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Epigenomics of Alzheimer's disease

  • David A. Bennett
    Correspondence
    Reprint requests: David A. Bennett, Rush Alzheimer's Disease Center, Rush University Medical Center, 600 South Paulina, Suite 1028, Chicago, IL 60612
    Affiliations
    Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Ill
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  • Lei Yu
    Affiliations
    Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Ill
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  • Jingyun Yang
    Affiliations
    Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Ill
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  • Gyan P. Srivastava
    Affiliations
    Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Mass

    Harvard Medical School, Boston, Mass

    Program in Medical and Population Genetics, Broad Institute, Cambridge, Mass
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  • Cristin Aubin
    Affiliations
    Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Mass

    Harvard Medical School, Boston, Mass

    Program in Medical and Population Genetics, Broad Institute, Cambridge, Mass
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  • Philip L. De Jager
    Affiliations
    Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Mass

    Harvard Medical School, Boston, Mass

    Program in Medical and Population Genetics, Broad Institute, Cambridge, Mass
    Search for articles by this author
      Alzheimer's disease (AD) is a large and growing public health problem. It is characterized by the accumulation of amyloid β peptides and abnormally phosphorylated tau proteins that are associated with cognitive decline and dementia. Much has been learned about the genomics of AD from linkage analyses and, more recently, genome-wide association studies. Several but not all aspects of the genomic landscape are involved in amyloid β metabolism. The moderate concordance of disease among twins suggests other factors, potentially epigenomic factors, are related to AD. We are at the earliest stages of examining the relation of the epigenome to the clinical and pathologic phenotypes that characterize AD. Our literature review suggests that there is some evidence of age-related changes in human brain methylation. Unfortunately, studies of AD have been relatively small with limited coverage of methylation sites and microRNA, let alone other epigenomic marks. We are in the midst of 2 large studies of human brains including coverage of more than 420,000 autosomal cytosine-guanine dinucleotides with the Illumina Infinium HumanMethylation450 BeadArray, and histone acetylation with chromatin immunoprecipitation sequencing. We present descriptive data to help inform other researchers what to expect from these approaches to better design and power their studies. We then discuss future directions to inform on the epigenomic architecture of AD.

      Abbreviations:

      AD (Alzheimer’s disease), APOE (apolipoprotein E), APP (amyloid precursor protein), BACE-1 (beta-site APP-cleaving enzyme 1 gene), CG (cytosine-guanine dinucleotide), ChIP-Seq (chromatin immunoprecipitation-sequencing), CVD (cerebrovascular disease), GWAS (genome-wide association studies), HDAC2 (Histone deacetylase 2), HS (hippocampal sclerosis), LBD (Lewy body disease), MCI (cognitive impairment), PSEN1 (presenilin 1 gene), PSEN2 (presenilin 2 gene), SORL1 (sortilin-related receptor, L(DLR class) A repeats containing gene), SRM LC-MS (selective reaction monitoring liquid chromatography-mass spectrometry), TDP-43 (TAR DNA-binding protein 43)
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      References

        • Prince M.
        • Bryce R.
        • Albanese E.
        • Wimo A.
        • Ribeiro W.
        • Ferri C.P.
        The global prevalence of dementia: a systematic review and metaanalysis.
        Alzheimers Dement. 2013; 9: 63-75
      1. Alzheimer's Research Trust. Dementia 2010: the economic burden of dementia and associated research funding in the United Kingdom. Available at: http://www.herc.ox.ac.uk/pubs/downloads/dementiafullreport. Accessed November 8, 2013.

        • Hurd M.D.
        • Martorell P.
        • Delavande A.
        • Mullen K.J.
        • Langa K.M.
        Monetary costs of dementia in the United States.
        N Engl J Med. 2013; 368: 1326-1334
        • Luengo-Fernandez R.
        • Leal J.
        • Gray A.M.
        UK research expenditure on dementia, heart disease, stroke and cancer: are levels of spending related to disease burden?.
        Eur J Neurol. 2012; 19: 149-154
      2. Alzheimer's Disease International. World Alzheimer Report 2013. Journey of caring: an analysis of long-term care for dementia. Available at: http://www.alz.co.uk/research/world-report-2013. Accessed November 8, 2013.

      3. Department of Health. The dementia challenge: fighting back against dementia. Available at: http://dementiachallenge.dh.gov.uk/. Accessed November 8, 2013.

      4. US Department of Health and Human Services. National Alzheimer's Project Act. Available at: http://aspe.hhs.gov/daltcp/napa/. Accessed November 8, 2013.

        • Nakanishi M.
        • Nakashima T.
        Features of the Japanese national dementia strategy in comparison with international dementia policies: how should a national dementia policy interact with the public health- and social-care systems?.
        Alzheimers Dement. 2013; 10: 468-476.e3
      5. Alzheimer Europe. National Dementia Plans. Available at: http://www.alzheimer-europe.org/Policy-in-Practice2/National-Dementia-Plans. Accessed November 8, 2013.

      6. National Alzheimer's Project Act. Available at: http://aspe.hhs.gov/daltcp/napa/. Accessed November 8, 2013.

        • Khachaturian Z.S.
        • Khachaturian A.S.
        • Thies W.
        The draft “National Plan” to address Alzheimer's disease—National Alzheimer's Project Act (NAPA).
        Alzheimers Dement. 2012; 8: 234-236
        • Khachaturian Z.S.
        Prospects for designating Alzheimer's disease research a national priority.
        Alzheimers Dement. 2011; 7: 557-561
        • Fox N.C.
        • Petersen R.C.
        The G8 Dementia Research Summit—a starter for eight?.
        Lancet. 2013; 382: 1968-1969
      7. G8 Dementia Summit: Prime Minister's speech. Available at: https://www.gov.uk/government/speeches/g8-dementia-summit-prime-ministers-speech. Accessed November 8, 2013.

        • Sperling R.A.
        • Aisen P.S.
        • Beckett L.A.
        • et al.
        Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.
        Alzheimers Dement. 2011; 7: 280-292
        • Albert M.S.
        • DeKosky S.T.
        • Dickson D.
        • et al.
        The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.
        Alzheimers Dement. 2011; 7: 270-279
        • McKhann G.M.
        • Knopman D.S.
        • Chertkow H.
        • et al.
        The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease.
        Alzheimers Dement. 2011; 7: 263-269
        • Schneider J.A.
        • Li J.L.
        • Li Y.
        • Wilson R.S.
        • Kordower J.H.
        • Bennett D.A.
        Substantia nigra tangles are related to gait impairment in older persons.
        Ann Neurol. 2006; 59: 166-173
        • Buchman A.S.
        • Yu L.
        • Wilson R.S.
        • Schneider J.A.
        • Bennett D.A.
        Association of brain pathology with the progression of frailty in older adults.
        Neurology. 2013; 80: 2055-2061
        • Wilson R.S.
        • Arnold S.E.
        • Schneider J.A.
        • Tang Y.
        • Bennett D.A.
        The relationship between cerebral Alzheimer's disease pathology and odour identification in old age.
        J Neurol Neurosurg Psychiatry. 2007; 78: 30-35
        • Lim A.S.P.
        • Yu L.
        • Kowgier M.
        • Schneider J.A.
        • Buchman A.S.
        • Bennett D.A.
        Modification of the relationship of the apolipoprotein E ε4 allele to the risk of Alzheimer disease and neurofibrillary tangle density by sleep.
        JAMA Neurol. 2013; 70: 1544-1551
        • Wilson R.S.
        • Nag S.
        • Boyle P.A.
        • et al.
        Brainstem aminergic nuclei and late-life depressive symptoms.
        JAMA Psychiatry. 2013; 70: 1320-1328
        • Hebert L.E.
        • Scherr P.A.
        • Bienias J.L.
        • Bennett D.A.
        • Evans D.A.
        Alzheimer disease in the US population: prevalence estimates using the 2000 census.
        Arch Neurol. 2003; 60: 1119-1122
        • Wilson R.S.
        • Weir D.R.
        • Leurgans S.E.
        • et al.
        Sources of variability in estimates of the prevalence of Alzheimer's disease in the United States.
        Alzheimers Dement. 2011; 7: 74-79
        • Brookmeyer R.
        • Evans D.A.
        • Hebert L.
        • et al.
        National estimates of the prevalence of Alzheimer's disease in the United States.
        Alzheimers Dement. 2011; 7: 61-73
        • James B.D.
        • Leurgans S.
        • Hebert L.E.
        • Scherr P.A.
        • Yaffe K.
        • Bennett B.D.
        Contribution of Alzheimer disease to mortality in the United States.
        Neurology. 2014; 82: 1045-1050
        • Plassman B.L.
        • Langa K.M.
        • Fisher G.G.
        • et al.
        Prevalence of cognitive impairment without dementia in the United States.
        Ann Intern Med. 2008; 148: 427-434
        • Plassman B.L.
        • Langa K.M.
        • McCammon R.J.
        • et al.
        Incidence of dementia and cognitive impairment, not dementia in the United States.
        Ann Neurol. 2011; 70: 418-426
        • Hyman B.T.
        • Phelps C.H.
        • Beach T.G.
        • et al.
        National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease.
        Alzheimers Dement. 2012; 8: 1-13
        • Montine T.J.
        • Phelps C.H.
        • Beach T.G.
        • et al.
        National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach.
        Acta Neuropathol. 2012; 123: 1-11
        • Bennett D.A.
        • Wilson R.S.
        • Boyle P.A.
        • Buchman A.S.
        • Schneider J.A.
        Relation of neuropathology to cognition in persons without cognitive impairment.
        Ann Neurol. 2012; 72: 599-609
        • Bennett D.A.
        • Schneider J.A.
        • Wilson R.S.
        • Bienias J.L.
        • Arnold S.E.
        Neurofibrillary tangles mediate the association of amyloid load with clinical Alzheimer disease and level of cognitive function.
        Arch Neurol. 2004; 61: 378-384
        • Bateman R.J.
        • Xiong C.
        • Benzinger T.L.S.
        • et al.
        Clinical and biomarker changes in dominantly inherited Alzheimer's disease.
        N Engl J Med. 2012; 367: 795-804
        • Whitehouse P.J.
        • Price D.L.
        • Struble R.G.
        • Clark A.W.
        • Coyle J.T.
        • Delon M.R.
        Alzheimer's disease and senile dementia: loss of neurons in the basal forebrain.
        Science. 1982; 215: 1237-1239
        • Rasool C.G.
        • Svendsen C.N.
        • Selkoe D.J.
        Neurofibrillary degeneration of cholinergic and noncholinergic neurons of the basal forebrain in Alzheimer's disease.
        Ann Neurol. 1986; 20: 482-488
        • Wilson R.S.
        • Nag S.
        • Boyle P.A.
        • et al.
        Neural reserve, neuronal density in the locus ceruleus, and cognitive decline.
        Neurology. 2013; 80: 1202-1208
        • Aluise C.D.
        • Robinson R.A.S.
        • Cai J.
        • Pierce W.M.
        • Markesbery W.R.
        • Butterfield D.A.
        Redox proteomics analysis of brains from subjects with amnestic mild cognitive impairment compared to brains from subjects with preclinical Alzheimer's disease: insights into memory loss in MCI.
        J Alzheimers Dis. 2011; 23: 257-269
        • Butterfield D.A.
        • Reed T.T.
        • Perluigi M.
        • et al.
        Elevated levels of 3-nitrotyrosine in brain from subjects with amnestic mild cognitive impairment: implications for the role of nitration in the progression of Alzheimer's disease.
        Brain Res. 2007; 1148: 243-248
        • Lue L.F.
        • Brachova L.
        • Civin W.H.
        • Rogers J.
        Inflammation, A beta deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration.
        J Neuropathol Exp Neurol. 1996; 55: 1083-1088
        • Blalock E.M.
        • Geddes J.W.
        • Chen K.C.
        • Porter N.M.
        • Markesbery W.R.
        • Landfield P.W.
        Incipient Alzheimer's disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses.
        Proc Natl Acad Sci U S A. 2004; 101: 2173-2178
        • Strozyk D.
        • Dickson D.W.
        • Lipton R.B.
        • et al.
        Contribution of vascular pathology to the clinical expression of dementia.
        Neurobiol Aging. 2010; 31: 1710-1720
        • Nelson P.T.
        • Smith C.D.
        • Abner E.L.
        • et al.
        Hippocampal sclerosis of aging, a prevalent and high-morbidity brain disease.
        Acta Neuropathol. 2013; 126: 161-177
        • Nelson P.T.
        • Schmitt F.A.
        • Lin Y.
        • et al.
        Hippocampal sclerosis in advanced age: clinical and pathological features.
        Brain. 2011; 134: 1506-1518
        • Wilson R.S.
        • Yu L.
        • Trojanowski J.Q.
        • et al.
        TDP-43 pathology, cognitive decline, and dementia in old age.
        JAMA Neurol. 2013; 70: 1418-1424
        • Neuropathology Group. Medical Research Council Cognitive F, Aging Study
        Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS).
        Lancet. 2001; 357: 169-175
        • White L.
        • Small B.J.
        • Petrovitch H.
        • et al.
        Recent clinical-pathologic research on the causes of dementia in late life: update from the Honolulu-Asia Aging Study.
        J Geriatr Psychiatry Neurol. 2005; 18: 224-227
        • Sonnen J.A.
        • Larson E.B.
        • Crane P.K.
        • et al.
        Pathological correlates of dementia in a longitudinal, population-based sample of aging.
        Ann Neurol. 2007; 62: 406-413
        • O'Brien R.J.
        • Resnick S.M.
        • Zonderman A.B.
        • et al.
        Neuropathologic studies of the Baltimore Longitudinal Study of Aging (BLSA).
        J Alzheimers Dis. 2009; 18: 665-675
        • Schneider J.A.
        • Arvanitakis Z.
        • Yu L.
        • Boyle P.A.
        • Leurgans S.E.
        • Bennett D.A.
        Cognitive impairment, decline and fluctuations in older community-dwelling subjects with Lewy bodies.
        Brain. 2012; 135: 3005-3014
        • Schneider J.A.
        • Arvanitakis Z.
        • Bang W.
        • Bennett D.A.
        Mixed brain pathologies account for most dementia cases in community-dwelling older persons.
        Neurology. 2007; 69: 2197-2204
        • Schneider J.A.
        • Arvanitakis Z.
        • Leurgans S.E.
        • Bennett D.A.
        The neuropathology of probable Alzheimer disease and mild cognitive impairment.
        Ann Neurol. 2009; 66: 200-208
        • Gorelick P.B.
        • Scuteri A.
        • Black S.E.
        • et al.
        Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American heart association/American stroke association.
        Stroke. 2011; 42: 2672-2713
        • Boyle P.A.
        • Wilson R.S.
        • Yu L.
        • et al.
        Much of late life cognitive decline is not due to common neurodegenerative pathologies.
        Ann Neurol. 2013; 74: 478-489
        • Arvanitakis Z.
        • Wilson R.S.
        • Bienias J.L.
        • Evans D.A.
        • Bennett D.A.
        Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function.
        Arch Neurol. 2004; 61: 661-666
        • Arvanitakis Z.
        • Schneider J.A.
        • Wilson R.S.
        • et al.
        Diabetes is related to cerebral infarction but not to AD pathology in older persons.
        Neurology. 2006; 67: 1960-1965
        • Wilson R.S.
        • Scherr P.A.
        • Schneider J.A.
        • Tang Y.
        • Bennett D.A.
        Relation of cognitive activity to risk of developing Alzheimer disease.
        Neurology. 2007; 69: 1911-1920
        • Wilson R.S.
        • Boyle P.A.
        • Yu L.
        • Barnes L.L.
        • Schneider J.A.
        • Bennett D.A.
        Life-span cognitive activity, neuropathologic burden, and cognitive aging.
        Neurology. 2013; 81: 314-321
        • Farrer L.A.
        • O'Sullivan D.M.
        • Cupples L.A.
        • Growdon J.H.
        • Myers R.H.
        Assessment of genetic risk for Alzheimer's disease among first-degree relatives.
        Ann Neurol. 1989; 25: 485-493
        • Mayeux R.
        • Sano M.
        • Chen J.
        • Tatemichi T.
        • Stern Y.
        Risk of dementia in first-degree relatives of patients with Alzheimer's disease and related disorders.
        Arch Neurol. 1991; 48: 269-273
        • Devi G.
        • Ottman R.
        • Tang M.X.
        • Marder K.
        • Stern Y.
        • Mayeux R.
        Familial aggregation of Alzheimer disease among whites, African Americans, and Caribbean Hispanics in northern Manhattan.
        Arch Neurol. 2000; 57: 72-77
        • Sleegers K.
        • Roks G.
        • Theuns J.
        • et al.
        Familial clustering and genetic risk for dementia in a genetically isolated Dutch population.
        Brain. 2004; 127: 1641-1649
        • Silverman J.M.
        • Ciresi G.
        • Smith C.J.
        • Marin D.B.
        • Schnaider-Beeri M.
        Variability of familial risk of Alzheimer disease across the late life span.
        Arch Gen Psychiatry. 2005; 62: 565-573
        • Wilson R.S.
        • Barral S.
        • Lee J.H.
        • et al.
        Heritability of different forms of memory in the Late Onset Alzheimer's Disease Family Study.
        J Alzheimers Dis. 2011; 23: 249-255
        • Ertekin-Taner N.
        • Graff-Radford N.
        • Younkin L.H.
        • et al.
        Heritability of plasma amyloid beta in typical late-onset Alzheimer's disease pedigrees.
        Genet Epidemiol. 2001; 21: 19-30
        • Goudsmit J.
        • White B.J.
        • Weitkamp L.R.
        • Keats B.J.
        • Morrow C.H.
        • Gajdusek D.C.
        Familial Alzheimer's disease in two kindreds of the same geographic and ethnic origin. A clinical and genetic study.
        J Neurol Sci. 1981; 49: 79-89
        • Spence M.A.
        • Heyman A.
        • Marazita M.L.
        • Sparkes R.S.
        • Weinberg T.
        Genetic linkage studies in Alzheimer's disease.
        Neurology. 1986; 36: 581-584
        • Bird T.D.
        • Lampe T.H.
        • Nemens E.J.
        • Miner G.W.
        • Sumi S.M.
        • Schellenberg G.D.
        Familial Alzheimer's disease in American descendants of the Volga Germans: probable genetic founder effect.
        Ann Neurol. 1988; 23: 25-31
        • Raiha I.
        • Kaprio J.
        • Koskenvuo M.
        • Rajala T.
        • Sourander L.
        Alzheimer's disease in Finnish twins.
        Lancet. 1996; 347: 573-578
        • Pedersen N.L.
        • Gatz M.
        • Berg S.
        • Johansson B.
        How heritable is Alzheimer's disease late in life? Findings from Swedish twins.
        Ann Neurol. 2004; 55: 180-185
        • Gatz M.
        • Pedersen N.L.
        • Berg S.
        • et al.
        Heritability for Alzheimer's disease: the study of dementia in Swedish twins.
        J Gerontol A Biol Sci Med Sci. 1997; 52: M117-M125
        • Breitner J.C.
        • Welsh K.A.
        • Gau B.A.
        • et al.
        Alzheimer's disease in the National Academy of Sciences-National Research Council Registry of Aging Twin Veterans. III. Detection of cases, longitudinal results, and observations on twin concordance.
        Arch Neurol. 1995; 52: 763-771
        • Heston L.L.
        • Mastri A.R.
        The genetics of Alzheimer's disease: associations with hematologic malignancy and Down's syndrome.
        Arch Gen Psychiatry. 1977; 34: 976-981
        • Owens D.
        • Dawson J.C.
        • Losin S.
        Alzheimer's disease in Down's syndrome.
        Am J Ment Defic. 1971; 75: 606-612
        • Ball M.J.
        • Nuttall K.
        Neurofibrillary tangles, granulovacuolar degeneration, and neuron loss in Down syndrome: quantitative comparison with Alzheimer dementia.
        Ann Neurol. 1980; 7: 462-465
        • Masters C.L.
        • Simms G.
        • Weinman N.A.
        • Multhaup G.
        • McDonald B.L.
        • Beyreuther K.
        Amyloid plaque core protein in Alzheimer disease and Down syndrome.
        Proc Natl Acad Sci U S A. 1985; 82: 4245-4249
        • Lai F.
        • Williams R.S.
        A prospective study of Alzheimer disease in Down syndrome.
        Arch Neurol. 1989; 46: 849-853
        • Wisniewski K.E.
        • Wisniewski H.M.
        • Wen G.Y.
        Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome.
        Anna Neurol. 1985; 17: 278-282
        • Margallo-Lana M.L.
        • Moore P.B.
        • Kay D.W.K.
        • et al.
        Fifteen-year follow-up of 92 hospitalized adults with Down's syndrome: incidence of cognitive decline, its relationship to age and neuropathology.
        J Intellect Disabil Res. 2007; 51: 463-477
        • 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.
        Science. 1987; 235: 885-890
        • Goate A.
        • Chartier-Harlin M.C.
        • Mullan M.
        • et al.
        Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.
        Nature. 1991; 349: 704-706
        • Murrell J.
        • Farlow M.
        • Ghetti B.
        • Benson M.D.
        A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease.
        Science. 1991; 254: 97-99
        • Chartier-Harlin M.C.
        • Crawford F.
        • Houlden H.
        • et al.
        Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene.
        Nature. 1991; 353: 844-846
        • Schellenberg G.D.
        • Bird T.D.
        • Wijsman E.M.
        • et al.
        Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14.
        Science. 1992; 258: 668-671
        • Mullan M.
        • Houlden H.
        • Windelspecht M.
        • et al.
        A locus for familial early-onset Alzheimer's disease on the long arm of chromosome 14, proximal to the alpha 1-antichymotrypsin gene.
        Nat Genet. 1992; 2: 340-342
        • St George-Hyslop P.
        • Haines J.
        • Rogaev E.
        • et al.
        Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14.
        Nat Genet. 1992; 2: 330-334
        • Van Broeckhoven C.
        • Backhovens H.
        • Cruts M.
        • et al.
        Mapping of a gene predisposing to early-onset Alzheimer's disease to chromosome 14q24.3.
        Nat Genet. 1992; 2: 335-339
        • Sherrington R.
        • Rogaev E.I.
        • Liang Y.
        • et al.
        Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease.
        Nature. 1995; 375: 754-760
        • Levy-Lahad E.
        • Wijsman E.M.
        • Nemens E.
        • et al.
        A familial Alzheimer's disease locus on chromosome 1.
        Science. 1995; 269: 970-973
        • Levy-Lahad E.
        • Wasco W.
        • Poorkaj P.
        • et al.
        Candidate gene for the chromosome 1 familial Alzheimer's disease locus.
        Science. 1995; 269: 973-977
        • 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.
        Nature. 1995; 376: 775-778
        • Pericak-Vance M.A.
        • Bebout J.L.
        • Gaskell P.C.
        • et al.
        Linkage studies in familial Alzheimer disease: evidence for chromosome 19 linkage.
        Am J Hum Genet. 1991; 48: 1034-1050
        • 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.
        Proc Natl Acad Sci U S A. 1993; 90: 1977-1981
        • Corder E.H.
        • Saunders A.M.
        • Strittmatter W.J.
        • et al.
        Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.
        Science. 1993; 261: 921-923
        • Corder E.H.
        • Saunders A.M.
        • Risch N.J.
        • et al.
        Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease.
        Nat Genet. 1994; 7: 180-184
        • Harold D.
        • Abraham R.
        • Hollingworth P.
        • et al.
        Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.
        Nat Genet. 2009; 41: 1088-1093
        • Lambert J.-C.
        • Heath S.
        • Even G.
        • et al.
        Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease.
        Nat Genet. 2009; 41: 1094-1099
        • Seshadri S.
        • Fitzpatrick A.L.
        • Ikram M.A.
        • et al.
        Genome-wide analysis of genetic loci associated with Alzheimer disease.
        JAMA. 2010; 303: 1832-1840
        • Jun G.
        • Naj A.C.
        • Beecham G.W.
        • et al.
        Meta-analysis confirms CR1, CLU, and PICALM as Alzheimer disease risk loci and reveals interactions with APOE genotypes.
        Arch Neurol. 2010; 67: 1473-1484
        • 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.
        Nat Genet. 2011; 43: 436-441
        • Hollingworth P.
        • Harold D.
        • Sims R.
        • et al.
        Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.
        Nat Genet. 2011; 43: 429-435
        • Lambert J.-C.
        • Ibrahim-Verbaas C.A.
        • Harold D.
        • et al.
        Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.
        Nat Genet. 2013; 45: 1452-1458
        • Tanzi R.E.
        The genetics of Alzheimer disease.
        Cold Spring Harb Perspect Med. 2012; 2 (a006296)
        • Schellenberg G.D.
        • Montine T.J.
        The genetics and neuropathology of Alzheimer's disease.
        Acta Neuropathol. 2012; 124: 305-323
        • Goate A.
        • Hardy J.
        Twenty years of Alzheimer's disease-causing mutations.
        J Neurochem. 2012; 120: 3-8
        • Selkoe D.
        • Mandelkow E.
        • Holtzman D.
        Deciphering Alzheimer disease.
        Cold Spring Harb Perspect Med. 2012; 2: a011460
        • Bertram L.
        • Tanzi R.E.
        The genetics of Alzheimer's disease.
        Prog Mol Biol Transl Sci. 2012; 107: 79-100
        • Vassar R.
        • Bennett B.D.
        • Babu-Khan S.
        • et al.
        Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE.
        Science. 1999; 286: 735-741
        • Yan R.
        • Bienkowski M.J.
        • Shuck M.E.
        • et al.
        Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity.
        Nature. 1999; 402: 533-537
        • Verghese P.B.
        • Castellano J.M.
        • Holtzman D.M.
        Apolipoprotein E in Alzheimer's disease and other neurological disorders.
        Lancet Neurol. 2011; 10: 241-252
        • Holtzman D.M.
        • Herz J.
        • Bu G.
        Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease.
        Cold Spring Harb Perspect Med. 2012; 2: a006312
        • Mahley R.W.
        • Huang Y.
        • Weisgraber K.H.
        Detrimental effects of apolipoprotein E4: potential therapeutic targets in Alzheimer's disease.
        Curr Alzheimer Res. 2007; 4: 537-540
        • Kline A.
        Apolipoprotein E, amyloid-ss clearance and therapeutic opportunities in Alzheimer's disease.
        Alzheimers Res Ther. 2012; 4: 32
        • Bennett D.A.
        • De Jager P.L.
        • Leurgans S.E.
        • Schneider J.A.
        Neuropathologic intermediate phenotypes enhance association to Alzheimer susceptibility alleles.
        Neurology. 2009; 72: 1495-1503
        • Goldman J.S.
        • Hahn S.E.
        • Catania J.W.
        • et al.
        Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors.
        Genet Med. 2011; 13: 597-605
        • Chibnik L.B.
        • Shulman J.M.
        • Leurgans S.E.
        • et al.
        CR1 is associated with amyloid plaque burden and age-related cognitive decline.
        Ann Neurol. 2011; 69: 560-569
        • Biffi A.
        • Shulman J.M.
        • Jagiella J.M.
        • et al.
        Genetic variation at CR1 increases risk of cerebral amyloid angiopathy.
        Neurology. 2012; 78: 334-341
        • Felsky D.
        • Szeszko P.
        • Yu L.
        • et al.
        The SORL1 gene and convergent neural risk for Alzheimer's disease across the human lifespan.
        Mol Psychiatry. 2014; 19: 1125-1132
        • Shulman J.M.
        • Chen K.
        • Keenan B.T.
        • et al.
        Genetic susceptibility for Alzheimer disease neuritic plaque pathology.
        JAMA Neurol. 2013; 70: 1150-1157
        • Hohman T.J.
        • Koran M.E.
        • Thornton-Wells T.
        Epistatic genetic effects among Alzheimer's candidate genes.
        PLoS ONE. 2013; 8 (e80839)
        • Cruchaga C.
        • Kauwe J.S.K.
        • Harari O.
        • et al.
        GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease.
        Neuron. 2013; 78: 256-268
        • Bradshaw E.M.
        • Chibnik L.B.
        • Keenan B.T.
        • et al.
        CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology.
        Nat Neurosci. 2013; 16: 848-850
        • Tohgi H.
        • Utsugisawa K.
        • Nagane Y.
        • Yoshimura M.
        • Genda Y.
        • Ukitsu M.
        Reduction with age in methylcytosine in the promoter region -224 approximately -101 of the amyloid precursor protein gene in autopsy human cortex.
        Brain Res Mol Brain Res. 1999; 70: 288-292
        • Tohgi H.
        • Utsugisawa K.
        • Nagane Y.
        • Yoshimura M.
        • Ukitsu M.
        • Genda Y.
        The methylation status of cytosines in a tau gene promoter region alters with age to downregulate transcriptional activity in human cerebral cortex.
        Neurosci Lett. 1999; 275: 89-92
        • Siegmund K.D.
        • Connor C.M.
        • Campan M.
        • et al.
        DNA methylation in the human cerebral cortex is dynamically regulated throughout the life span and involves differentiated neurons.
        PLoS ONE. 2007; 2 (e895)
        • Boks M.P.
        • Derks E.M.
        • Weisenberger D.J.
        • et al.
        The relationship of DNA methylation with age, gender and genotype in twins and healthy controls.
        PLoS ONE. 2009; 4: e6767
        • Christensen B.C.
        • Houseman E.A.
        • Marsit C.J.
        • et al.
        Aging and environmental exposures alter tissue-specific DNA methylation dependent upon CpG island context.
        PLoS Genet. 2009; 5: e1000602
        • Rakyan V.K.
        • Down T.A.
        • Maslau S.
        • et al.
        Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains.
        Genome Res. 2010; 20: 434-439
        • Bork S.
        • Pfister S.
        • Witt H.
        • et al.
        DNA methylation pattern changes upon long-term culture and aging of human mesenchymal stromal cells.
        Aging Cell. 2010; 9: 54-63
        • Bocklandt S.
        • Lin W.
        • Sehl M.E.
        • et al.
        Epigenetic predictor of age.
        PLoS ONE. 2011; 6 (e14821)
        • Hernandez D.G.
        • Nalls M.A.
        • Gibbs J.R.
        • et al.
        Distinct DNA methylation changes highly correlated with chronological age in the human brain.
        Hum Mol Genet. 2011; 20: 1164-1172
        • Koch C.M.
        • Suschek C.V.
        • Lin Q.
        • et al.
        Specific age-associated DNA methylation changes in human dermal fibroblasts.
        PLoS ONE. 2011; 6: e16679
        • Stepanow S.
        • Reichwald K.
        • Huse K.
        • et al.
        Allele-specific, age-dependent and BMI-associated DNA methylation of human MCHR1.
        PLoS ONE. 2011; 6: e17711
        • Numata S.
        • Ye T.
        • Hyde T.M.
        • et al.
        DNA methylation signatures in development and aging of the human prefrontal cortex.
        Am J Hum Genet. 2012; 90: 260-272
        • Garagnani P.
        • Bacalini M.G.
        • Pirazzini C.
        • et al.
        Methylation of ELOVL2 gene as a new epigenetic marker of age.
        Aging Cell. 2012; 11: 1132-1134
        • Madrigano J.
        • Baccarelli A.
        • Mittleman M.A.
        • et al.
        Aging and epigenetics: longitudinal changes in gene-specific DNA methylation.
        Epigenetics. 2012; 7: 63-70
        • Pirazzini C.
        • Giuliani C.
        • Bacalini M.G.
        • et al.
        Space/population and time/age in DNA methylation variability in humans: a study on IGF2/H19 locus in different Italian populations and in mono- and di-zygotic twins of different age.
        Aging. 2012; 4: 509-520
        • Bell J.T.
        • Tsai P.-C.
        • Yang T.-P.
        • et al.
        Epigenome-wide scans identify differentially methylated regions for age and age-related phenotypes in a healthy ageing population.
        PLoS Genet. 2012; 8: e1002629
        • Heyn H.
        • Li N.
        • Ferreira H.J.
        • et al.
        Distinct DNA methylomes of newborns and centenarians.
        Proc Natl Acad Sci U S A. 2012; 109: 10522-10527
        • Alisch R.S.
        • Barwick B.G.
        • Chopra P.
        • et al.
        Age-associated DNA methylation in pediatric populations.
        Genome Res. 2012; 22: 623-632
        • Gomes M.V.M.
        • Toffoli L.V.
        • Arruda D.W.
        • et al.
        Age-related changes in the global DNA methylation profile of leukocytes are linked to nutrition but are not associated with the MTHFR C677T genotype or to functional capacities.
        PLoS ONE. 2012; 7: e52570
        • Hannum G.
        • Guinney J.
        • Zhao L.
        • et al.
        Genome-wide methylation profiles reveal quantitative views of human aging rates.
        Mol Cell. 2013; 49: 359-367
        • West R.L.
        • Lee J.M.
        • Maroun L.E.
        Hypomethylation of the amyloid precursor protein gene in the brain of an Alzheimer's disease patient.
        J Mol Neurosci. 1995; 6: 141-146
        • Sontag E.
        • Hladik C.
        • Montgomery L.
        • et al.
        Downregulation of protein phosphatase 2A carboxyl methylation and methyltransferase may contribute to Alzheimer disease pathogenesis.
        J Neuropathol Exp Neurol. 2004; 63: 1080-1091
        • Wang S.C.
        • Oelze B.
        • Schumacher A.
        Age-specific epigenetic drift in late-onset Alzheimer's disease.
        PLoS ONE. 2008; 3: e2698
        • Barrachina M.
        • Ferrer I.
        DNA methylation of Alzheimer disease and tauopathy-related genes in postmortem brain.
        J Neuropathol Exp Neurol. 2009; 68: 880-891
        • Mastroeni D.
        • McKee A.
        • Grover A.
        • Rogers J.
        • Coleman P.D.
        Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer's disease.
        PLoS ONE. 2009; 4: e6617
        • Mastroeni D.
        • Grover A.
        • Delvaux E.
        • Whiteside C.
        • Coleman P.D.
        • Rogers J.
        Epigenetic changes in Alzheimer's disease: decrements in DNA methylation.
        Neurobiol Aging. 2010; 31: 2025-2037
        • Brohede J.
        • Rinde M.
        • Winblad B.
        • Graff C.
        A DNA methylation study of the amyloid precursor protein gene in several brain regions from patients with familial Alzheimer disease.
        J Neurogenet. 2010; 24: 179-181
        • Bollati V.
        • Galimberti D.
        • Pergoli L.
        • et al.
        DNA methylation in repetitive elements and Alzheimer disease.
        Brain Behav Immun. 2011; 25: 1078-1083
        • Sung H.Y.
        • Choi E.N.
        • Ahn Jo S.
        • Oh S.
        • Ahn J.H.
        Amyloid protein-mediated differential DNA methylation status regulates gene expression in Alzheimer's disease model cell line.
        Biochem Biophys Res Commun. 2011; 414: 700-705
        • D'Addario C.
        • Di Francesco A.
        • Arosio B.
        • et al.
        Epigenetic regulation of fatty acid amide hydrolase in Alzheimer disease.
        PLoS ONE. 2012; 7: e39186
        • Rao J.S.
        • Keleshian V.L.
        • Klein S.
        • Rapoport S.I.
        Epigenetic modifications in frontal cortex from Alzheimer's disease and bipolar disorder patients.
        Transl Psychiatry. 2012; 2: e132
        • Furuya T.K.
        • Silva P.N.O.
        • Payao S.L.M.
        • et al.
        Analysis of SNAP25 mRNA expression and promoter DNA methylation in brain areas of Alzheimer's Disease patients.
        Neuroscience. 2012; 220: 41-46
        • Arosio B.
        • Bulbarelli A.
        • Bastias Candia S.
        • et al.
        Pin1 contribution to Alzheimer's disease: transcriptional and epigenetic mechanisms in patients with late-onset Alzheimer's disease.
        Neurodegener Dis. 2012; 10: 207-211
        • Bakulski K.M.
        • Dolinoy D.C.
        • Sartor M.A.
        • et al.
        Genome-wide DNA methylation differences between late-onset Alzheimer's disease and cognitively normal controls in human frontal cortex.
        J Alzheimers Dis. 2012; 29: 571-588
        • Furuya T.K.
        • da Silva P.N.
        • Payao S.L.
        • et al.
        SORL1 and SIRT1 mRNA expression and promoter methylation levels in aging and Alzheimer's Disease.
        Neurochem Int. 2012; 61: 973-975
        • Sanchez-Mut J.V.
        • Aso E.
        • Panayotis N.
        • et al.
        DNA methylation map of mouse and human brain identifies target genes in Alzheimer's disease.
        Brain. 2013; 136: 3018-3027
        • Bradley-Whitman M.A.
        • Lovell M.A.
        Epigenetic changes in the progression of Alzheimer's disease.
        Mech Ageing Dev. 2013; 134: 486-495
        • Chouliaras L.
        • Mastroeni D.
        • Delvaux E.
        • et al.
        Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer's disease patients.
        Neurobiol Aging. 2013; 34: 2091-2099
        • Coppieters N.
        • Dieriks B.V.
        • Lill C.
        • Faull R.L.
        • Curtis M.A.
        • Dragunow M.
        Global changes in DNA methylation and hydroxymethylation in Alzheimer's disease human brain.
        Neurobiol Aging. 2014; 35: 1334-1344
        • Iwata A.
        • Nagata K.
        • Hatsuta H.
        • et al.
        Altered CpG methylation in sporadic Alzheimer's disease is associated with APP and MAPT dysregulation.
        Hum Mol Genet. 2014; 23: 648-656
        • Hernandez H.G.
        • Mahecha M.F.
        • Mejia A.
        • Arboleda H.
        • Forero D.A.
        Global long interspersed nuclear element 1 DNA methylation in a colombian sample of patients with late-onset Alzheimer's disease.
        Am J Alzheimers Dis Other Dement. 2014; 29: 50-53
        • Di Francesco A.
        • Arosio B.
        • Gussago C.
        • et al.
        Involvement of 5-lipoxygenase in Alzheimer's disease: a role for DNA methylation.
        J Alzheimers Dis. 2013; 37: 3-8
        • Silva P.N.
        • Furuya T.K.
        • Sampaio Braga I.
        • et al.
        CNP and DPYSL2 mRNA expression and promoter methylation levels in brain of Alzheimer's disease patients.
        J Alzheimers Dis. 2013; 33: 349-355
        • Taher N.
        • McKenzie C.
        • Garrett R.
        • Baker M.
        • Fox N.
        • Isaacs G.D.
        Amyloid-β alters the DNA methylation status of cell-fate genes in an Alzheimer's disease model.
        J Alzheimers Dis. 2014; 38: 831-844
        • Silva P.N.
        • Furuya T.K.
        • Braga I.L.
        • et al.
        Analysis of HSPA8 and HSPA9 mRNA expression and promoter methylation in the brain and blood of Alzheimer's disease patients.
        J Alzheimers Dis. 2014; 38: 165-170
        • Jones M.J.
        • Farre P.
        • McEwen L.M.
        • et al.
        Distinct DNA methylation patterns of cognitive impairment and trisomy 21 in Down syndrome.
        BMC Med Genomics. 2013; 6: 58
        • Condliffe D.
        • Wong A.
        • Troakes C.
        • et al.
        Cross-region reduction in 5-hydroxymethylcytosine in Alzheimer's disease brain.
        Neurobiol Aging. 2014; 35: 1850-1854
        • Zhang K.
        • Schrag M.
        • Crofton A.
        • Trivedi R.
        • Vinters H.
        • Kirsch W.
        Targeted proteomics for quantification of histone acetylation in Alzheimer's disease.
        Proteomics. 2012; 12: 1261-1268
        • Graff J.
        • Rei D.
        • Guan J.S.
        • et al.
        An epigenetic blockade of cognitive functions in the neurodegenerating brain.
        Nature. 2012; 483: 222-226
        • Hebert S.S.
        • Horre K.
        • Nicolai L.
        • et al.
        Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression.
        Proc Natl Acad Sci U S A. 2008; 105: 6415-6420
        • Sethi P.
        • Lukiw W.J.
        Micro-RNA abundance and stability in human brain: specific alterations in Alzheimer's disease temporal lobe neocortex.
        Neurosci Lett. 2009; 459: 100-104
        • Hebert S.S.
        • Horre K.
        • Nicolai L.
        • et al.
        MicroRNA regulation of Alzheimer's amyloid precursor protein expression.
        Neurobiol Dis. 2009; 33: 422-428
        • Nunez-Iglesias J.
        • Liu C.-C.
        • Morgan T.E.
        • Finch C.E.
        • Zhou X.J.
        Joint genome-wide profiling of miRNA and mRNA expression in Alzheimer's disease cortex reveals altered miRNA regulation.
        PLoS ONE. 2010; 5: e8898
        • Shioya M.
        • Obayashi S.
        • Tabunoki H.
        • et al.
        Aberrant microRNA expression in the brains of neurodegenerative diseases: miR-29a decreased in Alzheimer disease brains targets neurone navigator 3.
        Neuropathol Appl Neurobiol. 2010; 36: 320-330
        • Faghihi M.A.
        • Zhang M.
        • Huang J.
        • et al.
        Evidence for natural antisense transcript-mediated inhibition of microRNA function.
        Genome Biol. 2010; 11: R56
        • Cui J.G.
        • Li Y.Y.
        • Zhao Y.
        • Bhattacharjee S.
        • Lukiw W.J.
        Differential regulation of interleukin-1 receptor-associated kinase-1 (IRAK-1) and IRAK-2 by microRNA-146a and NF-kappaB in stressed human astroglial cells and in Alzheimer disease.
        J Biol Chem. 2010; 285: 38951-38960
        • Nelson P.T.
        • Wang W.X.
        MiR-107 is reduced in Alzheimer's disease brain neocortex: validation study.
        J Alzheimers Dis. 2010; 21: 75-79
        • Wang W.X.
        • Huang Q.
        • Hu Y.
        • Stromberg A.J.
        • Nelson P.T.
        Patterns of microRNA expression in normal and early Alzheimer's disease human temporal cortex: white matter versus gray matter.
        Acta Neuropathol. 2011; 121: 193-205
        • Geekiyanage H.
        • Chan C.
        MicroRNA-137/181c regulates serine palmitoyltransferase and in turn amyloid β, novel targets in sporadic Alzheimer's disease.
        J Neurosci. 2011; 31: 14820-14830
        • Smith P.
        • Al Hashimi A.
        • Girard J.
        • Delay C.
        • Hebert S.S.
        In vivo regulation of amyloid precursor protein neuronal splicing by microRNAs.
        J Neurochem. 2011; 116: 240-247
        • Culpan D.
        • Kehoe P.G.
        • Love S.
        Tumour necrosis factor-alpha (TNF-alpha) and miRNA expression in frontal and temporal neocortex in Alzheimer's disease and the effect of TNF-alpha on miRNA expression in vitro.
        Int J Mol Epidemiol Genet. 2011; 2: 156-162
        • Geekiyanage H.
        • Jicha G.A.
        • Nelson P.T.
        • Chan C.
        Blood serum miRNA: non-invasive biomarkers for Alzheimer's disease.
        Exp Neurol. 2012; 235: 491-496
        • Long J.M.
        • Ray B.
        • Lahiri D.K.
        MicroRNA-339-5p downregulates protein expression of the β-site amyloid precursor protein cleaving enzyme 1 (BACE1) in human primary brain cultures and is reduced in brain tissue specimens of Alzheimer's disease subjects.
        J Biol Chem. 2014; 289: 5184-5198
        • Lau P.
        • Bossers K.
        • Janky R.
        • et al.
        Alteration of the microRNA network during the progression of Alzheimer's disease.
        EMBO Mol Med. 2013; 5: 1613-1634
        • Leidinger P.
        • Backes C.
        • Deutscher S.
        • et al.
        A blood based 12-miRNA signature of Alzheimer disease patients.
        Genome Biol. 2013; 14: R78
        • Hebert S.S.
        • Wang W.-X.
        • Zhu Q.
        • Nelson P.T.
        A study of small RNAs from cerebral neocortex of pathology-verified Alzheimer's disease, dementia with lewy bodies, hippocampal sclerosis, frontotemporal lobar dementia, and non-demented human controls.
        J Alzheimers Dis. 2013; 35: 335-348
        • Wong H.-K.A.
        • Veremeyko T.
        • Patel N.
        • et al.
        De-repression of FOXO3a death axis by microRNA-132 and -212 causes neuronal apoptosis in Alzheimer's disease.
        Hum Mol Genet. 2013; 22: 3077-3092
        • Bennett D.A.
        • Schneider J.A.
        • Arvanitakis Z.
        • Wilson R.S.
        Overview and findings from the Religious Orders Study.
        Curr Alzheimer Res. 2012; 9: 628-645
        • Bennett D.A.
        • Schneider J.A.
        • Buchman A.S.
        • Barnes L.L.
        • Boyle P.A.
        • Wilson R.S.
        Overview and findings from the rush Memory and Aging Project.
        Curr Alzheimer Res. 2012; 9: 646-663
        • Ziller M.J.
        • Gu H.
        • Muller F.
        • et al.
        Charting a dynamic DNA methylation landscape of the human genome.
        Nature. 2013; 500: 477-481
        • Chibnik L.B.
        • Keenan B.T.
        • Srivastava G.
        • et al.
        Relation of DNA methylation in AD susceptibility genes with Alzheimer's disease phenotypes.
        The 12th Alzheimer's Association International Conference, Vancouver, BC2012
        • Rosenkrantz L.L.
        • Srivastava G.
        • Kaliszewska A.
        • et al.
        Correlation between CpG DNA methylation levels in peripheral CD4+ T cells and dorsal lateral prefrontal cortex tissue.
        Alzheimer's Association International Conference, Boston, MA2013
        • Keenan B.
        • Srivastava G.
        • Chibnik L.
        • De Jager P.L.
        • Bennett D.A.
        • Schneider J.A.
        An exploration of a functional unit of DNA methylation in the aging brain.
        Alzheimers Dement. 2013; 9: P172
        • De Jager P.L.
        • Srivastava G.
        • Eaton M.L.
        • et al.
        Genome-wide exploration of DNA methylation in the aging brain and its relation to Alzheimer's disease.
        Alzheimer's Association International Conference, Vancouver, BC2012
        • Yu L.
        • Srivastava G.
        • Chibnik L.B.
        • et al.
        Gene based association analysis of brain DNA methylation with Alzheimer's disease pathology using random permutation.
        Annual Meeting of the American Society of Human Genetics, Boston, MA2013
        • Lim A.S.
        • Srivastava G.P.
        • Yu L.
        • et al.
        Diurnal rhythms of clock gene DNA methylation and their relationship to rhythms of clock gene expression in the human cerebral cortex.
        Annual Meeting of the American Society of Human Genetics, Boston, MA2013
        • Zhu J.
        • Adli M.
        • Zou J.Y.
        • et al.
        Genome-wide chromatin state transitions associated with developmental and environmental cues.
        Cell. 2013; 152: 642-654
        • Eaton M.L.
        • Srivastava G.
        • Kundaje A.
        • et al.
        Integrating genotype, methylome, chromatin states and disease state in a cohort of 750 individuals.
        Annual Meeting of the American Society of Human Genetics, Boston, MA2013
        • Chuang D.M.
        • Leng Y.
        • Marinova Z.
        • Kim H.J.
        • Chiu C.T.
        Multiple roles of HDAC inhibition in neurodegenerative conditions.
        Trends Neurosci. 2009; 32: 591-601
        • Ernst J.
        • Kheradpour P.
        • Mikkelsen T.S.
        • et al.
        Mapping and analysis of chromatin state dynamics in nine human cell types.
        Nature. 2011; 473: 43-49
        • De Jager P.L.
        • Srivastava G.
        • Eaton M.L.
        • et al.
        Genome-wide scan of DNA methylation in the aging brain and its relation to Alzheimer's disease.
        Annual Meeting of the American Society of Human Genetics, San Francisco, CA2012
        • Guintivano J.
        • Aryee M.J.
        • Kaminsky Z.A.
        A cell epigenotype specific model for the correction of brain cellular heterogeneity bias and its application to age, brain region and major depression.
        Epigenetics. 2013; 8: 290-302