
  31. [46]Genin E Hannequin D Wallon D Sleegers K Hiltunen M Combarros O APOE and Alzheimer disease: a major gene with semi-dominant inheritance Mol Psychiatry 2011 16 903 907 10.1038/mp.2011.52 21556001 PMC3162068 · DOI · Paper page
  32. [47]Liu M Bian C Zhang J Wen F Apolipoprotein E gene polymorphism and Alzheimer’s disease in Chinese population: a meta-analysis Sci Rep. 2014 4 4383 10.1038/srep04383 24632849 PMC3955907 · DOI
  33. [48]Rajabli F Feliciano BE Celis K Hamilton-Nelson KL Whitehead PL Adams LA Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations PLoS Genet 2018 14 21007791 10.1371/journal.pgen.1007791 PMC6281216 30517106 · DOI · Paper page
  34. [49]Kamboh MI Aston CE Perez-Tur J Kokmen E Ferrell RE Hardy J DeKosky ST A novel mutation in the apolipoprotein E gene (APOE*4 Pittsburgh) is associated with the risk of late-onset Alzheimer’s disease Neurosci Lett 1999 263 129 132 10.1016/S0304-3940(99)00129-9 10213152 · DOI · Paper page
  35. [50]Medway CW, Abdul-Hay S, Mims T, Ma L, Bisceglio G, Zou F, et al. ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease. Mol Neurodegener 2014; 9:11. PMC3995879 24607147
  36. [51]Blue EE, Cheng A, Chen S, Yu CE; Alzheimer’s Disease Genetics Consortium. Association of uncommon, noncoding variants in the APOE region with risk of Alzheimer disease in adults of European ancestry JAMA Netw Open 2020; 3(10):e2017666. PMC7582128 33090224
  37. [52]Grupe A Abraham R Li Y Rowland C Hollingworth P Morgan A Evidence for novel susceptibility genes for late-onset Alzheimer’s disease from a genome-wide association study of putative functional variants Hum Mol Genet 2007 16 865 873 10.1093/hmg/ddm031 17317784 · DOI · Paper page
  38. [53]Coon KD Myers AJ Craig DW Webster JA Pearson JV Lince DH A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer’s disease J Clin Psych 2007 68 613 618 10.4088/JCP.v68n0419 17474819 · DOI · Paper page
  39. [54]Reiman EM Webster JA Myers AJ Hardy J Dunckley T Zismann VL GAB2 alleles modify Alzheimer’s risk in APOE epsilon4 carriers Neuron 2007 54 713 720 10.1016/j.neuron.2007.05.022 17553421 PMC2587162 · DOI · Paper page
  40. [55]Li H Wetten S Li L St Jean PL Upmanyu R Surh L Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease Arch Neurol 2008 65 45 53 10.1001/archneurol.2007.3 17998437 · DOI · Paper page
  41. [56]Bertram L Lange C Mullin K Parkinson M Hsiao M Hogan MF Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE Am J Hum Genet 2008 83 623 632 10.1016/j.ajhg.2008.10.008 18976728 PMC2668052 · DOI · Paper page
  42. [57]Beecham GW Martin ER Li YJ Slifer MA Gilbert JR Haines JL Pericak-Vance MA Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease Am J Hum Genet 2009 84 35 43 10.1016/j.ajhg.2008.12.008 19118814 PMC2668056 · DOI · Paper page
  43. [58]Abraham R Moskvina V Sims R Hollingworth P Morgan A Georgieva L A genome-wide association study for late-onset Alzheimer’s disease using DNA pooling BMC Med Genomics 2008 1 44 10.1186/1755-8794-1-44 18823527 PMC2570675 · DOI · Paper page
  44. [59]Carrasquillo MM Zou F Pankratz VS Wilcox SL Ma L Walker LP Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer’s disease Nat Genet 2009 41 192 198 10.1038/ng.305 19136949 PMC2873177 · DOI · Paper page
  45. [61]Lambert JC, Heath S, EvenG, Campion D, SleegersK, HiltunenM, et al. Genomewide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 2009; 41:1094–1099. 19734903
  46. [62]Seshadri S Fitzpatrick AL Ikram MA DeStefano AL Gudnaso V Boada M Genome-wide association analysis of genetic loci associated with Alzheimer disease JAMA 2010 303 1832 1840 10.1001/jama.2010.574 20460622 PMC2989531 · DOI · Paper page
  47. [63]Hollingworth P Harold D Sims R Gerrish A Lambert JC Carrasquillo MM Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease Nat Genet 2011 43 429 435 10.1038/ng.803 21460840 PMC3084173 · DOI · Paper page
  48. [66]Kamboh MI, Demirci FY, Wang X, Minster RL, Carrasquillo MM, Pankratz VS, et al. Genome-wide association study of Alzheimer’s disease. Transl Psychiatry 2012; 2:e117. PMC3365264 22832961
  49. [67]Jonsson T, Stefansson H, Steinberg,S. Jonsdottir I, Jonsson PV, Snaedal J, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 2013; 368:107–116. PMC3677583 23150908
  50. [68]Rosenthal SL, Bamne MN, Wang X, Berman S, Snitz BE, Klunk WE, et al. More evidence for association of a rare TREM2 mutation (R47H) with Alzheimer’s disease risk. Neurobiol Aging 2015; 36:2443.e21e2443.e26. PMC4465085 26058841
  51. [69]Ruiz A, Heilmann S, Becker T, Hernandez I, Wagner H, Thelen M, 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. PMC3944635 24495969
  52. [71]Liu JZ Erlich Y Pickrell JK Case-control association mapping by proxy using family history of disease Nat Genet 2017 49 325 331 10.1038/ng.3766 28092683 · DOI · Paper page
  53. [73]Jansen IR Savage JE Watanabe K Bryois J Williams DM Steinberg S Genome-wide meta analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk Nat Genet 2019 51 404 413 10.1038/s41588-018-0311-9 30617256 PMC6836675 · DOI · Paper page
  54. [74]Kunkle BW Grenier-Boley B Sims R Bis JC Damptte V Naj AC Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing Nat Genet 2019 51 414 430 10.1038/s41588-019-0358-2 30820047 PMC6463297 · DOI · Paper page
  55. [75]Schwartzentruber J Cooper S Liu JZ Barrio-Hernandez I Bello E Kumasaka N Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer’s disease risk genes Nat Genet 2021 53 392 402 10.1038/s41588-020-00776-w 33589840 PMC7610386 · DOI · Paper page
  56. [76]Wightman DP Jansen IE Savage JE Shadrin AA Bahrami S Holland D A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease Nat Genet 2021 53 1276 1282 10.1038/s41588-021-00921-z 34493870 PMC10243600 · DOI · Paper page
  57. [77]Greaves CV Rohrer JD An update on genetic frontotemporal dementia J Neurol 2019 266 2075 2086 10.1007/s00415-019-09363-4 31119452 PMC6647117 · DOI · Paper page
  58. [78]Li Z Farias FHG Dube U Del-Aquila JL Mihindukulasuriya KA Fernandez MV The TMEM106B FTLD-protective variant, rs1990621, is also associated with increased neuronal proportion Acta Neuropathol 2020 139 45 61 10.1007/s00401-019-02066-0 31456032 PMC6942643 · DOI · Paper page
  59. [79]Bellenguez C, Küçükali F, Jansen I, Andrade V, Moreno-Grau S, Amin N, et al. New insights on the genetic etiology of Alzheimer’s and related dementia. medRxiv preprint 2020.10.01.20200659. 10.1101/2020.10.01.20200659. Nat Genet 2022; in press. PMC9005347 35379992 · DOI
  60. [80]Naj AC, Leonenko G, Jian X, Grenier-Boley B, Dalmasso C, Bellenguez C, et al. Genome-wide meta-analysis of late-onset Alzheimer’s disease using rare variant imputation in 65,602 subjects identifies novel rare variant locus NCK2: The International Genomics of Alzheimer’s Project (IGAP). medRxiv preprint 2021.03.14.21253553. 10.1101/2021.03.14.21253553. · DOI
  61. [81]Jun G Ibrahim-Verbaas CA Vronskaya M Lambert J-C Chung J Naj AC A novel Alzheimer disease locus located near the gene coding tau protein Mol Psychiatry 2016 21 108 117 10.1038/mp.2015.23 25778476 PMC4573764 · DOI · Paper page
  62. [82]Ma Y Jun GR Zhang X Chung J Naj AC Chen Y Analysis of whole-exome sequencing data for Alzheimer disease stratified by APOE genotype JAMA Neurol 2019 76 1099 1108 10.1001/jamaneurol.2019.1456 31180460 PMC6563544 · DOI
  63. [83]Fan K-S Feingold E Rosenthal SL Demirci FY Ganguli M Lopez OL Kamboh MI Whole-exome sequencing analysis of Alzheimer’s disease in non-APOE*4 carriers J Alzheimer Dis 2020 76 1553 1565 10.3233/JAD-200037 PMC7484092 32651314 · DOI
  64. [84]Reitz C Jun G Naj A Rajbhandary R Vardarajan BN Wang LS Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4, and the risk of late-onset Alzheimer disease in African Americans JAMA 2013 309 1483 1492 10.1001/jama.2013.2973 23571587 PMC3667653 · DOI · Paper page
  65. [85]Kunkle BW Schmidt M Klein HU Naj AC Hamilton-Nelson KL Larson EB Novel Alzheimer disease risk loci and pathways in African American individuals using the African Genome Resources Panel: A meta-analysis JAMA Neurol 2021 78 102 113 10.1001/jamaneurol.2020.3536 33074286 PMC7573798 · DOI
  66. [86]Logue MW Schu M Vardarajan BN Farrell J Bennett DA Buxbaum JD Two rare AKAP9 variants are associated with Alzheimer’s disease in African Americans Alzheimers Dement 2014 10 609 618 10.1016/j.jalz.2014.06.010 25172201 PMC4253055 · DOI · Paper page
  67. [87]Mez J Chung J Jun G Kriegel J Bourlas AP Sherva R Two novel loci, COBL and SLC10A2, for Alzheimer’s disease in African Americans Alzheimers Dement 2017 13 119 129 10.1016/j.jalz.2016.09.002 27770636 PMC5318231 · DOI
  68. [88]Reitz C, Mayeux R; Alzheimer’s Disease Genetics Consortium. TREM2 and neurodegenerative disease. N Engl J Med. 2013;369:1564–1565. PMC3980568 24131184
  69. [90]Zhou X Chen Y Mok KY Zhao Q Chen K Chen Y Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer’s disease pathogenesis Proc Natl Acad Sci USA 2018 115 1697 1706 10.1073/pnas.1715554115 29432188 PMC5828602 · DOI · Paper page
  70. [91]Wang HZ Bi R Hu QX Xiang Q Zhang C Zhang DF Validating GWAS-identified risk loci for Alzheimer’s disease in Han Chinese populations Mol Neurobiol 2016 53 379 390 10.1007/s12035-014-9015-z 25452228 · DOI
  71. [93]Shigemizu D Mitsumori R Akiyama S Miyashita A Morizono T Higaki S Ethnic and trans-ethnic genome-wide association studies identify new loci influencing Japanese Alzheimer’s disease risk Transl Psychiatry 2021 11 51 10.1038/s41398-021-01272-3 33654092 PMC7925686 · DOI · Paper page
  72. [95]Redensek S Trost M Dolzan V Genetic determinants of Parkinson’s disease: can they help to stratify the patients based on the underlying molecular defect? Front Aging Neurosci 2017 9 20 10.3389/fnagi.2017.00020 28239348 PMC5301007 · DOI
  73. [97]Bien SA Pankow JS Haessler J Lu YN Pankratz N Rohde RR Transethnic insight into the genetics of glycaemic traits: fine-mapping results from the Population Architecture Using Genomics and Epidemiology PAGE) consortium Diabetologia 2017 60 2384 2398 10.1007/s00125-017-4405-1 28905132 PMC5918310 · DOI
  74. [98]Wojcik GL Graff M Nishimura KK Tao R Haessler J Gignoux CR Genetic analyses of diverse populations improve discovery for complex traits Nature 2019 570 514 518 10.1038/s41586-019-1310-4 31217584 PMC6785182 · DOI · Paper page
  75. [99]Bien SA, Wojcik GL, Hodonsky CJ, Gignoux CR, Cheng I, Matise TC et al. The future of genomic studies must be globally representative: Perspectives from PAGE. Annu Rev Genom Hum Genet 2109; 20:181–200. PMC7012212 30978304
  76. [100]Jun GR Chung J Mez J Barber R Beecham GW Bennett DA Transethnic genome-wide scan identifies novel Alzheimer’s disease loci Alzheimer’s Dementia 2017 13 727 738 10.1016/j.jalz.2016.12.012 28183528 PMC5496797 · DOI · Paper page
  77. [101]Gurdasani D Barroso I Zeggini E Sandhu MS Genomics of disease risk in globally diverse populations Nat Rev Genet 2019 20 520 535 10.1038/s41576-019-0144-0 31235872 · DOI
  78. [102]Kruglyak L The road to genome-wide association studies Nat Rev Genet 2008 9 314 318 10.1038/nrg2316 18283274 · DOI
  79. [103]Bis JC, Jian X, Kunkle BW, Chen Y, Hamilton-Nelson KL, Bush WS, et al. Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation. Mol Psychiatry 2020; 25:1859–1875. Published online 14 August 2018. PMC6375806 30108311
  80. [104]Brody JA Morrison AC Bis JC O’Connell JR Brown MR Huffman JE Analysis commons, a team approach to discovery in a big-data environment for genetic epidemiology Nat Genet 2017 49 1560 1563 10.1038/ng.3968 29074945 PMC5720686 · DOI
  81. [105]The International HapMap Consortium A second generation human haplotype map of over 3 million SNPs Nature 2007 449 851 861 10.1038/nature06258 17943122 PMC2689609 · DOI · Paper page
  82. [106]Hirschhorn JN Genomewide association studies–illuminating biologic pathways N Engl J Med 2009 360 1699 1701 10.1056/NEJMp0808934 19369661 · DOI
  83. [107]Beecham GW, Bis JC, Martin ER, Choi SH, DeStefano AL, van Duijn CM, et al. The Alzheimer’s Disease Sequencing Project: Study design and sample selection. Neurol Genet 2017; 3(5):e194. PMC5646177 29184913
  84. [108]Adekar SP Klyubin I Macy S Rowan MJ Solomon A Dessain SK O’Nuallain B Inherent anti-amyloidogenic activity of human immunoglobulin gamma heavy chains J Bio Chem 2010 285 1066 1077 10.1074/jbc.M109.044321 19889627 PMC2801233 · DOI
  85. [110]Farh KK Marson A Zhu J Kleinewietfeld M Housley WJ Beik S Genetic and epigenetic fine mapping of causal autoimmune disease variants Nature 2015 518 337 343 10.1038/nature13835 25363779 PMC4336207 · DOI · Paper page
  86. [111]Belkadi A Bolze A Itan Y Cobat A Vincent QB Antipenko A Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants Proc Natl Acad Sci USA 2015 112 5473 5478 10.1073/pnas.1418631112 25827230 PMC4418901 · DOI
  87. [112]Prokopenko D Morgan SL Mullin K Hofmann O Chapman B Kirchner R Whole-genome sequencing reveals new Alzheimer’s disease-associated rare variants in loci related to synaptic function and neuronal development Alzheimers Dement 2021 17 1509 1527 10.1002/alz.12319 33797837 PMC8519060 · DOI · Paper page
  88. [113]Zhang B Gaiteri C Bodea L-G Wang Z McElwee J Podtelezhnikov AA Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease Cell 2013 153 707 720 10.1016/j.cell.2013.03.030 23622250 PMC3677161 · DOI · Paper page
  89. [114]Mathys H Davila-Velderrain J Peng Z Gao F Mohammadi S Young JZ Single-cell transcriptomic analysis of Alzheimer’s disease Nature 2019 570 332 337 10.1038/s41586-019-1195-2 31042697 PMC6865822 · DOI · Paper page
  90. [116]International Genomics of Alzheimer’s Disease Consortium (IGAP). Convergent genetic and expression data implicate immunity in Alzheimer’s disease. Azheimers Dement 2015;11:658–671. PMC4672734 25533204
  91. [118]Gerring ZF, Gamazon ER, White A, Derks EM. Integrative network-based analysis reveals gene networks and novel drug repositioning candidates for Alzheimer disease. Neurol Genet 2021; 7:e622. PMC8441674 34532569
  92. [119]Porcu E, Rueger S, Lepik K, eQTLGen Consortium, BIOS Consortium, Santoni FA, et al. Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits. Nat Commun 2019; 10: 3300. PMC6656778 31341166
  93. [120]Gallagher MD Chen-Plotkin AS The post-GWAS era: From association to function Am J Hum Genet 2018 102 717 730 10.1016/j.ajhg.2018.04.002 29727686 PMC5986732 · DOI · Paper page
  94. [121]Steinberg S Stefansson H Jonsson T Johannsdottir H Ingason A Helgason H Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease Nat Genet 2015 47 445 447 10.1038/ng.3246 25807283 · DOI · Paper page
  95. [122]Barbosa AC Kim MS Ertunc M Adachi M Nelson ED McAnally J MEF2C, a transcription factor that facilitates learning and memory by negative regulation of synapse numbers and function Proc Natl Acad Sci USA 2008 105 9391 9396 10.1073/pnas.0802679105 18599438 PMC2453723 · DOI · Paper page
  96. [123]Young AMH Kumasaka N Calvert F Hammond TR Knights A Panousis N A map of transcriptional heterogeneity and regulatory variation in human microglia Nat Genet 2021 53 861 868 10.1038/s41588-021-00875-2 34083789 PMC7610960 · DOI · Paper page
  97. [124]Corces MR, Shcherbina A, Kundu S, Gloudemans MJ. Frésard L, Granja JM, et al. Single-cell epigenomic analyses implicate candidate causal variants at inherited risk loci for Alzheimer’s and Parkinson’s diseases. Nat Genet 2020; 52:1158–1168. PMC7606627 33106633
  98. [126]Yao DW O’Connor LJ Price AL Gusev A Quantifying genetic effects on disease mediated by assayed gene expression levels Nat Genet 2020 52 626 633 10.1038/s41588-020-0625-2 32424349 PMC7276299 · DOI
  99. [127]Nalls MA Blauwendraat C Vallerga CL Heilbron K Bandres-Ciga S Chang D Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies Lancet Neurol 2019 18 1091 1102 10.1016/S1474-4422(19)30320-5 31701892 PMC8422160 · DOI · Paper page
  100. [129]Davies G Lam M Harris SE Trampush JW Luciano M Hill WD Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function Nat Commun 2018 9 2098 10.1038/s41467-018-04362-x 29844566 PMC5974083 · DOI
  101. [131]Zhang Y Qi G Park JH Chatterjee N Estimation of complex effect size distributions using summary-level statistics from genome-wide association studies across 32 complex traits Nat Genet 2018 50 1318 1326 10.1038/s41588-018-0193-x 30104760 · DOI · Paper page
  102. [133]Holland D, Frei O, Desikan R, Fan C-C, Shadrin AA, Smeland OB, et al. The genetic architecture of human complex phenotypes is modulated by linkage disequilibrium and heterozygosity. Genetics 2021; 217:iyaa046. PMC8045737 33789345
  103. [134]Deming Y Li Z Kapoor M Harari O Del-Aguila JL Black K Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers Acta Neuropathol 2017 133 839 856 10.1007/s00401-017-1685-y 28247064 PMC5613285 · DOI · Paper page
  104. [135]Yan Q Nho K Del-Aguila JL Wang X Risacher SL Fan KH Genome-wide association study of brain amyloid deposition as measured by Pittsburgh Compound-B (PiB)-PET imaging Mol Psychiatry 2021 26 309 321 10.1038/s41380-018-0246-7 30361487 PMC6219464 · DOI · Paper page
  105. [136]Raghavan NS Dumitrescu L Mormino E Mahoney ER Lee AJ Gao Y Association between common variants in RBFOX1, an RNA-binding protein, and brain amyloidosis in early and preclinical Alzheimer disease JAMA Neurol 2020 77 1288 1298 10.1001/jamaneurol.2020.1760 32568366 PMC7309575 · DOI
  106. [137]Damotte V, van der Lee SJ, Chouraki V, Grenier-Boley B, Simino J, Adams H, et al. Plasma amyloid β levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome-wide association study in over 12,000 non-demented participants. Alzheimers Dement 2021. 10.1002/alz.12333. Online ahead of print. PMC8597077 34002480 · DOI
  107. [138]Niu LD Xu W Li JQ Tan CC Cao XP Yu J Genome-wide association study of cerebrospinal fluid neurofilament light levels in non-demented elders Ann Transl Med 2019 7 22 657 10.21037/atm.2019.10.66 31930058 PMC6944624 · DOI
  108. [139]Wang ZT Chen SD Xu W Chen KL Wang HF Tan CC Genome-wide association study identifies CD1A associated with rate of increase in plasma neurofilament light in non-demented elders Aging (Albany NY) 2019 11 4521 4535 10.18632/aging.102066 31295725 PMC6660034 · DOI
  109. [140]Beecham GW, Hamilton K, Naj AC, Martin ER, Huentelman M, Myers AJ, et al. Genome-wide association meta-analysis of neuropathologic features of Alzheimer’s disease and related dementias. PLoS Genet 2014; 10(9):e1004606. PMC4154667 25188341
  110. [141]Dumitrescu L Mahoney ER Mukherjee S Lee ML Bush WS Engelman CD Genetic variants and functional pathways associated with resilience to Alzheimer’s disease Brain 2020 143 2561 2575 10.1093/brain/awaa209 32844198 PMC7447518 · DOI
  111. [144]Naj AC Jun G Reitz C Kunkle BW Perry W Park YS Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study JAMA Neurol 2014 71 1394 1404 10.1001/jamaneurol.2014.1491 25199842 PMC4314944 · DOI · Paper page
  112. [145]Huang KL, Marcora E, Pimenova AA, Di Narzo AF, Kapoor M, Jin SCA, et al. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nat Neurosci 2017; 20:1052–1061. PMC5759334 28628103
  113. [146]Kamboh MI A brief synopsis on the genetics of Alzheimer’s disease Curr Genet Med Rep 2018 6 133 135 10.1007/s40142-018-0155-8 30460168 PMC6223698 · DOI · Paper page
  114. [147]Puzzo D Argyrousi EK Staniszewski A Zhang H Calcagno E Zuccarello E Tau is not necessary for amyloid-beta-induced synaptic and memory impairments J Clin Invest 2020 130 4831 4844 10.1172/JCI137040 32544084 PMC7456211 · DOI
  115. [148]Pickett EK, Herrmann AG, McQueen J, Abt K, Dando O, Tulloch J, et al. Amyloid beta and tau cooperate to cause reversible behavioral and transcriptional deficits in a model of Alzheimer’s disease. Cell reports 2019; 29:3592–604 e5. PMC6915767 31825838
  116. [150]Mullard A Landmark Alzheimer’s drug approval confounds research community Nature 2021 594 309 310 10.1038/d41586-021-01546-2 34103732 · DOI
  117. [151]Walsh S, Merrick R, Milne R, Brayne C. Aducanumab for Alzheimer’s disease? BMJ 2021; 374:n1682. PMC8258645 34226181

Authors
Kamboh, M. I.
Affiliations
University of Pittsburgh (US)
Corresponding author
Kamboh, M. Ilyas
ORCID
Kamboh, M. Ilyas
Venue
Neurotherapeutics
Publisher
Elsevier BV
Published
2022-01
Volume
19
Issue
1
Pages
152-172
ISSN
1878-7479 (ISSN-L)
DOI
10.1007/s13311-021-01152-0
PMC
PMC9130391
OpenAlex
W4200218594
Cited by
73
References
154
Citations by year
2026: 12 · 2025: 17 · 2024: 19 · 2023: 15 · 2022: 10
FWCI
1.47
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurotherapeutics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
national institute on aging (AG041718, AG030653, AG064877, P30-AG066468)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
Alzheimer's disease, Alzheimer's disease genetics, late-onset Alzheimer's disease, early-onset Alzheimer's disease, apolipoprotein E, genetic susceptibility loci, APP, presenilin 1, presenilin 2, functional genomics, causal gene identification, molecular pathways, therapeutic target, neurodegeneration
MeSH terms
Alzheimer Disease, Humans, Neurodegenerative Diseases, Genetic Predisposition to Disease, Genomics, Genome-Wide Association Study

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