{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T19:15:22Z","timestamp":1792178122093,"version":"4.4.0"},"reference-count":149,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2018,4,24]],"date-time":"2018-04-24T00:00:00Z","timestamp":1524528000000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1K08AG054727-01A1"],"award-info":[{"award-number":["1K08AG054727-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"DOI":"10.3389\/fmed.2018.00108","type":"journal-article","created":{"date-parts":[[2018,4,24]],"date-time":"2018-04-24T00:45:32Z","timestamp":1524530732000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":69,"title":["The Role of Genetics in Advancing Precision Medicine for Alzheimer\u2019s Disease\u2014A Narrative Review"],"prefix":"10.3389","volume":"5","author":[{"given":"Yun","family":"Freudenberg-Hua","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Davies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2018,4,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"203","DOI":"10.1097\/00002093-200210000-00001","article-title":"Relative frequencies of Alzheimer disease, Lewy body, vascular and frontotemporal dementia, and hippocampal sclerosis in the state of Florida brain bank","volume":"16","author":"Barker","year":"2002","journal-title":"Alzheimer Dis Assoc Disord"},{"key":"B2","doi-asserted-by":"publisher","first-page":"2673","DOI":"10.1016\/S0140-6736(17)31363-6","article-title":"Dementia prevention, intervention, and care","volume":"390","author":"Livingston","year":"2017","journal-title":"Lancet"},{"key":"B3","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/S0140-6736(14)61347-7","article-title":"The burden of disease in older people and implications for health policy and practice","volume":"385","author":"Prince","year":"2015","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/j.jalz.2016.03.001","article-title":"2016 Alzheimer\u2019s disease facts and figures","volume":"12","year":"2016","journal-title":"Alzheimers Dement"},{"key":"B5","doi-asserted-by":"publisher","first-page":"2112","DOI":"10.1016\/S0140-6736(05)67889-0","article-title":"Global prevalence of dementia: a Delphi consensus study","volume":"366","author":"Ferri","year":"2005","journal-title":"Lancet"},{"key":"B6","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1038\/nature15816","article-title":"Building the foundation for genomics in precision medicine","volume":"526","author":"Aronson","year":"2015","journal-title":"Nature"},{"key":"B7","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1097\/ACM.0000000000000585","article-title":"Varieties of integrative scholarship: why rules of evidence, criteria, and standards matter","volume":"90","author":"McGaghie","year":"2015","journal-title":"Acad Med"},{"key":"B8","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1038\/nrg796","article-title":"Candidate-gene approaches for studying complex genetic traits: practical considerations","volume":"3","author":"Tabor","year":"2002","journal-title":"Nat Rev Genet"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e1002812","DOI":"10.1371\/journal.pgen.1002812","article-title":"Guidelines for genome-wide association studies","volume":"8","author":"Barsh","year":"2012","journal-title":"PLoS Genet"},{"key":"B10","doi-asserted-by":"publisher","first-page":"D896","DOI":"10.1093\/nar\/gkw1133","article-title":"The new NHGRI-EBI catalog of published genome-wide association studies (GWAS Catalog)","volume":"45","author":"MacArthur","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"B11","first-page":"146","article-title":"\u00dcber eine eigenartige Erkrankung der Hirnrinde","volume":"64","author":"Alzheimer","year":"1907","journal-title":"Allgemeine Zeitschrift f\u00fcr Psychiatrie und Psychisch-Gerichtliche Medizin"},{"key":"B12","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.jalz.2011.03.005","article-title":"The diagnosis of dementia due to Alzheimer\u2019s disease: recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"McKhann","year":"2011","journal-title":"Alzheimers Dement"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1019","DOI":"10.1016\/S0140-6736(10)61349-9","article-title":"Alzheimer\u2019s disease","volume":"377","author":"Ballard","year":"2011","journal-title":"Lancet"},{"key":"B14","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1016\/S0140-6736(15)01124-1","article-title":"Alzheimer\u2019s disease","volume":"388","author":"Scheltens","year":"2016","journal-title":"Lancet"},{"key":"B15","doi-asserted-by":"publisher","first-page":"429","DOI":"10.7326\/0003-4819-113-6-429","article-title":"Survival of outpatients with Alzheimer-type dementia","volume":"113","author":"Walsh","year":"1990","journal-title":"Ann Intern Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1212\/WNL.41.4.479","article-title":"The Consortium to Establish a Registry for Alzheimer\u2019s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer\u2019s disease","volume":"41","author":"Mirra","year":"1991","journal-title":"Neurology"},{"key":"B17","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1007\/s00401-006-0127-z","article-title":"Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry","volume":"112","author":"Braak","year":"2006","journal-title":"Acta Neuropathol"},{"key":"B18","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1097\/00005072-199710000-00002","article-title":"Consensus recommendations for the postmortem diagnosis of Alzheimer disease from the National Institute on Aging and the Reagan Institute Working Group on diagnostic criteria for the neuropathological assessment of Alzheimer disease","volume":"56","author":"Hyman","year":"1997","journal-title":"J Neuropathol Exp Neurol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1007\/s00401-008-0466-z","article-title":"Criteria for the neuropathological diagnosis of dementing disorders: routes out of the swamp?","volume":"117","author":"Jellinger","year":"2009","journal-title":"Acta Neuropathol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.jalz.2011.03.003","article-title":"Toward defining the preclinical stages of Alzheimer\u2019s disease: recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"Sperling","year":"2011","journal-title":"Alzheimers Dement"},{"key":"B21","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.jalz.2011.03.008","article-title":"The diagnosis of mild cognitive impairment due to Alzheimer\u2019s disease: recommendations from the National Institute on Aging-Alzheimer\u2019s Association workgroups on diagnostic guidelines for Alzheimer\u2019s disease","volume":"7","author":"Albert","year":"2011","journal-title":"Alzheimers Dement"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jalz.2011.10.007","article-title":"National Institute on Aging-Alzheimer\u2019s Association guidelines for the neuropathologic assessment of Alzheimer\u2019s disease","volume":"8","author":"Hyman","year":"2012","journal-title":"Alzheimers Dement"},{"key":"B23","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1212\/WNL.0000000000002923","article-title":"A\/T\/N: an unbiased descriptive classification scheme for Alzheimer disease biomarkers","volume":"87","author":"Jack","year":"2016","journal-title":"Neurology"},{"key":"B24","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1002\/ana.24388","article-title":"Hippocampal sclerosis and TDP-43 pathology in aging and Alzheimer disease","volume":"77","author":"Nag","year":"2015","journal-title":"Ann Neurol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1001\/archneur.57.5.713","article-title":"The relative frequency of \u201cdementia of unknown etiology\u201d increases with age and is nearly 50% in nonagenarians","volume":"57","author":"Crystal","year":"2000","journal-title":"Arch Neurol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1007\/s00401-013-1211-9","article-title":"Staging TDP-43 pathology in Alzheimer\u2019s disease","volume":"127","author":"Josephs","year":"2014","journal-title":"Acta Neuropathol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1007\/s004010100415","article-title":"Dementia with Lewy bodies and Alzheimer\u2019s disease","volume":"102","author":"Rosenberg","year":"2001","journal-title":"Acta Neuropathol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1016\/j.ajpath.2015.12.001","article-title":"Precision medicine: clarity for the complexity of dementia","volume":"186","author":"Cholerton","year":"2016","journal-title":"Am J Pathol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1001\/archneurol.2011.157","article-title":"Ecology of the aging human brain","volume":"68","author":"Sonnen","year":"2011","journal-title":"Arch Neurol"},{"key":"B30","doi-asserted-by":"publisher","first-page":"142","DOI":"10.3389\/fneur.2015.00142","article-title":"Autosomal dominant Alzheimer disease: a unique resource to study CSF biomarker changes in preclinical AD","volume":"6","author":"Schindler","year":"2015","journal-title":"Front Neurol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1001\/archneurol.2008.596","article-title":"Cerebrospinal fluid {beta}-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain","volume":"66","author":"Tapiola","year":"2009","journal-title":"Arch Neurol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1016\/j.biopsych.2009.01.027","article-title":"Beta amyloid in Alzheimer\u2019s disease: increased deposition in brain is reflected in reduced concentration in cerebrospinal fluid","volume":"65","author":"Grimmer","year":"2009","journal-title":"Biol Psychiatry"},{"key":"B33","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1002\/ana.21559","article-title":"Decreased cerebrospinal fluid Abeta(42) correlates with brain atrophy in cognitively normal elderly","volume":"65","author":"Fagan","year":"2009","journal-title":"Ann Neurol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1016\/S1474-4422(17)30159-X","article-title":"Strategic roadmap for an early diagnosis of Alzheimer\u2019s disease based on biomarkers","volume":"16","author":"Frisoni","year":"2017","journal-title":"Lancet Neurol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/j.jalz.2016.09.008","article-title":"Recommendations for CSF AD biomarkers in the diagnostic evaluation of dementia","volume":"13","author":"Simonsen","year":"2017","journal-title":"Alzheimers Dement"},{"key":"B36","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1056\/NEJMoa1202753","article-title":"Clinical and biomarker changes in dominantly inherited Alzheimer\u2019s disease","volume":"367","author":"Bateman","year":"2012","journal-title":"N Engl J Med"},{"key":"B37","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1001\/jamaneurol.2017.0263","article-title":"Hierarchical organization of Tau and amyloid deposits in the cerebral cortex","volume":"74","author":"Sepulcre","year":"2017","journal-title":"JAMA Neurol"},{"key":"B38","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological stageing of Alzheimer-related changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"38","DOI":"10.3978\/j.issn.2305-5839.2015.01.19","article-title":"Rate of early onset Alzheimer\u2019s disease: a systematic review and meta-analysis","volume":"3","author":"Zhu","year":"2015","journal-title":"Ann Transl Med"},{"key":"B40","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1086\/302553","article-title":"Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum","volume":"65","author":"Campion","year":"1999","journal-title":"Am J Hum Genet"},{"key":"B41","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1177\/1533317514545825","article-title":"The patterns of inheritance in early-onset dementia: Alzheimer\u2019s disease and frontotemporal dementia","volume":"30","author":"Jarmolowicz","year":"2015","journal-title":"Am J Alzheimers Dis Other Demen"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1817","DOI":"10.2147\/CIA.S116724","article-title":"A genetic screen of the mutations in the Korean patients with early-onset Alzheimer\u2019s disease","volume":"11","author":"An","year":"2016","journal-title":"Clin Interv Aging"},{"key":"B43","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1038\/349704a0","article-title":"Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer\u2019s disease","volume":"349","author":"Goate","year":"1991","journal-title":"Nature"},{"key":"B44","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1038\/375754a0","article-title":"Cloning of a gene bearing missense mutations in early-onset familial Alzheimer\u2019s disease","volume":"375","author":"Sherrington","year":"1995","journal-title":"Nature"},{"key":"B45","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1038\/376775a0","article-title":"Familial Alzheimer\u2019s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer\u2019s disease type 3 gene","volume":"376","author":"Rogaev","year":"1995","journal-title":"Nature"},{"key":"B46","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1126\/science.7638621","article-title":"Candidate gene for the chromosome 1 familial Alzheimer\u2019s disease locus","volume":"269","author":"Levy-Lahad","year":"1995","journal-title":"Science"},{"key":"B47","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/alzrt107","article-title":"Molecular consequences of amyloid precursor protein and presenilin mutations causing autosomal-dominant Alzheimer\u2019s disease","volume":"4","author":"Weggen","year":"2012","journal-title":"Alzheimers Res Ther"},{"key":"B48","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1038\/nature11283","article-title":"A mutation in App protects against Alzheimer\u2019s disease and age-related cognitive decline","volume":"488","author":"Jonsson","year":"2012","journal-title":"Nature"},{"key":"B49","doi-asserted-by":"publisher","first-page":"E476","DOI":"10.1073\/pnas.1618657114","article-title":"Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Abeta42 and Abeta40 peptides by gamma-secretase","volume":"114","author":"Sun","year":"2017","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B50","doi-asserted-by":"publisher","first-page":"30990","DOI":"10.1074\/jbc.M114.589069","article-title":"Molecular mechanisms of Alzheimer disease protection by the A673T allele of amyloid precursor protein","volume":"289","author":"Maloney","year":"2014","journal-title":"J Biol Chem"},{"key":"B51","doi-asserted-by":"publisher","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol Med"},{"key":"B52","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1186\/s40478-014-0135-5","article-title":"Inconsistencies and controversies surrounding the amyloid hypothesis of Alzheimer\u2019s disease","volume":"2","author":"Morris","year":"2014","journal-title":"Acta Neuropathol Commun"},{"key":"B53","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1002\/ana.20009","article-title":"Imaging brain amyloid in Alzheimer\u2019s disease with Pittsburgh compound-B","volume":"55","author":"Klunk","year":"2004","journal-title":"Ann Neurol"},{"key":"B54","doi-asserted-by":"publisher","first-page":"1718","DOI":"10.1212\/01.wnl.0000261919.22630.ea","article-title":"Imaging beta-amyloid burden in aging and dementia","volume":"68","author":"Rowe","year":"2007","journal-title":"Neurology"},{"key":"B55","doi-asserted-by":"publisher","first-page":"1509","DOI":"10.1001\/archneur.65.11.1509","article-title":"Frequent amyloid deposition without significant cognitive impairment among the elderly","volume":"65","author":"Aizenstein","year":"2008","journal-title":"Arch Neurol"},{"key":"B56","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1212\/WNL.0b013e3181bc010c","article-title":"Relationships between biomarkers in aging and dementia","volume":"73","author":"Jagust","year":"2009","journal-title":"Neurology"},{"key":"B57","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1038\/nn.4018","article-title":"Three dimensions of the amyloid hypothesis: time, space and \u2018wingmen\u2019","volume":"18","author":"Musiek","year":"2015","journal-title":"Nat Neurosci"},{"key":"B58","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1001\/archpsyc.63.2.168","article-title":"Role of genes and environments for explaining Alzheimer disease","volume":"63","author":"Gatz","year":"2006","journal-title":"Arch Gen Psychiatry"},{"key":"B59","doi-asserted-by":"publisher","first-page":"1977","DOI":"10.1073\/pnas.90.5.1977","article-title":"Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease","volume":"90","author":"Strittmatter","year":"1993","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B60","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1126\/science.8346443","article-title":"Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer\u2019s disease in late onset families","volume":"261","author":"Corder","year":"1993","journal-title":"Science"},{"key":"B61","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1001\/jama.1997.03550160069041","article-title":"Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium","volume":"278","author":"Farrer","year":"1997","journal-title":"JAMA"},{"key":"B62","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1038\/mp.2011.52","article-title":"APOE and Alzheimer disease: a major gene with semi-dominant inheritance","volume":"16","author":"Genin","year":"2011","journal-title":"Mol Psychiatry"},{"key":"B63","first-page":"439","article-title":"Apolipoprotein E and Alzheimer disease: genotype-specific risks by age and sex","volume":"60","author":"Bickeboller","year":"1997","journal-title":"Am J Hum Genet"},{"key":"B64","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/1471-2377-8-9","article-title":"APOE epsilon 4 lowers age at onset and is a high risk factor for Alzheimer\u2019s disease; a case control study from central Norway","volume":"8","author":"Sando","year":"2008","journal-title":"BMC Neurol"},{"key":"B65","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1002\/mgg3.86","article-title":"Disease variants in genomes of 44 centenarians","volume":"2","author":"Freudenberg-Hua","year":"2014","journal-title":"Mol Genet Genomic Med"},{"key":"B66","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1126\/science.3283935","article-title":"Apolipoprotein E: cholesterol transport protein with expanding role in cell biology","volume":"240","author":"Mahley","year":"1988","journal-title":"Science"},{"key":"B67","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/nrneurol.2012.263","article-title":"Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy","volume":"9","author":"Liu","year":"2013","journal-title":"Nat Rev Neurol"},{"key":"B68","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/j.biopsych.2017.03.003","article-title":"Apolipoprotein E, receptors, and modulation of Alzheimer\u2019s disease","volume":"83","author":"Zhao","year":"2018","journal-title":"Biol Psychiatry"},{"key":"B69","doi-asserted-by":"publisher","first-page":"8913","DOI":"10.1073\/pnas.1207022109","article-title":"Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer\u2019s disease","volume":"109","author":"Frieden","year":"2012","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B70","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1038\/nature24016","article-title":"ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy","volume":"549","author":"Shi","year":"2017","journal-title":"Nature"},{"key":"B71","doi-asserted-by":"publisher","first-page":"e1001130","DOI":"10.1371\/journal.pgen.1001130","article-title":"Dementia revealed: novel chromosome 6 locus for late-onset Alzheimer disease provides genetic evidence for folate-pathway abnormalities","volume":"6","author":"Naj","year":"2010","journal-title":"PLoS Genet"},{"key":"B72","doi-asserted-by":"publisher","first-page":"200.e13","DOI":"10.1016\/j.neurobiolaging.2016.02.024","article-title":"Assessment of the genetic variance of late-onset Alzheimer\u2019s disease","volume":"41","author":"Ridge","year":"2016","journal-title":"Neurobiol Aging"},{"key":"B73","doi-asserted-by":"publisher","first-page":"3096","DOI":"10.1093\/hmg\/ddw150","article-title":"Differential burden of rare protein truncating variants in Alzheimer\u2019s disease patients compared to centenarians","volume":"25","author":"Freudenberg-Hua","year":"2016","journal-title":"Hum Mol Genet"},{"key":"B74","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1056\/NEJMoa1211851","article-title":"TREM2 variants in Alzheimer\u2019s disease","volume":"368","author":"Guerreiro","year":"2013","journal-title":"N Engl J Med"},{"key":"B75","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1056\/NEJMoa1211103","article-title":"Variant of TREM2 associated with the risk of Alzheimer\u2019s disease","volume":"368","author":"Jonsson","year":"2013","journal-title":"N Engl J Med"},{"key":"B76","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1038\/nature12825","article-title":"Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer\u2019s disease","volume":"505","author":"Cruchaga","year":"2014","journal-title":"Nature"},{"key":"B77","doi-asserted-by":"publisher","first-page":"E2","DOI":"10.1038\/nature14038","article-title":"PLD3 variants in population studies","volume":"520","author":"Van Der Lee","year":"2015","journal-title":"Nature"},{"key":"B78","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.1038\/nm.3736","article-title":"A rare mutation in UNC5C predisposes to late-onset Alzheimer\u2019s disease and increases neuronal cell death","volume":"20","author":"Wetzel-Smith","year":"2014","journal-title":"Nat Med"},{"key":"B79","doi-asserted-by":"publisher","first-page":"609","DOI":"10.1016\/j.jalz.2014.06.010","article-title":"Two rare AKAP9 variants are associated with Alzheimer\u2019s disease in African Americans","volume":"10","author":"Logue","year":"2014","journal-title":"Alzheimers Dement"},{"key":"B80","doi-asserted-by":"publisher","first-page":"3987","DOI":"10.1093\/hmg\/ddp323","article-title":"Potential late-onset Alzheimer\u2019s disease-associated mutations in the ADAM10 gene attenuate {alpha}-secretase activity","volume":"18","author":"Kim","year":"2009","journal-title":"Hum Mol Genet"},{"key":"B81","doi-asserted-by":"publisher","first-page":"1373","DOI":"10.1038\/ng.3916","article-title":"Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer\u2019s disease","volume":"49","author":"Sims","year":"2017","journal-title":"Nat Genet"},{"key":"B82","doi-asserted-by":"publisher","first-page":"2134","DOI":"10.1212\/WNL.0000000000002627","article-title":"ABCA7 rare variants and Alzheimer disease risk","volume":"86","author":"Le Guennec","year":"2016","journal-title":"Neurology"},{"key":"B83","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1038\/ng.3246","article-title":"Loss-of-function variants in ABCA7 confer risk of Alzheimer\u2019s disease","volume":"47","author":"Steinberg","year":"2015","journal-title":"Nat Genet"},{"key":"B84","doi-asserted-by":"publisher","first-page":"814","DOI":"10.1016\/S1474-4422(15)00133-7","article-title":"Mutations in ABCA7 in a Belgian cohort of Alzheimer\u2019s disease patients: a targeted resequencing study","volume":"14","author":"Cuyvers","year":"2015","journal-title":"Lancet Neurol"},{"key":"B85","doi-asserted-by":"publisher","first-page":"e31039","DOI":"10.1371\/journal.pone.0031039","article-title":"Rare variants in APP, PSEN1 and PSEN2 increase risk for Ad in late-onset Alzheimer\u2019s disease families","volume":"7","author":"Cruchaga","year":"2012","journal-title":"PLoS One"},{"key":"B86","doi-asserted-by":"publisher","first-page":"e1007045","DOI":"10.1371\/journal.pgen.1007045","article-title":"Analysis of neurodegenerative Mendelian genes in clinically diagnosed Alzheimer disease","volume":"13","author":"Fernandez","year":"2017","journal-title":"PLoS Genet"},{"key":"B87","doi-asserted-by":"publisher","first-page":"E3","DOI":"10.1038\/nature14039","article-title":"PLD3 in non-familial Alzheimer\u2019s disease","volume":"520","author":"Heilmann","year":"2015","journal-title":"Nature"},{"key":"B88","doi-asserted-by":"publisher","first-page":"E7","DOI":"10.1038\/nature14040","article-title":"PLD3 gene variants and Alzheimer\u2019s disease","volume":"520","author":"Hooli","year":"2015","journal-title":"Nature"},{"key":"B89","doi-asserted-by":"publisher","first-page":"E1","DOI":"10.1038\/nature14036","article-title":"PLD3 and sporadic Alzheimer\u2019s disease risk","volume":"520","author":"Lambert","year":"2015","journal-title":"Nature"},{"key":"B90","doi-asserted-by":"publisher","first-page":"968","DOI":"10.1016\/j.cell.2013.10.037","article-title":"SnapShot: genetics of Alzheimer\u2019s disease","volume":"155","author":"Guerreiro","year":"2013","journal-title":"Cell"},{"key":"B91","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.biopsych.2014.05.006","article-title":"Alzheimer\u2019s disease risk genes and mechanisms of disease pathogenesis","volume":"77","author":"Karch","year":"2015","journal-title":"Biol Psychiatry"},{"key":"B92","doi-asserted-by":"publisher","first-page":"665","DOI":"10.2147\/CIA.S105769","article-title":"Genes associated with Alzheimer\u2019s disease: an overview and current status","volume":"11","author":"Giri","year":"2016","journal-title":"Clin Interv Aging"},{"key":"B93","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1038\/ni.3102","article-title":"Innate immunity in Alzheimer\u2019s disease","volume":"16","author":"Heneka","year":"2015","journal-title":"Nat Immunol"},{"key":"B94","doi-asserted-by":"publisher","first-page":"388","DOI":"10.1016\/S1474-4422(15)70016-5","article-title":"Neuroinflammation in Alzheimer\u2019s disease","volume":"14","author":"Heneka","year":"2015","journal-title":"Lancet Neurol"},{"key":"B95","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1038\/nrn3880","article-title":"Immune attack: the role of inflammation in Alzheimer disease","volume":"16","author":"Heppner","year":"2015","journal-title":"Nat Rev Neurosci"},{"key":"B96","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1016\/j.neuron.2016.06.015","article-title":"TREM2 Binds to apolipoproteins, including APOE and CLU\/APOJ, and thereby facilitates uptake of amyloid-beta by microglia","volume":"91","author":"Yeh","year":"2016","journal-title":"Neuron"},{"key":"B97","doi-asserted-by":"publisher","first-page":"1061","DOI":"10.1016\/j.cell.2015.01.049","article-title":"TREM2 lipid sensing sustains the microglial response in an Alzheimer\u2019s disease model","volume":"160","author":"Wang","year":"2015","journal-title":"Cell"},{"key":"B98","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1186\/s13024-016-0137-9","article-title":"Expression and processing analyses of wild type and p.R47H TREM2 variant in Alzheimer\u2019s disease brains","volume":"11","author":"Ma","year":"2016","journal-title":"Mol Neurodegener"},{"key":"B99","doi-asserted-by":"publisher","first-page":"W214","DOI":"10.1093\/nar\/gkq537","article-title":"The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function","volume":"38","author":"Warde-Farley","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"B100","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1016\/j.compbiolchem.2015.04.005","article-title":"Principles for the organization of gene-sets","volume":"59","author":"Li","year":"2015","journal-title":"Comput Biol Chem"},{"key":"B101","doi-asserted-by":"publisher","first-page":"748","DOI":"10.1038\/nature08185","article-title":"Common polygenic variation contributes to risk of schizophrenia and bipolar disorder","volume":"460","author":"Purcell","year":"2009","journal-title":"Nature"},{"key":"B102","doi-asserted-by":"publisher","first-page":"214.e7","DOI":"10.1016\/j.neurobiolaging.2016.07.018","article-title":"Polygenic score prediction captures nearly all common genetic risk for Alzheimer\u2019s disease","volume":"49","author":"Escott-Price","year":"2017","journal-title":"Neurobiol Aging"},{"key":"B103","doi-asserted-by":"publisher","first-page":"3673","DOI":"10.1093\/brain\/awv268","article-title":"Common polygenic variation enhances risk prediction for Alzheimer\u2019s disease","volume":"138","author":"Escott-Price","year":"2015","journal-title":"Brain"},{"key":"B104","doi-asserted-by":"publisher","first-page":"e1000864","DOI":"10.1371\/journal.pgen.1000864","article-title":"The genetic interpretation of area under the Roc curve in genomic profiling","volume":"6","author":"Wray","year":"2010","journal-title":"PLoS Genet"},{"key":"B105","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1038\/nrg3457","article-title":"Pitfalls of predicting complex traits from SNPs","volume":"14","author":"Wray","year":"2013","journal-title":"Nat Rev Genet"},{"key":"B106","doi-asserted-by":"publisher","first-page":"832","DOI":"10.1093\/hmg\/dds491","article-title":"Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer\u2019s disease, multiple sclerosis and endometriosis","volume":"22","author":"Lee","year":"2013","journal-title":"Hum Mol Genet"},{"key":"B107","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1016\/j.jalz.2015.05.016","article-title":"Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population-based perspective","volume":"11","author":"Baumgart","year":"2015","journal-title":"Alzheimers Dement"},{"key":"B108","doi-asserted-by":"publisher","first-page":"1737","DOI":"10.1001\/archneur.59.11.1737","article-title":"Dementia and Alzheimer disease incidence: a prospective cohort study","volume":"59","author":"Kukull","year":"2002","journal-title":"Arch Neurol"},{"key":"B109","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1097\/EDE.0b013e31822708b5","article-title":"The association between blood pressure and incident Alzheimer disease: a systematic review and meta-analysis","volume":"22","author":"Power","year":"2011","journal-title":"Epidemiology"},{"key":"B110","doi-asserted-by":"publisher","first-page":"1299","DOI":"10.1136\/jnnp-2015-310548","article-title":"Meta-analysis of modifiable risk factors for Alzheimer\u2019s disease","volume":"86","author":"Xu","year":"2015","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"B111","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1001\/jama.300.9.1027","article-title":"Effect of physical activity on cognitive function in older adults at risk for Alzheimer disease: a randomized trial","volume":"300","author":"Lautenschlager","year":"2008","journal-title":"JAMA"},{"key":"B112","doi-asserted-by":"publisher","first-page":"1454","DOI":"10.1001\/jama.292.12.1454","article-title":"Physical activity, including walking, and cognitive function in older women","volume":"292","author":"Weuve","year":"2004","journal-title":"JAMA"},{"key":"B113","doi-asserted-by":"publisher","first-page":"1447","DOI":"10.1001\/jama.292.12.1447","article-title":"Walking and dementia in physically capable elderly men","volume":"292","author":"Abbott","year":"2004","journal-title":"JAMA"},{"key":"B114","doi-asserted-by":"publisher","first-page":"73","DOI":"10.7326\/0003-4819-144-2-200601170-00004","article-title":"Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older","volume":"144","author":"Larson","year":"2006","journal-title":"Ann Intern Med"},{"key":"B115","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1093\/aje\/kwi092","article-title":"Physical activity, Apoe genotype, and dementia risk: findings from the cardiovascular health cognition study","volume":"161","author":"Podewils","year":"2005","journal-title":"Am J Epidemiol"},{"key":"B116","doi-asserted-by":"publisher","first-page":"2316","DOI":"10.1212\/01.WNL.0000147474.29994.35","article-title":"Physical activity in relation to cognitive decline in elderly men: the fine study","volume":"63","author":"Van Gelder","year":"2004","journal-title":"Neurology"},{"key":"B117","doi-asserted-by":"publisher","first-page":"e017497","DOI":"10.1136\/bmjopen-2017-017497","article-title":"Association between exercise and the risk of dementia: results from a nationwide longitudinal study in China","volume":"7","author":"Zhou","year":"2017","journal-title":"BMJ Open"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glx234","article-title":"Exercise training for preventing dementia, mild cognitive impairment, and clinically meaningful cognitive decline: a systematic review and meta-analysis","author":"Barreto","year":"2017","journal-title":"J Gerontol A Biol Sci Med Sci"},{"key":"B119","doi-asserted-by":"publisher","first-page":"2026","DOI":"10.1212\/WNL.0000000000003955","article-title":"Effect of a long-term intensive lifestyle intervention on prevalence of cognitive impairment","volume":"88","author":"Espeland","year":"2017","journal-title":"Neurology"},{"key":"B120","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1016\/S0140-6736(86)92972-7","article-title":"Apolipoprotein E isoforms, serum cholesterol, and cancer","volume":"1","author":"Katan","year":"1986","journal-title":"Lancet"},{"key":"B121","doi-asserted-by":"publisher","first-page":"R89","DOI":"10.1093\/hmg\/ddu328","article-title":"Mendelian randomization: genetic anchors for causal inference in epidemiological studies","volume":"23","author":"Davey Smith","year":"2014","journal-title":"Hum Mol Genet"},{"key":"B122","doi-asserted-by":"publisher","first-page":"1925","DOI":"10.1001\/jama.2017.17219","article-title":"Mendelian randomization","volume":"318","author":"Emdin","year":"2017","journal-title":"JAMA"},{"key":"B123","doi-asserted-by":"publisher","first-page":"j5375","DOI":"10.1136\/bmj.j5375","article-title":"Modifiable pathways in Alzheimer\u2019s disease: Mendelian randomisation analysis","volume":"359","author":"Larsson","year":"2017","journal-title":"BMJ"},{"key":"B124","doi-asserted-by":"publisher","first-page":"465","DOI":"10.3233\/JAD-2010-1240","article-title":"Cigarette smoking is a risk factor for Alzheimer\u2019s disease: an analysis controlling for tobacco industry affiliation","volume":"19","author":"Cataldo","year":"2010","journal-title":"J Alzheimers Dis"},{"key":"B125","doi-asserted-by":"publisher","first-page":"e1001841; discussion e1001841","DOI":"10.1371\/journal.pmed.1001841","article-title":"Associations between potentially modifiable risk factors and Alzheimer disease: a Mendelian randomization study","volume":"12","author":"Ostergaard","year":"2015","journal-title":"PLoS Med"},{"key":"B126","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1038\/nrg2764","article-title":"Gene\u2013environment-wide association studies: emerging approaches","volume":"11","author":"Thomas","year":"2010","journal-title":"Nat Rev Genet"},{"key":"B127","doi-asserted-by":"publisher","first-page":"1949","DOI":"10.1212\/WNL.54.10.1949","article-title":"Estrogen use, APOE, and cognitive decline: evidence of gene-environment interaction","volume":"54","author":"Yaffe","year":"2000","journal-title":"Neurology"},{"key":"B128","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1056\/NEJMoa1106668","article-title":"Donepezil and memantine for moderate-to-severe Alzheimer\u2019s disease","volume":"366","author":"Howard","year":"2012","journal-title":"N Engl J Med"},{"key":"B129","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1186\/alzrt269","article-title":"Alzheimer\u2019s disease drug-development pipeline: few candidates, frequent failures","volume":"6","author":"Cummings","year":"2014","journal-title":"Alzheimers Res Ther"},{"key":"B130","doi-asserted-by":"publisher","DOI":"10.1126\/science.aal0759","article-title":"Another Alzheimer\u2019s drug flops in pivotal clinical trial","author":"Carroll","year":"2017","journal-title":"Science"},{"key":"B131","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1016\/j.trci.2017.04.005","article-title":"Phase II clinical trials of anti-amyloid beta antibodies: when is enough, enough?","volume":"3","author":"Gold","year":"2017","journal-title":"Alzheimers Dement (N Y)"},{"key":"B132","doi-asserted-by":"publisher","first-page":"1706","DOI":"10.1056\/NEJMp1701047","article-title":"The failure of solanezumab \u2013 how the Fda saved taxpayers billions","volume":"376","author":"Sacks","year":"2017","journal-title":"N Engl J Med"},{"key":"B133","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1038\/nature19323","article-title":"The antibody aducanumab reduces Abeta plaques in Alzheimer\u2019s disease","volume":"537","author":"Sevigny","year":"2016","journal-title":"Nature"},{"key":"B134","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1038\/nrneurol.2013.223","article-title":"Alzheimer disease therapy \u2013 moving from amyloid-beta to tau","volume":"9","author":"Giacobini","year":"2013","journal-title":"Nat Rev Neurol"},{"key":"B135","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/nrneurol.2015.177","article-title":"CAP \u2013 advancing the evaluation of preclinical Alzheimer disease treatments","volume":"12","author":"Reiman","year":"2016","journal-title":"Nat Rev Neurol"},{"key":"B136","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/j.trci.2017.05.002","article-title":"Alzheimer\u2019s disease drug development pipeline: 2017","volume":"3","author":"Cummings","year":"2017","journal-title":"Alzheimers Dement (N Y)"},{"key":"B137","doi-asserted-by":"publisher","first-page":"107","DOI":"10.21037\/atm.2016.03.05","article-title":"Toward precision medicine in Alzheimer\u2019s disease","volume":"4","author":"Reitz","year":"2016","journal-title":"Ann Transl Med"},{"key":"B138","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.jalz.2016.07.005","article-title":"The Dian-Tu next generation Alzheimer\u2019s prevention trial: adaptive design and disease progression model","volume":"13","author":"Bateman","year":"2017","journal-title":"Alzheimers Dement"},{"key":"B139","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1002\/ana.24910","article-title":"Fluorodeoxyglucose metabolism associated with tau-amyloid interaction predicts memory decline","volume":"81","author":"Hanseeuw","year":"2017","journal-title":"Ann Neurol"},{"key":"B140","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/j.jalz.2014.02.004","article-title":"Clinical utility of cerebrospinal fluid biomarkers in the diagnosis of early Alzheimer\u2019s disease","volume":"11","author":"Blennow","year":"2015","journal-title":"Alzheimers Dement"},{"key":"B141","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1038\/nature25456","article-title":"High performance plasma amyloid-beta biomarkers for Alzheimer\u2019s disease","volume":"554","author":"Nakamura","year":"2018","journal-title":"Nature"},{"key":"B142","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1126\/science.aaf3934","article-title":"beta2-Adrenoreceptor is a regulator of the alpha-synuclein gene driving risk of Parkinson\u2019s disease","volume":"357","author":"Mittal","year":"2017","journal-title":"Science"},{"key":"B143","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.atg.2016.01.001","article-title":"Only a click away \u2013 DTC genetics for ancestry, health, love \u2026 and more: a view of the business and regulatory landscape","volume":"8","author":"Phillips","year":"2016","journal-title":"Appl Transl Genom"},{"key":"B144","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1038\/ng1509","article-title":"Low Ldl cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9","volume":"37","author":"Cohen","year":"2005","journal-title":"Nat Genet"},{"key":"B145","doi-asserted-by":"publisher","first-page":"1338","DOI":"10.1016\/j.jacl.2017.08.016","article-title":"Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia","volume":"11","author":"Defesche","year":"2017","journal-title":"J Clin Lipidol"},{"key":"B146","doi-asserted-by":"publisher","first-page":"1410","DOI":"10.1016\/j.jalz.2017.09.010","article-title":"Alzheimer\u2019s disease sequencing project discovery and replication criteria for cases and controls: data from a community-based prospective cohort study with autopsy follow-up","volume":"13","author":"Crane","year":"2017","journal-title":"Alzheimers Dement"},{"key":"B147","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1097\/GIM.0b013e31821d69b8","article-title":"Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American college of medical genetics and the national society of genetic counselors","volume":"13","author":"Goldman","year":"2011","journal-title":"Genet Med"},{"key":"B148","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1001\/journalofethics.2017.19.7.ecas4-1707","article-title":"How should clinicians counsel a woman with a strong family history of early-onset Alzheimer\u2019s disease about her pregnancy?","volume":"19","author":"Mapes","year":"2017","journal-title":"AMA J Ethics"},{"key":"B149","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1186\/gm425","article-title":"Harm, hype and evidence: Elsi research and policy guidance","volume":"5","author":"Caulfield","year":"2013","journal-title":"Genome Med"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"http:\/\/journal.frontiersin.org\/article\/10.3389\/fmed.2018.00108\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2018,4,24]],"date-time":"2018-04-24T00:45:37Z","timestamp":1524530737000},"score":1,"resource":{"primary":{"URL":"http:\/\/journal.frontiersin.org\/article\/10.3389\/fmed.2018.00108\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,24]]},"references-count":149,"alternative-id":["10.3389\/fmed.2018.00108"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2018.00108","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,24]]},"article-number":"108"}}