[1] Gatz M, Pedersen N L, Berg S, et al. Heritability for Alzheimer's disease:The study of dementia in Swedish twins[J]. Journals of Gerontology Series A:Biological Sciences and Medical Sciences, 1997, 52(2):M117-125.
[2] Ridge P G, Mukherjee S, Crane P K, et al. Alzheimer's disease:Analyzing the missing heritability[J]. PloS One, 2013, 8(11):e79771.
[3] Gatz M, Reynolds C A, Fratiglioni L, et al. Role of genes and environments for explaining Alzheimer disease[J]. Archives of General Psychiatry, 2006, 63(2):168-174.
[4] Tenesa A, Haley C S. The heritability of human disease:Estimation, uses and abuses[J]. Nature Reviews:Genetics, 2013, 14(2):139-149.
[5] Schellenberg G D, Pericak-Vance M A, Wijsman E M, et al. Linkage analysis of familial Alzheimer disease, using chromosome 21 markers[J]. American Journal of Human Genetics, 1991, 48(3):563-583.
[6] Kamino K, Orr H T, Payami H, et al. Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region[J]. American Journal of Human Genetics, 1992, 51(5):998-1014.
[7] St George-Hyslop P H, Tanzi R E, Polinsky R J, et al. The genetic defect causing familial Alzheimer's disease maps on chromosome 21[J]. Science, 1987, 235(4791):885-890.
[8] Schellenberg G D, Bird T D, Wijsman E M, et al. Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14[J]. Science, 1992, 258(5082):668-671.
[9] St George-Hyslop P, Haines J, Rogaev E, et al. Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14[J]. Nature Genetics, 1992, 2(4):330-334.
[10] van Broeckhoven C, Backhovens H, Cruts M, et al. Mapping of a gene predisposing to early-onset Alzheimer's disease to chromosome 14q24.3[J]. Nature Genetics, 1992, 2(4):335-339.
[11] Levy-Lahad E, Wijsman E M, Nemens E, et al. A familial Alzheimer's disease locus on chromosome 1[J]. Science, 1995, 269(5226):970-973.
[12] Rogaev E I, Sherrington R, Rogaeva E A, et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene[J]. Nature, 1995, 376(6543):775-778.
[13] Guerreiro R, Bras J, Hardy J. SnapShot:Genetics of Alzheimer's disease[J]. Cell, 2013, 155(4):968-968.e1.
[14] Hardy J A, Higgins G A. Alzheimer's disease:The amyloid cascade hypothesis[J]. Science, 1992, 256(5054):184-185.
[15] Hardy J, Selkoe D J. The amyloid hypothesis of Alzheimer's disease:Progress and problems on the road to therapeutics[J]. Science, 2002, 297(5580):353-356.
[16] Tanzi R E, Bertram L. Twenty years of the Alzheimer's disease amyloid hypothesis:A genetic perspective[J]. Cell, 2005, 120(4):545-555.
[17] Tanzi R E. The genetics of Alzheimer disease[J]. Cold Spring Harbor Perspectives in Medicine, 2012, 2(10):a006296.
[18] van Cauwenberghe C, van Broeckhoven C, Sleegers K. The genetic landscape of Alzheimer disease:Clinical implications and perspectives[J]. Genetics in Medicine, 2016, 18(5):421-430.
[19] Rademakers R, Cruts M, Sleegers K, et al. Linkage and association studies identify a novel locus for Alzheimer disease at 7q36 in a Dutch population-based sample[J]. American Journal of Human Genetics, 2005, 77(4):643-652.
[20] Wang G, Zhang D F, Jiang H Y, et al. Mutation and association analyses of dementia-causal genes in Han Chinese patients with early-onset and familial Alzheimer's disease[J]. Journal of Psychiatric Research, 2019, 113:141-147.
[21] Purcell S. Variancecomponents models for gene-environment interaction in twin analysis[J]. Twin Research, 2002, 5(6):554-571.
[22] Kaprio J. Twins and the mystery of missing heritability:The contribution of gene-environment interactions[J]. Journal of Internal Medicine, 2012, 272(5):440-448.
[23] Manuck S B, McCaffery J M. Gene-environment interaction[J]. Annual Review of Psychology, 2014, 65:41-70.
[24] Pulst S M. Genetic linkage analysis[J]. Archives of Neurology, 1999, 56(6):667-672.
[25] The 1000 Genomes Project Consortium. A global reference for human genetic variation[J]. Nature, 2015, 526(7571):68-74.
[26] Rodriguez-Murillo L, Greenberg D A. Genetic association analysis:A primer on how it works, its strengths and its weaknesses[J]. International Journal of Andrology, 2008, 31(6):546-556.
[27] Strittmatter W J, Saunders A M, Schmechel D, et al. Apolipoprotein E:High-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease[J]. PNAS, 1993, 90(5):1977-1981.
[28] Saunders A M, Strittmatter W J, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease[J]. Neurology, 1993, 43(8):1467-1472.
[29] Lambert J C, Ibrahim-Verbaas C A, Harold D, et al. Meta-analysis of 74046 individuals identifies 11 new susceptibility loci for Alzheimer's disease[J]. Nature Genetics, 2013, 45(12):1452-1458.
[30] Zhang D F, Li J, Wu H, et al. CFH variants affect structural and functional brain changes and genetic risk of Alzheimer's disease[J]. Neuropsychopharmacology, 2016, 41(4):1034-1045.
[31] Bertram L, McQueen M B, Mullin K, et al. Systematic meta-analyses of Alzheimer disease genetic association studies:The AlzGene database[J]. Nature Genetics, 2007, 39(1):17-23.
[32] Tam V, Patel N, Turcotte M, et al. Benefits and limitations of genome-wide association studies[J]. Nature Reviews:Genetics, 2019, 20(8):467-484.
[33] Grupe A, Abraham R, Li Y, et al. Evidence for novel susceptibility genes for late-onset Alzheimer's disease from a genome-wide association study of putative functional variants[J]. Human Molecular Genetics, 2007, 16(8):865-873.
[34] Reiman E M, Webster J A, Myers A J, et al. GAB2 alleles modify Alzheimer's risk in ApoE ε4 carriers[J]. Neuron, 2007, 54(5):713-720.
[35] Lambert J C, Heath S, Even G, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease[J]. Nature Genetics, 2009, 41(10):1094-1099.
[36] Harold D, Abraham R, Hollingworth P, et al. Genomewide association study identifies variants at CLU and PICALM associated with Alzheimer's disease[J]. Nature Genetics, 2009, 41(10):1088-1093.
[37] Seshadri S, Fitzpatrick A L, Ikram M A, et al. Genomewide analysis of genetic loci associated with Alzheimer disease[J]. JAMA, 2010, 303(18):1832-1840.
[38] Hollingworth P, Harold D, Sims R, et al. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease[J]. Nature Genetics, 2011, 43(5):429-435.
[39] Naj A C, Jun G, Beecham G W, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease[J]. Nature Genetics, 2011, 43(5):436-441.
[40] Karch C M, Goate A M. Alzheimer's disease risk genes and mechanisms of disease pathogenesis[J]. Biological Psychiatry, 2015, 77(1):43-51.
[41] Wang H Z, Bi R, Hu Q X, et al. Validating GWAS-identified risk loci for Alzheimer's disease in Han Chinese populations[J]. Molecular Neurobiology, 2016, 53(1):379-390.
[42] Thomas R S, Henson A, Gerrish A, et al. Decreasing the expression of PICALM reduces endocytosis and the activity of beta-secretase:Implications for Alzheimer's disease[J]. BMC Neuroscience, 2016, 17(1):50.
[43] Sakae N, Liu C C, Shinohara M, et al. ABCA7 deficiency accelerates amyloid-beta Generation and Alzheimer's neuronal pathology[J]. Journal of Neuroscience, 2016, 36(13):3848-3859.
[44] Marioni R E, Harris S E, Zhang Q, et al. GWAS on family history of Alzheimer's disease[J]. Translational Psychiatry, 2018, 8(1):99.
[45] Jansen I E, Savage J E, Watanabe K, et al. Genomewide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk[J]. Nature Genetics, 2019, 51(3):404-413.
[46] Kunkle B W, Grenier-Boley B, Sims R, et al. Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing[J]. Nature Genetics, 2019, 51(3):414-430.
[47] Wightman D P, Jansen I E, Savage J E, et al. Largest GWAS (N=1,126,563) of Alzheimer's disease implicates microglia and immune cells[J/OL]. medRxiv, 2020, https://doi.org/10.1101/2020.11.20.20235275.
[48] Bellenguez C, Küçükali F, Jansen I, et al. New insights on the genetic etiology of Alzheimer's and related dementia[J/OL]. medRxiv, 2020, https://doi.org/10.1101/2020.10.01.20200659.
[49] Jonsson T, Stefansson H, Steinberg S, et al. Variant of TREM2 associated with the risk of Alzheimer's disease[J]. New England Journal of Medicine, 2013, 368(2):107-116.
[50] Guerreiro R, Wojtas A, Bras J, et al. TREM2 variants in Alzheimer's disease[J]. New England Journal of Medicine, 2013, 368(2):117-127.
[51] Cheng-Hathaway P J, Reed-Geaghan E G, Jay T R, et al. The Trem2 R47H variant confers loss-of-functionlike phenotypes in Alzheimer's disease[J]. Molecular Neurodegeneration, 2018, 13(1):29.
[52] Condello C, Yuan P, Grutzendler J. Microglia-mediated neuroprotection, TREM2, and Alzheimer's disease:Evidence from optical imaging[J]. Biological Psychiatry[J]. 2018, 83(4):377-387.
[53] Wetzel-Smith M K, Hunkapiller J, Bhangale T R, et al. A rare mutation in UNC5C predisposes to late-onset Alzheimer's disease and increases neuronal cell death[J]. Nature Medicine, 2014. 20(12):1452-1457.
[54] Steinberg S, Stefansson H, Jonsson T, et al. Loss-offunction variants in ABCA7 confer risk of Alzheimer's disease[J]. Nature Genetics, 2015, 47(5):445-447.
[55] Beecham G W, Vardarajan B, Blue E, et al. Rare genetic variation implicated in non-Hispanic white families with Alzheimer disease[J]. Neurology Genetics, 2018, 4(6):e286.
[56] Raghavan N S, Brickman A M, Andrews H, et al. Whole-exome sequencing in 20197 persons for rare variants in Alzheimer's disease[J]. Annals of Clinical and Translational Neurology, 2018, 5(7):832-842.
[57] Cruchaga C, Karch C M, Jin S C, et al. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer's disease[J]. Nature, 2014, 505(7484):550-554.
[58] Sims R, van der Lee S J, Naj A C, et al. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease[J]. Nature Genetics, 2017, 49(9):1373-1384.
[59] Logue M W, Schu M, Vardarajan B N, et al. Acomprehensive genetic association study of Alzheimer disease in African Americans[J]. Archives of Neurology, 2011, 68(12):1569-1579.
[60] Mez J, Chung J, Jun G, et al. Two novel loci, COBL and SLC10A2, for Alzheimer's disease in African Americans[J]. Alzheimers Dement, 2017, 13(2):119-129.
[61] Kunkle B W, Schmidt M, Klein H U, et al. Novel Alzheimer disease risk loci and pathways in African American individuals using the African genome resources panel:A meta-analysis[J]. JAMA Neurology, 2021, 78(1):102-113.
[62] Miyashita A, Koike A, Jun G, et al. SORL1 is genetically associated with late-onset Alzheimer's disease in Japanese, Koreans and Caucasians[J]. PloS One, 2013, 8(4):e58618.
[63] Hirano A, Ohara T, Takahashi A, et al. A genome-wide association study of late-onset Alzheimer's disease in a Japanese population[J]. Psychiatric Genetics, 2015, 25(4):139-146.
[64] Shigemizu D, Mitsumori R, Akiyama S, et al. Ethnic and trans-ethnic genome-wide association studies identify new loci influencing Japanese Alzheimer's disease risk[J]. Translational Psychiatry, 2021, 11(1):151.
[65] Kang S, Gim J, Gunasekaran T I, et al. APOE-stratified genome-wide association study suggests potential novel genes for late-onset Alzheimer's disease in East-Asian descent[J/OL]. medRxiv, 2021, https://doi.org/10.1101/2020.07.02.20145557.
[66] Zhou X, Chen Y, Mok K Y, et al. Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer's disease pathogenesis[J]. PNAS, 2018, 115(8):1697-1706.
[67] Zhang D F, Fan Y, Xu M, et al. Complement C7 is a novel risk gene for Alzheimer's disease in Han Chinese[J]. National Science Review, 2019, 6(2):257-274.
[68] Wang B B, Bao S Y, Zhang Z G, et al. A rare variant in MLKL confers susceptibility to ApoE ε4-negative Alzheimer's disease in Hong Kong Chinese population[J]. Neurobiol Aging, 2018, 68(160):160.e1-160.e7.
[69] Jia L F, Li F Y, Wei C B, et al. Prediction of Alzheimer's disease using multi-variants from a Chinese genome-wide association study[J]. Brain, 2020, 144(3):924-937..
[70] Andrews S J, Fulton-Howard B, Goate A. Interpretation of risk loci from genome-wide association studies of Alzheimer's disease[J]. Lancet Neurology, 2020, 19(4):326-335.
[71] Lunnon K, Smith R, Hannon E, et al. Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease[J]. Nature Neuroscience, 2014, 17(9):1164-1170.
[72] de Jager P L, Srivastava G, Lunnon K, et al. Alzheimer's disease:Early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci[J]. Nature Neuroscience, 2014, 17(9):1156-1163.
[73] Nativio R, Donahue G, Berson A, et al. Dysregulation of the epigenetic landscape of normal aging in Alzheimer's disease[J]. Nature Neuroscience, 2018, 21(4):497-505.
[74] Marzi S J, Leung S K, Ribarska T, et al. A histone acetylome-wide association study of Alzheimer's disease identifies disease-associated H3K27ac differences in the entorhinal cortex[J]. Nature Neuroscience, 2018. 21(11):1618-1627.
[75] Klein H U, McCabe C, Gjoneska E, et al. Epigenomewide study uncovers large-scale changes in histone acetylation driven by tau pathology in aging and Alzheimer's human brains[J]. Nature Neuroscience, 2019, 22(1):37-46.
[76] Kikuchi M, Hara N, Hasegawa M, et al. Enhancer variants associated with Alzheimer's disease affect gene expression via chromatin looping[J]. BMC Medical Genomics, 2019, 12(1):128.
[77] Chen Y, Zhu J, Lum P Y, et al. Variations in DNA elucidate molecular networks that cause disease[J]. Nature, 2008, 452(7186):429-435.
[78] Blalock E M, Geddes J W, Chen K C, et al. Incipient Alzheimer's disease:Microarray correlation analyses reveal major transcriptional and tumor suppressor responses[J]. PNAS, 2004, 101(7):2173-2178.
[79] Hokama M, Oka S, Leon J, et al. Altered expression of diabetes-related genes in Alzheimer's disease brains:The Hisayama study[J]. Cerebral Cortex, 2014, 24(9):2476-2488.
[80] Lai M K, Esiri M M, Tan M G. Genome-wide profiling of alternative splicing in Alzheimer's disease[J]. Genom Data, 2014, 2:290-292.
[81] Miller J A, Woltjer R L, Goodenbour J M, et al. Genes and pathways underlying regional and cell type changes in Alzheimer's disease[J]. Genome Medicine, 2013, 5(5):48.
[82] Blalock E M, Buechel H M, Popovic J, et al. Microarray analyses of laser-captured hippocampus reveal distinct gray and white matter signatures associated with incipient Alzheimer's disease[J]. Journal of Chemical Neuroanatomy, 2011, 42(2):118-126.
[83] Webster J A, Gibbs J R, Clarke J, et al. Genetic control of human brain transcript expression in Alzheimer disease[J]. American Journal of Human Genetics, 2009, 84(4):445-458.
[84] Xu M, Zhang D F, Luo R, et al. A systematic integrated analysis of brain expression profiles reveals YAP1 and other prioritized hub genes as important upstream regulators in Alzheimer's disease[J]. Alzheimers Dementia, 2018, 14(2):215-229.
[85] Mathys H, Davila-Velderrain J, Peng Z, et al. Singlecell transcriptomic analysis of Alzheimer's disease[J]. Nature, 2019, 570(7761):332-337.
[86] Grubman A, Chew G, Ouyang J F, et al. A single-cell atlas of entorhinal cortex from individuals with Alzheimer's disease reveals cell-type-specific gene expression regulation[J]. Nature Neuroscience, 2019, 22(12):2087-2097.
[87] Lau S F, Cao H, Fu A K Y, et al. Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer's disease[J]. PNAS, 2020, 117(41):25800-25809.
[88] Zhang B, Gaiteri C, Bodea L G, et al. Integrated systems approach identifies genetic nodes and networks in lateonset Alzheimer's disease[J]. Cell, 2013, 153(3):707-720.
[89] Andreev V P, Petyuk V A, Brewer H M, et al. Labelfree quantitative LC-MS proteomics of Alzheimer's disease and normally aged human brains[J]. Journal of Proteome Research, 2012, 11(6):3053-3067.
[90] Johnson E C B, Dammer E B, Duong D M, et al. Largescale proteomic analysis of Alzheimer's disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation[J]. Nature Medicine, 2020, 26(5):769-780.
[91] Wingo A P, Liu Y, Gerasimov E S, et al. Integrating human brain proteomes with genome-wide association data implicates new proteins in Alzheimer's disease pathogenesis[J]. Nature Genetics, 2021, 53(2):143-146.
[92] Toledo J B, Arnold M, Kastenmüller G, et al. Metabolic network failures in Alzheimer's disease:A biochemical road map[J]. Alzheimers Dementia, 2017, 13(9):965-984.
[93] Mapstone M, Cheema A K, Fiandaca M S, et al. Plasma phospholipids identify antecedent memory impairment in older adults[J]. Nature Medicine, 2014, 20(4):415-418.
[94] Xiong F, Ge W, Ma C. Quantitative proteomics reveals distinctcomposition of amyloid plaques in Alzheimer's disease[J]. Alzheimers Dementia, 2019, 15(3):429-440.
[95] Small K S, Hedman A K, Grundberg E, et al. Identification of an imprinted master trans regulator at the KLF14 locus related to multiple metabolic phenotypes[J]. Nature Genetics, 2011, 43(6):561-564.
[96] Jia J, Parikh H, Xiao W, et al. An integrated transcriptome and epigenome analysis identifies a novel candidate gene for pancreatic cancer[J]. BMC Medical Genomics, 2013, 6(1):33.
[97] Dumitriu A, Golji J, Labadorf A T, et al. Integrative analyses of proteomics and RNA transcriptomics implicate mitochondrial processes, protein folding pathways and GWAS loci in Parkinson disease[J]. BMC Medical Genomics, 2016, 9(1):5.
[98] Maurano M T, Humbert R, Rynes E, et al. Systematic localization ofcommon disease-associated variation in regulatory DNA[J]. Science, 2012, 337(6099):1190-1195.
