Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory and other cognitive functions. AD can be classified into familial AD (FAD) and sporadic AD (SAD) based on heritability and into early onset AD (EOAD) and late onset AD (LOAD) based on age of onset. LOAD cases are more prevalent with genetically complex architecture. In spite of significant research focused on understanding the etiological mechanisms, search for diagnostic biomarker(s) and disease-modifying therapy is still on. In this article, we aim to comprehensively review AD literature on established etiological mechanisms including role of beta-amyloid and apolipoprotein E (APOE) along with promising newer etiological factors such as epigenetic modifications that have been associated with AD suggesting its multifactorial nature. As genomic studies have recently played a significant role in elucidating AD pathophysiology, a systematic review of findings from genome-wide linkage (GWL), genome-wide association (GWA), genome-wide expression (GWE), and epigenome-wide association studies (EWAS) was conducted. The availability of multi-dimensional genomic data has further coincided with the advent of computational and network biology approaches in recent years. Our review highlights the importance of integrative approaches involving genomics and systems biology perspective in elucidating AD pathophysiology. The promising newer approaches may provide reliable means of early and more specific diagnosis and help identify therapeutic interventions for LOAD.
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References
WHO dementia fact sheet 2012 (last accessed 20.1.2015)—http://www.who.int/mediacentre/factsheets/fs362/en/
Maurer K, Volk S, Gerbaldo H (1997) Auguste D and Alzheimer’s disease. Lancet 349(9064):1546–1549. doi:10.1016/S0140-6736(96)10203-8
Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C et al (2012) National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 8(1):1–13. doi:10.1016/j.jalz.2011.10.007
Prince M, Albanese E, Guerchet M, Prina M (2014) The World Alzheimer Report 2014, dementia and risk reduction: an analysis of protective and modifiable factors
Cipriani G, Borin G, Del Debbio A, Di Fiorino M (2015) Personality and dementia. J Nerv Ment Dis 203(3):210–214. doi:10.1097/NMD.0000000000000264
Fodero-Tavoletti MT, Villemagne VL, Rowe CC, Masters CL, Barnham KJ, Cappai R (2011) Amyloid-beta: the seeds of darkness. Int J Biochem Cell Biol 43(9):1247–1251. doi:10.1016/j.biocel.2011.05.001
Ritchie K, Lovestone S (2002) The dementias. Lancet 360(9347):1759–1766. doi:10.1016/S0140-6736(02)11667-9
Strobel G. Early Onset Familial AD. What Is Early Onset Familial Alzheimer Disease (eFAD)? http://www.alzforum.org/early-onset-familial-ad/overview/what-early-onset-familial-alzheimer-disease-efad
Ryman DC, Acosta-Baena N, Aisen PS, Bird T, Danek A, Fox NC, Goate A, Frommelt P et al (2014) Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology 83(3):253–260. doi:10.1212/WNL.0000000000000596
Jimenez-Escrig A, Gomez-Tortosa E, Baron M, Rabano A, Arcos-Burgos M, Palacios LG, Yusta A, Anta P et al (2005) A multigenerational pedigree of late-onset Alzheimer’s disease implies new genetic causes. Brain 128(Pt 7):1707–1715. doi:10.1093/brain/awh501
Bateman RJ, Aisen PS, De Strooper B, Fox NC, Lemere CA, Ringman JM, Salloway S, Sperling RA et al (2011) Autosomal-dominant Alzheimers disease: a review and proposal for the prevention of Alzheimer's disease. Alzheimers Res Ther 3(1):1. doi:10.1186/alzrt59
Panegyres PK, Chen HY (2013) Differences between early and late onset Alzheimer’s disease. Am J Neurodegener Dis 2(4):300–306
Balin BJ, Hudson AP (2014) Etiology and pathogenesis of late-onset Alzheimer’s disease. Curr Allergy Asthma Rep 14(3):417. doi:10.1007/s11882-013-0417-1
Bras J, Guerreiro R, Hardy J (2012) Use of next-generation sequencing and other whole-genome strategies to dissect neurological disease. Nat Rev Neurosci 13(7):453–464. doi:10.1038/nrn3271
Smith AV (2012) Genetic analysis: moving between linkage and association. Cold Spring Harb Protoc 2012(2):174–182. doi:10.1101/pdb.top067819
Hudson NJ, Dalrymple BP, Reverter A (2012) Beyond differential expression: the quest for causal mutations and effector molecules. BMC Genomics 13:356. doi:10.1186/1471-2164-13-356
Lord J, Lu AJ, Cruchaga C (2014) Identification of rare variants in Alzheimer’s disease. Front Genet 5:369. doi:10.3389/fgene.2014.00369
Du Y, Xie J, Chang W, Han Y, Cao G (2012) Genome-wide association studies: inherent limitations and future challenges. Front Med 6(4):444–450. doi:10.1007/s11684-012-0225-3
Boehnke M (1994) Limits of resolution of genetic linkage studies: implications for the positional cloning of human disease genes. Am J Hum Genet 55(2):379–390
Hardy JA, Higgins GA (1992) Alzheimer’s disease: the amyloid cascade hypothesis. Science 256(5054):184–185
Hoe HS, Lee HK, Pak DT (2012) The upside of APP at synapses. CNS Neurosci Ther 18(1):47–56. doi:10.1111/j.1755-5949.2010.00221.x
Barber RC (2012) The genetics of Alzheimer’s disease. Scientifica (Cairo) 2012:246210. doi:10.6064/2012/246210
Selkoe DJ, Podlisny MB, Joachim CL, Vickers EA, Lee G, Fritz LC, Oltersdorf T (1988) Beta-amyloid precursor protein of Alzheimer disease occurs as 110- to 135-kilodalton membrane-associated proteins in neural and nonneural tissues. Proc Natl Acad Sci U S A 85(19):7341–7345
Nalivaeva NN, Turner AJ (2013) The amyloid precursor protein: a biochemical enigma in brain development, function and disease. FEBS Lett 587(13):2046–2054. doi:10.1016/j.febslet.2013.05.010
Octave JN, Pierrot N, Ferao Santos S, Nalivaeva NN, Turner AJ (2013) From synaptic spines to nuclear signaling: nuclear and synaptic actions of the amyloid precursor protein. J Neurochem 126(2):183–190. doi:10.1111/jnc.12239
Jung CK, Herms J (2012) Role of APP for dendritic spine formation and stability. Exp Brain Res 217(3–4):463–470. doi:10.1007/s00221-011-2939-x
Dawkins E, Small DH (2014) Insights into the physiological function of the beta-amyloid precursor protein: beyond Alzheimer’s disease. J Neurochem 129(5):756–769. doi:10.1111/jnc.12675
Zheng H, Koo EH (2006) The amyloid precursor protein: beyond amyloid. Mol Neurodegener 1:5. doi:10.1186/1750-1326-1-5
Cirrito JR, May PC, O'Dell MA, Taylor JW, Parsadanian M, Cramer JW, Audia JE, Nissen JS et al (2003) In vivo assessment of brain interstitial fluid with microdialysis reveals plaque-associated changes in amyloid-beta metabolism and half-life. J Neurosci 23(26):8844–8853
Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM (2006) Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo. Nat Med 12(7):856–861. doi:10.1038/nm1438
Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81(2):741–766
Nordberg A (2008) Amyloid plaque imaging in vivo: current achievement and future prospects. Eur J Nucl Med Mol Imaging 35(Suppl 1):S46–S50. doi:10.1007/s00259-007-0700-2
Villemagne VL, Pike KE, Darby D, Maruff P, Savage G, Ng S, Ackermann U, Cowie TF et al (2008) Abeta deposits in older non-demented individuals with cognitive decline are indicative of preclinical Alzheimer’s disease. Neuropsychologia 46(6):1688–1697. doi:10.1016/j.neuropsychologia.2008.02.008
Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30(4):572–580. doi:10.1002/ana.410300410
Lesne S, Kotilinek L, Ashe KH (2008) Plaque-bearing mice with reduced levels of oligomeric amyloid-beta assemblies have intact memory function. Neuroscience 151(3):745–749. doi:10.1016/j.neuroscience.2007.10.054
Benilova I, Karran E, De Strooper B (2012) The toxic Abeta oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci 15(3):349–357. doi:10.1038/nn.3028
McLean CA, Cherny RA, Fraser FW, Fuller SJ, Smith MJ, Beyreuther K, Bush AI, Masters CL (1999) Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol 46(6):860–866
Westerman MA, Cooper-Blacketer D, Mariash A, Kotilinek L, Kawarabayashi T, Younkin LH, Carlson GA, Younkin SG et al (2002) The relationship between Abeta and memory in the Tg2576 mouse model of Alzheimer’s disease. J Neurosci 22(5):1858–1867
Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM (2005) Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron 45(5):675–688. doi:10.1016/j.neuron.2005.01.040
Arendash GW, Lewis J, Leighty RE, McGowan E, Cracchiolo JR, Hutton M, Garcia MF (2004) Multi-metric behavioral comparison of APPsw and P301L models for Alzheimer’s disease: linkage of poorer cognitive performance to tau pathology in forebrain. Brain Res 1012(1–2):29–41. doi:10.1016/j.brainres.2004.02.081
Bitan G, Kirkitadze MD, Lomakin A, Vollers SS, Benedek GB, Teplow DB (2003) Amyloid beta-protein (Abeta) assembly: Abeta 40 and Abeta 42 oligomerize through distinct pathways. Proc Natl Acad Sci U S A 100(1):330–335. doi:10.1073/pnas.222681699
O'Nuallain B, Freir DB, Nicoll AJ, Risse E, Ferguson N, Herron CE, Collinge J, Walsh DM (2010) Amyloid beta-protein dimers rapidly form stable synaptotoxic protofibrils. J Neurosci 30(43):14411–14419. doi:10.1523/JNEUROSCI.3537-10.2010
Hung LW, Ciccotosto GD, Giannakis E, Tew DJ, Perez K, Masters CL, Cappai R, Wade JD et al (2008) Amyloid-beta peptide (Abeta) neurotoxicity is modulated by the rate of peptide aggregation: Abeta dimers and trimers correlate with neurotoxicity. J Neurosci 28(46):11950–11958. doi:10.1523/JNEUROSCI.3916-08.2008
Zahs KR, Ashe KH (2013) beta-Amyloid oligomers in aging and Alzheimer’s disease. Front Aging Neurosci 5:28. doi:10.3389/fnagi.2013.00028
Lesne S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH (2006) A specific amyloid-beta protein assembly in the brain impairs memory. Nature 440(7082):352–357. doi:10.1038/nature04533
Scherzer-Attali R, Farfara D, Cooper I, Levin A, Ben-Romano T, Trudler D, Vientrov M, Shaltiel-Karyo R et al (2012) Naphthoquinone-tryptophan reduces neurotoxic Abeta*56 levels and improves cognition in Alzheimer’s disease animal model. Neurobiol Dis 46(3):663–672. doi:10.1016/j.nbd.2012.03.005
Ono K, Condron MM, Teplow DB (2009) Structure-neurotoxicity relationships of amyloid beta-protein oligomers. Proc Natl Acad Sci U S A 106(35):14745–14750. doi:10.1073/pnas.0905127106
Mucke L, Selkoe DJ (2012) Neurotoxicity of amyloid beta-protein: synaptic and network dysfunction. Cold Spring Harb Perspect Med 2(7):a006338. doi:10.1101/cshperspect.a006338a006338
Klein WL (2013) Synaptotoxic amyloid-beta oligomers: a molecular basis for the cause, diagnosis, and treatment of Alzheimer’s disease? J Alzheimers Dis 33(Suppl 1):S49–S65. doi:10.3233/JAD-2012-129039
Gotz J, Streffer JR, David D, Schild A, Hoerndli F, Pennanen L, Kurosinski P, Chen F (2004) Transgenic animal models of Alzheimer’s disease and related disorders: histopathology, behavior and therapy. Mol Psychiatry 9(7):664–683. doi:10.1038/sj.mp.40015084001508
Bao F, Wicklund L, Lacor PN, Klein WL, Nordberg A, Marutle A (2012) Different beta-amyloid oligomer assemblies in Alzheimer brains correlate with age of disease onset and impaired cholinergic activity. Neurobiol Aging 33(4):825. doi:10.1016/j.neurobiolaging.2011.05.003, e821-813
Umeda T, Tomiyama T, Sakama N, Tanaka S, Lambert MP, Klein WL, Mori H (2011) Intraneuronal amyloid beta oligomers cause cell death via endoplasmic reticulum stress, endosomal/lysosomal leakage, and mitochondrial dysfunction in vivo. J Neurosci Res 89(7):1031–1042. doi:10.1002/jnr.22640
Amadoro G, Corsetti V, Atlante A, Florenzano F, Capsoni S, Bussani R, Mercanti D, Calissano P (2012) Interaction between NH(2)-tau fragment and Abeta in Alzheimer’s disease mitochondria contributes to the synaptic deterioration. Neurobiol Aging 33(4):833. doi:10.1016/j.neurobiolaging.2011.08.001, e831-825
Garcia-Escudero V, Martin-Maestro P, Perry G, Avila J (2013) Deconstructing mitochondrial dysfunction in Alzheimer disease. Oxid Med Cell Longev 2013:162152. doi:10.1155/2013/162152
Watson D, Castano E, Kokjohn TA, Kuo YM, Lyubchenko Y, Pinsky D, Connolly ES Jr, Esh C et al (2005) Physicochemical characteristics of soluble oligomeric Abeta and their pathologic role in Alzheimer’s disease. Neurol Res 27(8):869–881. doi:10.1179/016164105X49436
Goodman Y, Mattson MP (1994) Secreted forms of beta-amyloid precursor protein protect hippocampal neurons against amyloid beta-peptide-induced oxidative injury. Exp Neurol 128(1):1–12. doi:10.1006/exnr.1994.1107
Camandola S, Mattson MP (2011) Aberrant subcellular neuronal calcium regulation in aging and Alzheimer’s disease. Biochim Biophys Acta 1813(5):965–973. doi:10.1016/j.bbamcr.2010.10.005
Bozyczko-Coyne D, O'Kane TM, Wu ZL, Dobrzanski P, Murthy S, Vaught JL, Scott RW (2001) CEP-1347/KT-7515, an inhibitor of SAPK/JNK pathway activation, promotes survival and blocks multiple events associated with Abeta-induced cortical neuron apoptosis. J Neurochem 77(3):849–863
Tare M, Modi RM, Nainaparampil JJ, Puli OR, Bedi S, Fernandez-Funez P, Kango-Singh M, Singh A (2011) Activation of JNK signaling mediates amyloid-ss-dependent cell death. PLoS One 6(9), e24361. doi:10.1371/journal.pone.0024361PONE-D-11-11860
Dhawan G, Floden AM, Combs CK (2012) Amyloid-beta oligomers stimulate microglia through a tyrosine kinase dependent mechanism. Neurobiol Aging 33(10):2247–2261. doi:10.1016/j.neurobiolaging.2011.10.027
Perez JL, Carrero I, Gonzalo P, Arevalo-Serrano J, Sanz-Anquela JM, Ortega J, Rodriguez M, Gonzalo-Ruiz A (2010) Soluble oligomeric forms of beta-amyloid (Abeta) peptide stimulate Abeta production via astrogliosis in the rat brain. Exp Neurol 223(2):410–421. doi:10.1016/j.expneurol.2009.10.013
Ebenezer PJ, Weidner AM, LeVine H 3rd, Markesbery WR, Murphy MP, Zhang L, Dasuri K, Fernandez-Kim SO et al (2010) Neuron specific toxicity of oligomeric amyloid-beta: role for JUN-kinase and oxidative stress. J Alzheimers Dis 22(3):839–848. doi:10.3233/JAD-2010-101161
De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, Klein WL (2007) Abeta oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem 282(15):11590–11601. doi:10.1074/jbc.M607483200
Butterfield DA (2002) Amyloid beta-peptide (1-42)-induced oxidative stress and neurotoxicity: implications for neurodegeneration in Alzheimer’s disease brain. A review. Free Radic Res 36(12):1307–1313
Zhang Y, Lu L, Jia J, Jia L, Geula C, Pei J, Xu Z, Qin W et al (2014) A lifespan observation of a novel mouse model: in vivo evidence supports abeta oligomer hypothesis. PLoS One 9(1), e85885. doi:10.1371/journal.pone.0085885PONE-D-13-37776
Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe DJ (2011) Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci U S A 108(14):5819–5824. doi:10.1073/pnas.1017033108
Tu S, Okamoto S, Lipton SA, Xu H (2014) Oligomeric Abeta-induced synaptic dysfunction in Alzheimer’s disease. Mol Neurodegener 9(1):48. doi:10.1186/1750-1326-9-48
Marcello E, Epis R, Saraceno C, Di Luca M (2012) Synaptic dysfunction in Alzheimer’s disease. Adv Exp Med Biol 970:573–601. doi:10.1007/978-3-7091-0932-8_25
Walsh DM, Selkoe DJ (2004) Deciphering the molecular basis of memory failure in Alzheimer’s disease. Neuron 44(1):181–193. doi:10.1016/j.neuron.2004.09.010S0896627304006038
LaFerla FM, Oddo S (2005) Alzheimer’s disease: Abeta, tau and synaptic dysfunction. Trends Mol Med 11(4):170–176. doi:10.1016/j.molmed.2005.02.009
Pimplikar SW, Nixon RA, Robakis NK, Shen J, Tsai LH (2010) Amyloid-independent mechanisms in Alzheimer’s disease pathogenesis. J Neurosci 30(45):14946–14954. doi:10.1523/JNEUROSCI.4305-10.2010
Robakis NK (2011) Mechanisms of AD neurodegeneration may be independent of Abeta and its derivatives. Neurobiol Aging 32(3):372–379. doi:10.1016/j.neurobiolaging.2010.05.022
Skaper SD (2012) Alzheimer’s disease and amyloid: culprit or coincidence? Int Rev Neurobiol 102:277–316. doi:10.1016/B978-0-12-386986-9.00011-9
Bali J, Gheinani AH, Zurbriggen S, Rajendran L (2012) Role of genes linked to sporadic Alzheimer’s disease risk in the production of beta-amyloid peptides. Proc Natl Acad Sci U S A 109(38):15307–15311. doi:10.1073/pnas.1201632109
Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC, Yarasheski KE, Bateman RJ (2010) Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 330(6012):1774. doi:10.1126/science.1197623
Sambamurti K, Greig NH, Utsuki T, Barnwell EL, Sharma E, Mazell C, Bhat NR, Kindy MS et al (2011) Targets for AD treatment: conflicting messages from gamma-secretase inhibitors. J Neurochem 117(3):359–374. doi:10.1111/j.1471-4159.2011.07213.x
Sperling RA, Jack CR Jr, Aisen PS (2011) Testing the right target and right drug at the right stage. Sci Transl Med 3(111):111cm133. doi:10.1126/scitranslmed.3002609
Schneider LS, Lahiri DK (2009) The perils of Alzheimer's drug development. Curr Alzheimer Res 6(1):77–78
Selkoe DJ (2011) Resolving controversies on the path to Alzheimer's therapeutics. Nat Med 17(9):1060–1065. doi:10.1038/nm.2460
Seabrook GR, Ray WJ, Shearman M, Hutton M (2007) Beyond amyloid: the next generation of Alzheimer’s disease therapeutics. Mol Interv 7(5):261–270. doi:10.1124/mi.7.5.8
Town T (2010) Alzheimer’s disease beyond Abeta. Expert Rev Neurother 10(5):671–675
Nagga K, Wattmo C, Zhang Y, Wahlund LO, Palmqvist S (2014) Cerebral inflammation is an underlying mechanism of early death in Alzheimer’s disease: a 13-year cause-specific multivariate mortality study. Alzheimers Res Ther 6(4):41. doi:10.1186/alzrt271
Pratico D, Uryu K, Leight S, Trojanoswki JQ, Lee VM (2001) Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosci 21(12):4183–4187
Treusch S, Hamamichi S, Goodman JL, Matlack KE, Chung CY, Baru V, Shulman JM, Parrado A et al (2011) Functional links between Abeta toxicity, endocytic trafficking, and Alzheimer’s disease risk factors in yeast. Science 334(6060):1241–1245. doi:10.1126/science.1213210
Pera M, Alcolea D, Sanchez-Valle R, Guardia-Laguarta C, Colom-Cadena M, Badiola N, Suarez-Calvet M, Llado A et al (2013) Distinct patterns of APP processing in the CNS in autosomal-dominant and sporadic Alzheimer disease. Acta Neuropathol 125(2):201–213. doi:10.1007/s00401-012-1062-9
Li R, Lindholm K, Yang LB, Yue X, Citron M, Yan R, Beach T, Sue L et al (2004) Amyloid beta peptide load is correlated with increased beta-secretase activity in sporadic Alzheimer’s disease patients. Proc Natl Acad Sci U S A 101(10):3632–3637. doi:10.1073/pnas.02056891010205689101
Zempel H, Thies E, Mandelkow E, Mandelkow EM (2010) Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines. J Neurosci 30(36):11938–11950. doi:10.1523/JNEUROSCI.2357-10.2010
Shipton OA, Leitz JR, Dworzak J, Acton CE, Tunbridge EM, Denk F, Dawson HN, Vitek MP et al (2011) Tau protein is required for amyloid {beta}-induced impairment of hippocampal long-term potentiation. J Neurosci 31(5):1688–1692. doi:10.1523/JNEUROSCI.2610-10.2011
De Felice FG, Wu D, Lambert MP, Fernandez SJ, Velasco PT, Lacor PN, Bigio EH, Jerecic J et al (2008) Alzheimer’s disease-type neuronal tau hyperphosphorylation induced by A beta oligomers. Neurobiol Aging 29(9):1334–1347. doi:10.1016/j.neurobiolaging.2007.02.029
LaFerla FM (2010) Pathways linking Abeta and tau pathologies. Biochem Soc Trans 38(4):993–995. doi:10.1042/BST0380993
Seino Y, Kawarabayashi T, Wakasaya Y, Watanabe M, Takamura A, Yamamoto-Watanabe Y, Kurata T, Abe K et al (2010) Amyloid beta accelerates phosphorylation of tau and neurofibrillary tangle formation in an amyloid precursor protein and tau double-transgenic mouse model. J Neurosci Res 88(16):3547–3554. doi:10.1002/jnr.22516
Oddo S, Caccamo A, Tran L, Lambert MP, Glabe CG, Klein WL, LaFerla FM (2006) Temporal profile of amyloid-beta (Abeta) oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology. J Biol Chem 281(3):1599–1604. doi:10.1074/jbc.M507892200
Maia LF, Kaeser SA, Reichwald J, Hruscha M, Martus P, Staufenbiel M, Jucker M (2013) Changes in amyloid-beta and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci Transl Med 5(194):194re192. doi:10.1126/scitranslmed.3006446
Gotz J, Schild A, Hoerndli F, Pennanen L (2004) Amyloid-induced neurofibrillary tangle formation in Alzheimer’s disease: insight from transgenic mouse and tissue-culture models. Int J Dev Neurosci 22(7):453–465. doi:10.1016/j.ijdevneu.2004.07.013
Choi SH, Kim YH, Hebisch M, Sliwinski C, Lee S, D'Avanzo C, Chen H, Hooli B et al (2014) A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature 515(7526):274–278. doi:10.1038/nature13800
Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580):353–356. doi:10.1126/science.1072994297/5580/353
Wang JZ, Xia YY, Grundke-Iqbal I, Iqbal K (2013) Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration. J Alzheimers Dis 33(Suppl 1):S123–S139. doi:10.3233/JAD-2012-129031
Bloom GS (2014) Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol 71(4):505–508. doi:10.1001/jamaneurol.2013.5847
Martin L, Latypova X, Wilson CM, Magnaudeix A, Perrin ML, Terro F (2013) Tau protein phosphatases in Alzheimer’s disease: the leading role of PP2A. Ageing Res Rev 12(1):39–49. doi:10.1016/j.arr.2012.06.008
Heraud C, Goufak D, Ando K, Leroy K, Suain V, Yilmaz Z, De Decker R, Authelet M et al (2014) Increased misfolding and truncation of tau in APP/PS1/tau transgenic mice compared to mutant tau mice. Neurobiol Dis 62:100–112. doi:10.1016/j.nbd.2013.09.010
Pooler AM, Noble W, Hanger DP, Pooler AM, Noble W, Hanger DP (2014) A role for tau at the synapse in Alzheimer’s disease pathogenesis. Neuropharmacology 76(Pt A):1–8. doi:10.1016/j.neuropharm.2013.09.018
Kanekiyo T, Xu H, Bu G (2014) ApoE and Abeta in Alzheimer’s disease: accidental encounters or partners? Neuron 81(4):740–754. doi:10.1016/j.neuron.2014.01.045
Mahley RW, Weisgraber KH, Huang Y (2006) Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer’s disease. Proc Natl Acad Sci U S A 103(15):5644–5651. doi:10.1073/pnas.0600549103
Huang Y, Weisgraber KH, Mucke L, Mahley RW (2004) Apolipoprotein E: diversity of cellular origins, structural and biophysical properties, and effects in Alzheimer’s disease. J Mol Neurosci 23(3):189–204. doi:10.1385/JMN:23:3:189
Huang Y, Mahley RW (2014) Apolipoprotein E: structure and function in lipid metabolism, neurobiology, and Alzheimer’s diseases. Neurobiol Dis. doi:10.1016/j.nbd.2014.08.025
Reiman EM, Uecker A, Caselli RJ, Lewis S, Bandy D, de Leon MJ, De Santi S, Convit A et al (1998) Hippocampal volumes in cognitively normal persons at genetic risk for Alzheimer’s disease. Ann Neurol 44(2):288–291. doi:10.1002/ana.410440226
Shaw P, Lerch JP, Pruessner JC, Taylor KN, Rose AB, Greenstein D, Clasen L, Evans A et al (2007) Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study. Lancet Neurol 6(6):494–500. doi:10.1016/S1474-4422(07)70106-0
Caselli RJ, Reiman EM, Osborne D, Hentz JG, Baxter LC, Hernandez JL, Alexander GG (2004) Longitudinal changes in cognition and behavior in asymptomatic carriers of the APOE e4 allele. Neurology 62(11):1990–1995
Caselli RJ, Reiman EM, Locke DE, Hutton ML, Hentz JG, Hoffman-Snyder C, Woodruff BK, Alexander GE et al (2007) Cognitive domain decline in healthy apolipoprotein E epsilon4 homozygotes before the diagnosis of mild cognitive impairment. Arch Neurol 64(9):1306–1311. doi:10.1001/archneur.64.9.1306
Bu G (2009) Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci 10(5):333–344. doi:10.1038/nrn2620
Huang Y, Mucke L (2012) Alzheimer mechanisms and therapeutic strategies. Cell 148(6):1204–1222. doi:10.1016/j.cell.2012.02.040
Arendt T, Schindler C, Bruckner MK, Eschrich K, Bigl V, Zedlick D, Marcova L (1997) Plastic neuronal remodeling is impaired in patients with Alzheimer’s disease carrying apolipoprotein epsilon 4 allele. J Neurosci 17(2):516–529
Teter B (2004) ApoE-dependent plasticity in Alzheimer’s disease. J Mol Neurosci 23(3):167–179. doi:10.1385/JMN:23:3:167
Hashimoto T, Serrano-Pozo A, Hori Y, Adams KW, Takeda S, Banerji AO, Mitani A, Joyner D et al (2012) Apolipoprotein E, especially apolipoprotein E4, increases the oligomerization of amyloid beta peptide. J Neurosci 32(43):15181–15192. doi:10.1523/JNEUROSCI.1542-12.2012
Tai LM, Bilousova T, Jungbauer L, Roeske SK, Youmans KL, Yu C, Poon WW, Cornwell LB et al (2013) Levels of soluble apolipoprotein E/amyloid-beta (Abeta) complex are reduced and oligomeric Abeta increased with APOE4 and Alzheimer disease in a transgenic mouse model and human samples. J Biol Chem 288(8):5914–5926. doi:10.1074/jbc.M112.442103
Cerf E, Gustot A, Goormaghtigh E, Ruysschaert JM, Raussens V (2011) High ability of apolipoprotein E4 to stabilize amyloid-beta peptide oligomers, the pathological entities responsible for Alzheimer’s disease. FASEB J 25(5):1585–1595. doi:10.1096/fj.10-175976
Kim J, Basak JM, Holtzman DM (2009) The role of apolipoprotein E in Alzheimer’s disease. Neuron 63(3):287–303. doi:10.1016/j.neuron.2009.06.026
Xu H, Finkelstein DI, Adlard PA (2014) Interactions of metals and apolipoprotein E in Alzheimer’s disease. Front Aging Neurosci 6:121. doi:10.3389/fnagi.2014.00121
Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, Fagan AM, Morris JC et al (2011) Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med 3(89):89ra57. doi:10.1126/scitranslmed.3002156
Barthel H, Gertz HJ, Dresel S, Peters O, Bartenstein P, Buerger K, Hiemeyer F, Wittemer-Rump SM et al (2011) Cerebral amyloid-beta PET with florbetaben (18F) in patients with Alzheimer’s disease and healthy controls: a multicentre phase 2 diagnostic study. Lancet Neurol 10(5):424–435. doi:10.1016/S1474-4422(11)70077-1
LaDu MJ, Falduto MT, Manelli AM, Reardon CA, Getz GS, Frail DE (1994) Isoform-specific binding of apolipoprotein E to beta-amyloid. J Biol Chem 269(38):23403–23406
LaDu MJ, Pederson TM, Frail DE, Reardon CA, Getz GS, Falduto MT (1995) Purification of apolipoprotein E attenuates isoform-specific binding to beta-amyloid. J Biol Chem 270(16):9039–9042
Michaelson DM (2014) ApoE4: the most prevalent yet understudied risk factor for Alzheimer’s disease. Alzheimers Dement. doi:10.1016/j.jalz.2014.06.015
Ji Y, Gong Y, Gan W, Beach T, Holtzman DM, Wisniewski T (2003) Apolipoprotein E isoform-specific regulation of dendritic spine morphology in apolipoprotein E transgenic mice and Alzheimer’s disease patients. Neuroscience 122(2):305–315
Egensperger R, Kosel S, von Eitzen U, Graeber MB (1998) Microglial activation in Alzheimer disease: association with APOE genotype. Brain Pathol 8(3):439–447
Reiman EM, Caselli RJ, Yun LS, Chen K, Bandy D, Minoshima S, Thibodeau SN, Osborne D (1996) Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med 334(12):752–758. doi:10.1056/NEJM199603213341202
Zlokovic BV (2013) Cerebrovascular effects of apolipoprotein E: implications for Alzheimer disease. JAMA Neurol 70(4):440–444. doi:10.1001/jamaneurol.2013.2152
Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C et al (2012) Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485(7399):512–516. doi:10.1038/nature11087
Nishitsuji K, Hosono T, Nakamura T, Bu G, Michikawa M (2011) Apolipoprotein E regulates the integrity of tight junctions in an isoform-dependent manner in an in vitro blood–brain barrier model. J Biol Chem 286(20):17536–17542. doi:10.1074/jbc.M111.225532
Hatters DM, Zhong N, Rutenber E, Weisgraber KH (2006) Amino-terminal domain stability mediates apolipoprotein E aggregation into neurotoxic fibrils. J Mol Biol 361(5):932–944. doi:10.1016/j.jmb.2006.06.080
Garai K, Baban B, Frieden C (2011) Self-association and stability of the ApoE isoforms at low pH: implications for ApoE-lipid interactions. Biochemistry 50(29):6356–6364. doi:10.1021/bi2006702
Huang Y (2010) Abeta-independent roles of apolipoprotein E4 in the pathogenesis of Alzheimer’s disease. Trends Mol Med 16(6):287–294. doi:10.1016/j.molmed.2010.04.004
Rohn TT (2013) Proteolytic cleavage of apolipoprotein E4 as the keystone for the heightened risk associated with Alzheimer’s disease. Int J Mol Sci 14(7):14908–14922. doi:10.3390/ijms140714908
Strittmatter WJ, Weisgraber KH, Huang DY, Dong LM, Salvesen GS, Pericak-Vance M, Schmechel D, Saunders AM et al (1993) Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease. Proc Natl Acad Sci U S A 90(17):8098–8102
Strittmatter WJ, Saunders AM, Goedert M, Weisgraber KH, Dong LM, Jakes R, Huang DY, Pericak-Vance M et al (1994) Isoform-specific interactions of apolipoprotein E with microtubule-associated protein tau: implications for Alzheimer disease. Proc Natl Acad Sci U S A 91(23):11183–11186
Sanan DA, Weisgraber KH, Russell SJ, Mahley RW, Huang D, Saunders A, Schmechel D, Wisniewski T et al (1994) Apolipoprotein E associates with beta amyloid peptide of Alzheimer’s disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3. J Clin Invest 94(2):860–869. doi:10.1172/JCI117407
Weisgraber KH (1994) Apolipoprotein E: structure-function relationships. Adv Protein Chem 45:249–302
Harris FM, Brecht WJ, Xu Q, Tesseur I, Kekonius L, Wyss-Coray T, Fish JD, Masliah E et al (2003) Carboxyl-terminal-truncated apolipoprotein E4 causes Alzheimer’s disease-like neurodegeneration and behavioral deficits in transgenic mice. Proc Natl Acad Sci U S A 100(19):10966–10971. doi:10.1073/pnas.14343981001434398100
Brecht WJ, Harris FM, Chang S, Tesseur I, Yu GQ, Xu Q, Dee Fish J, Wyss-Coray T et al (2004) Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J Neurosci 24(10):2527–2534. doi:10.1523/JNEUROSCI.4315-03.200424/10/2527
Andrews-Zwilling Y, Bien-Ly N, Xu Q, Li G, Bernardo A, Yoon SY, Zwilling D, Yan TX et al (2010) Apolipoprotein E4 causes age- and Tau-dependent impairment of GABAergic interneurons, leading to learning and memory deficits in mice. J Neurosci 30(41):13707–13717. doi:10.1523/JNEUROSCI.4040-10.2010
Miyata M, Smith JD (1996) Apolipoprotein E allele-specific antioxidant activity and effects on cytotoxicity by oxidative insults and beta-amyloid peptides. Nat Genet 14(1):55–61. doi:10.1038/ng0996-55
Moir RD, Atwood CS, Romano DM, Laurans MH, Huang X, Bush AI, Smith JD, Tanzi RE (1999) Differential effects of apolipoprotein E isoforms on metal-induced aggregation of A beta using physiological concentrations. Biochemistry 38(14):4595–4603. doi:10.1021/bi982437dbi982437d
Harris FM, Brecht WJ, Xu Q, Mahley RW, Huang Y (2004) Increased tau phosphorylation in apolipoprotein E4 transgenic mice is associated with activation of extracellular signal-regulated kinase: modulation by zinc. J Biol Chem 279(43):44795–44801. doi:10.1074/jbc.M408127200M408127200
Shinohara M, Sato N, Kurinami H, Takeuchi D, Takeda S, Shimamura M, Yamashita T, Uchiyama Y et al (2010) Reduction of brain beta-amyloid (Abeta) by fluvastatin, a hydroxymethylglutaryl-CoA reductase inhibitor, through increase in degradation of amyloid precursor protein C-terminal fragments (APP-CTFs) and Abeta clearance. J Biol Chem 285(29):22091–22102. doi:10.1074/jbc.M110.102277
Poirier J, Miron J, Picard C, Gormley P, Theroux L, Breitner J, Dea D (2014) Apolipoprotein E and lipid homeostasis in the etiology and treatment of sporadic Alzheimer’s disease. Neurobiol Aging 35(Suppl 2):S3–S10. doi:10.1016/j.neurobiolaging.2014.03.037
Lahiri DK, Maloney B, Basha MR, Ge YW, Zawia NH (2007) How and when environmental agents and dietary factors affect the course of Alzheimer’s disease: the “LEARn” model (latent early-life associated regulation) may explain the triggering of AD. Curr Alzheimer Res 4(2):219–228
Reitz C (2012) Alzheimer’s disease and the amyloid cascade hypothesis: a critical review. Int J Alzheimers Dis 2012:369808. doi:10.1155/2012/369808
Abalan F (1984) Alzheimer’s disease and malnutrition: a new etiological hypothesis. Med Hypotheses 15(4):385–393
Rapoport SI (1989) Hypothesis: Alzheimer’s disease is a phylogenetic disease. Med Hypotheses 29(3):147–150
Deshmukh VD, Deshmukh SV (1990) Stress-adaptation failure hypothesis of Alzheimer’s disease. Med Hypotheses 32(4):293–295
Hardy J, Allsop D (1991) Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 12(10):383–388
Davis JN, Hunnicutt EJ Jr, Chisholm JC (1995) A mitochondrial bottleneck hypothesis of Alzheimer’s disease. Mol Med Today 1(5):240–247
Swerdlow RH, Khan SM (2004) A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease. Med Hypotheses 63(1):8–20. doi:10.1016/j.mehy.2003.12.045
Swerdlow RH, Burns JM, Khan SM (2014) The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives. Biochim Biophys Acta 1842(8):1219–1231. doi:10.1016/j.bbadis.2013.09.010
Leuner K, Muller WE, Reichert AS (2012) From mitochondrial dysfunction to amyloid beta formation: novel insights into the pathogenesis of Alzheimer’s disease. Mol Neurobiol 46(1):186–193. doi:10.1007/s12035-012-8307-4
Pollard HB, Arispe N, Rojas E (1995) Ion channel hypothesis for Alzheimer amyloid peptide neurotoxicity. Cell Mol Neurobiol 15(5):513–526
Kagan BL, Hirakura Y, Azimov R, Azimova R, Lin MC (2002) The channel hypothesis of Alzheimer’s disease: current status. Peptides 23(7):1311–1315
Marczynski TJ (1995) GABAergic deafferentation hypothesis of brain aging and Alzheimer’s disease; pharmacologic profile of the benzodiazepine antagonist, flumazenil. Rev Neurosci 6(3):221–258
Brier MR, Thomas JB, Ances BM (2014) Network dysfunction in Alzheimer’s disease: refining the disconnection hypothesis. Brain Connect 4(5):299–311. doi:10.1089/brain.2014.0236
Ying W (1996) Deleterious network hypothesis of Alzheimer’s disease. Med Hypotheses 46(5):421–428
Olney JW, Wozniak DF, Farber NB (1997) Excitotoxic neurodegeneration in Alzheimer disease. New hypothesis and new therapeutic strategies. Arch Neurol 54(10):1234–1240
Markesbery WR (1997) Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med 23(1):134–147
Padurariu M, Ciobica A, Lefter R, Serban IL, Stefanescu C, Chirita R (2013) The oxidative stress hypothesis in Alzheimer’s disease. Psychiatr Danub 25(4):401–409
Pratico D (2008) Oxidative stress hypothesis in Alzheimer’s disease: a reappraisal. Trends Pharmacol Sci 29(12):609–615. doi:10.1016/j.tips.2008.09.001
Francis PT, Palmer AM, Snape M, Wilcock GK (1999) The cholinergic hypothesis of Alzheimer’s disease: a review of progress. J Neurol Neurosurg Psychiatry 66(2):137–147
Sivaprakasam K (2006) Towards a unifying hypothesis of Alzheimer’s disease: cholinergic system linked to plaques, tangles and neuroinflammation. Curr Med Chem 13(18):2179–2188
Yatin SM, Aksenov M, Butterfield DA (1999) The antioxidant vitamin E modulates amyloid beta-peptide-induced creatine kinase activity inhibition and increased protein oxidation: implications for the free radical hypothesis of Alzheimer’s disease. Neurochem Res 24(3):427–435
Tabet N, Mantle D, Orrell M (2000) Free radicals as mediators of toxicity in Alzheimer’s disease: a review and hypothesis. Adverse Drug React Toxicol Rev 19(2):127–152
Subramaniam R, Koppal T, Green M, Yatin S, Jordan B, Drake J, Butterfield DA (1998) The free radical antioxidant vitamin E protects cortical synaptosomal membranes from amyloid beta-peptide (25–35) toxicity but not from hydroxynonenal toxicity: relevance to the free radical hypothesis of Alzheimer’s disease. Neurochem Res 23(11):1403–1410
Kemppainen NM, Aalto S, Karrasch M, Nagren K, Savisto N, Oikonen V, Viitanen M, Parkkola R et al (2008) Cognitive reserve hypothesis: Pittsburgh Compound B and fluorodeoxyglucose positron emission tomography in relation to education in mild Alzheimer’s disease. Ann Neurol 63(1):112–118. doi:10.1002/ana.21212
Bigio EH, Hynan LS, Sontag E, Satumtira S, White CL (2002) Synapse loss is greater in presenile than senile onset Alzheimer disease: implications for the cognitive reserve hypothesis. Neuropathol Appl Neurobiol 28(3):218–227
Scarmeas N, Zarahn E, Anderson KE, Habeck CG, Hilton J, Flynn J, Marder KS, Bell KL et al (2003) Association of life activities with cerebral blood flow in Alzheimer disease: implications for the cognitive reserve hypothesis. Arch Neurol 60(3):359–365
Robakis NK (2003) An Alzheimer’s disease hypothesis based on transcriptional dysregulation. Amyloid 10(2):80–85
Zhu X, Raina AK, Perry G, Smith MA (2004) Alzheimer’s disease: the two-hit hypothesis. Lancet Neurol 3(4):219–226. doi:10.1016/S1474-4422(04)00707-0
Furuta N, Yoshioka I, Fukuizumi T, Tominaga K, Nishihara T, Fukuda J (2007) Morphological features of cartilage observed during mandibular distraction in rabbits. Int J Oral Maxillofac Surg 36(3):243–249. doi:10.1016/j.ijom.2006.09.018
Tanzi RE (2005) The synaptic Abeta hypothesis of Alzheimer disease. Nat Neurosci 8(8):977–979. doi:10.1038/nn0805-977
Iqbal K, Grundke-Iqbal I (2005) Metabolic/signal transduction hypothesis of Alzheimer’s disease and other tauopathies. Acta Neuropathol 109(1):25–31. doi:10.1007/s00401-004-0951-y
Shen J, Kelleher RJ 3rd (2007) The presenilin hypothesis of Alzheimer’s disease: evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci U S A 104(2):403–409. doi:10.1073/pnas.0608332104
Landfield PW, Blalock EM, Chen KC, Porter NM (2007) A new glucocorticoid hypothesis of brain aging: implications for Alzheimer’s disease. Curr Alzheimer Res 4(2):205–212
Woods J, Snape M, Smith MA (2007) The cell cycle hypothesis of Alzheimer’s disease: suggestions for drug development. Biochim Biophys Acta 1772(4):503–508. doi:10.1016/j.bbadis.2006.12.004
Bush AI, Tanzi RE (2008) Therapeutics for Alzheimer’s disease based on the metal hypothesis. Neurotherapeutics 5(3):421–432. doi:10.1016/j.nurt.2008.05.001
Davenward S, Bentham P, Wright J, Crome P, Job D, Polwart A, Exley C (2013) Silicon-rich mineral water as a non-invasive test of the ‘aluminum hypothesis’ in Alzheimer’s disease. J Alzheimers Dis 33(2):423–430. doi:10.3233/JAD-2012-121231
Exley C (2005) The aluminium-amyloid cascade hypothesis and Alzheimer’s disease. Subcell Biochem 38:225–234
Craddock TJ, Tuszynski JA, Chopra D, Casey N, Goldstein LE, Hameroff SR, Tanzi RE (2012) The zinc dyshomeostasis hypothesis of Alzheimer’s disease. PLoS One 7(3), e33552. doi:10.1371/journal.pone.0033552
Squitti R, Polimanti R (2012) Copper hypothesis in the missing hereditability of sporadic Alzheimer’s disease: ATP7B gene as potential harbor of rare variants. J Alzheimers Dis 29(3):493–501. doi:10.3233/JAD-2011-111991
Khachaturian ZS (1994) Calcium hypothesis of Alzheimer’s disease and brain aging. Ann N Y Acad Sci 747:1–11
Thibault O, Gant JC, Landfield PW (2007) Expansion of the calcium hypothesis of brain aging and Alzheimer’s disease: minding the store. Aging Cell 6(3):307–317. doi:10.1111/j.1474-9726.2007.00295.x
Berridge MJ (2010) Calcium hypothesis of Alzheimer’s disease. Pflugers Arch 459(3):441–449. doi:10.1007/s00424-009-0736-1
Niranjan R (2013) Molecular basis of etiological implications in Alzheimer’s disease: focus on neuroinflammation. Mol Neurobiol 48(3):412–428. doi:10.1007/s12035-013-8428-4
Han SD, Bondi MW (2008) Revision of the apolipoprotein E compensatory mechanism recruitment hypothesis. Alzheimers Dement 4(4):251–254. doi:10.1016/j.jalz.2008.02.006
Lucas HR, Rifkind JM (2013) Considering the vascular hypothesis of Alzheimer’s disease: effect of copper associated amyloid on red blood cells. Adv Exp Med Biol 765:131–138. doi:10.1007/978-1-4614-4989-8_19
Alcina A, Fedetz M, Fernandez O, Saiz A, Izquierdo G, Lucas M, Leyva L, Garcia-Leon JA et al (2013) Identification of a functional variant in the KIF5A-CYP27B1-METTL1-FAM119B locus associated with multiple sclerosis. J Med Genet 50(1):25–33. doi:10.1136/jmedgenet-2012-101085
de la Torre JC (2010) The vascular hypothesis of Alzheimer’s disease: bench to bedside and beyond. Neurodegener Dis 7(1–3):116–121. doi:10.1159/000285520
Claassen JA, Jansen RW (2006) Cholinergically mediated augmentation of cerebral perfusion in Alzheimer’s disease and related cognitive disorders: the cholinergic-vascular hypothesis. J Gerontol A Biol Sci Med Sci 61(3):267–271
Zlokovic BV (2005) Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci 28(4):202–208. doi:10.1016/j.tins.2005.02.001
Small SA, Duff K (2008) Linking Abeta and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis. Neuron 60(4):534–542. doi:10.1016/j.neuron.2008.11.007
Hooper C, Killick R, Lovestone S (2008) The GSK3 hypothesis of Alzheimer’s disease. J Neurochem 104(6):1433–1439. doi:10.1111/j.1471-4159.2007.05194.x
Herrup K (2010) Reimagining Alzheimer’s disease—an age-based hypothesis. J Neurosci 30(50):16755–16762. doi:10.1523/JNEUROSCI.4521-10.2010
Piacentini R, De Chiara G, Li Puma DD, Ripoli C, Marcocci ME, Garaci E, Palamara AT, Grassi C (2014) HSV-1 and Alzheimer’s disease: more than a hypothesis. Front Pharmacol 5:97. doi:10.3389/fphar.2014.00097
Ethell DW (2010) An amyloid-notch hypothesis for Alzheimer’s disease. Neuroscientist 16(6):614–617. doi:10.1177/1073858410366162
Maccioni RB, Farias G, Morales I, Navarrete L (2010) The revitalized tau hypothesis on Alzheimer’s disease. Arch Med Res 41(3):226–231. doi:10.1016/j.arcmed.2010.03.007
Ferreira ST, Klein WL (2011) The Abeta oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiol Learn Mem 96(4):529–543. doi:10.1016/j.nlm.2011.08.003
Anderson VC, Lenar DP, Quinn JF, Rooney WD (2011) The blood–brain barrier and microvascular water exchange in Alzheimer’s disease. Cardiovasc Psychiatry Neurol 2011:615829. doi:10.1155/2011/615829
Giaccone G, Orsi L, Cupidi C, Tagliavini F (2011) Lipofuscin hypothesis of Alzheimer’s disease. Dement Geriatr Cogn Disord Extra 1(1):292–296. doi:10.1159/000329544000329544
Yurov YB, Vorsanova SG, Iourov IY (2011) The DNA replication stress hypothesis of Alzheimer’s disease. ScientificWorldJournal 11:2602–2612. doi:10.1100/2011/625690
Funk KE, Kuret J (2012) Lysosomal fusion dysfunction as a unifying hypothesis for Alzheimer’s disease pathology. Int J Alzheimers Dis 2012:752894. doi:10.1155/2012/752894
Ostergaard L, Aamand R, Gutierrez-Jimenez E, Ho YC, Blicher JU, Madsen SM, Nagenthiraja K, Dalby RB et al (2013) The capillary dysfunction hypothesis of Alzheimer’s disease. Neurobiol Aging 34(4):1018–1031. doi:10.1016/j.neurobiolaging.2012.09.011
Cochran JN, Hall AM, Roberson ED (2014) The dendritic hypothesis for Alzheimer’s disease pathophysiology. Brain Res Bull 103:18–28. doi:10.1016/j.brainresbull.2013.12.004
Wood WG, Li L, Muller WE, Eckert GP (2014) Cholesterol as a causative factor in Alzheimer’s disease: a debatable hypothesis. J Neurochem 129(4):559–572. doi:10.1111/jnc.12637
Dawn Teare M, Barrett JH (2005) Genetic linkage studies. Lancet 366(9490):1036–1044. doi:10.1016/S0140-6736(05)67382-5
Lander E, Kruglyak L (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat Genet 11(3):241–247. doi:10.1038/ng1195-241
Ertekin-Taner N (2007) Genetics of Alzheimer’s disease: a centennial review. Neurol Clin 25(3):611–667. doi:10.1016/j.ncl.2007.03.009, v
Guerreiro RJ, Gustafson DR, Hardy J (2012) The genetic architecture of Alzheimer’s disease: beyond APP, PSENs and APOE. Neurobiol Aging 33(3):437–456. doi:10.1016/j.neurobiolaging.2010.03.025
Butler AW, Ng MY, Hamshere ML, Forabosco P, Wroe R, Al-Chalabi A, Lewis CM, Powell JF (2009) Meta-analysis of linkage studies for Alzheimer’s disease—a web resource. Neurobiol Aging 30(7):1037–1047. doi:10.1016/j.neurobiolaging.2009.03.013
Lee JH, Cheng R, Graff-Radford N, Foroud T, Mayeux R (2008) Analyses of the National Institute on Aging Late-Onset Alzheimer’s disease Family Study: implication of additional loci. Arch Neurol 65(11):1518–1526. doi:10.1001/archneur.65.11.1518
Sillen A, Andrade J, Lilius L, Forsell C, Axelman K, Odeberg J, Winblad B, Graff C (2008) Expanded high-resolution genetic study of 109 Swedish families with Alzheimer's disease. Eur J Hum Genet 16(2):202–208
Hamshere ML, Holmans PA, Avramopoulos D, Bassett SS, Blacker D, Bertram L, Wiener H, Rochberg N et al (2007) Genome-wide linkage analysis of 723 affected relative pairs with late-onset Alzheimer’s disease. Hum Mol Genet 16(22):2703–2712. doi:10.1093/hmg/ddm224
Liu F, Arias-Vasquez A, Sleegers K, Aulchenko YS, Kayser M, Sanchez-Juan P, Feng BJ, Bertoli-Avella AM et al (2007) A genomewide screen for late-onset Alzheimer disease in a genetically isolated Dutch population. Am J Hum Genet 81(1):17–31. doi:10.1086/518720
Lee JH, Cheng R, Santana V, Williamson J, Lantigua R, Medrano M, Arriaga A, Stern Y et al (2006) Expanded genomewide scan implicates a novel locus at 3q28 among Caribbean hispanics with familial Alzheimer disease. Arch Neurol 63(11):1591–1598. doi:10.1001/archneur.63.11.1591
Bassett SS, Avramopoulos D, Perry RT, Wiener H, Watson B Jr, Go RC, Fallin MD (2006) Further evidence of a maternal parent-of-origin effect on chromosome 10 in late-onset Alzheimer’s disease. Am J Med Genet B Neuropsychiatr Genet 141B(5):537–540. doi:10.1002/ajmg.b.30350
Holmans P, Hamshere M, Hollingworth P, Rice F, Tunstall N, Jones S, Moore P, Wavrant DeVrieze F et al (2005) Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer’s disease. Am J Med Genet B Neuropsychiatr Genet 135B(1):24–32. doi:10.1002/ajmg.b.30114
Blacker D, Bertram L, Saunders AJ, Moscarillo TJ, Albert MS, Wiener H, Perry RT, Collins JS et al (2003) Results of a high-resolution genome screen of 437 Alzheimer’s disease families. Hum Mol Genet 12(1):23–32
Scott WK, Hauser ER, Schmechel DE, Welsh-Bohmer KA, Small GW, Roses AD, Saunders AM, Gilbert JR et al (2003) Ordered-subsets linkage analysis detects novel Alzheimer disease loci on chromosomes 2q34 and 15q22. Am J Hum Genet 73(5):1041–1051. doi:10.1086/379083
Myers A, Wavrant De-Vrieze F, Holmans P, Hamshere M, Crook R, Compton D, Marshall H, Meyer D et al (2002) Full genome screen for Alzheimer disease: stage II analysis. Am J Med Genet 114(2):235–244. doi:10.1002/ajmg.10183
Li YJ, Scott WK, Hedges DJ, Zhang F, Gaskell PC, Nance MA, Watts RL, Hubble JP et al (2002) Age at onset in two common neurodegenerative diseases is genetically controlled. Am J Hum Genet 70(4):985–993
Curtis D, North BV, Sham PC (2001) A novel method of two-locus linkage analysis applied to a genome scan for late onset Alzheimer’s disease. Ann Hum Genet 65(Pt 5):473–481. doi:10.1017/S0003480001008776
Pericak-Vance MA, Grubber J, Bailey LR, Hedges D, West S, Santoro L, Kemmerer B, Hall JL, Saunders AM, Roses AD, Small GW, Scott WK, Conneally PM, Vance JM, Haines JL (2000) Identification of novel genes in late-onset Alzheimer's disease. Exp Gerontol 35 (9-10):1343–1352.
Olson JM, Goddard KA, Dudek DM (2002) A second locus for very-late-onset Alzheimer disease: a genome scan reveals linkage to 20p and epistasis between 20p and the amyloid precursor protein region. Am J Hum Genet 71(1):154–161. doi:10.1086/341034
Kehoe P, Wavrant-De Vrieze F, Crook R, Wu WS, Holmans P, Fenton I, Spurlock G, Norton N et al (1999) A full genome scan for late onset Alzheimer’s disease. Hum Mol Genet 8(2):237–245
Pericak-Vance MA, Bass MP, Yamaoka LH, Gaskell PC, Scott WK, Terwedow HA, Menold MM, Conneally PM, Small GW, Vance JM, Saunders AM, Roses AD, Haines JL (1997) Complete genomic screen in late-onset familial Alzheimer disease. Evidence for a new locus on chromosome 12. JAMA 278 (15):1237–1241
Miller JA, Woltjer RL, Goodenbour JM, Horvath S, Geschwind DH (2013) Genes and pathways underlying regional and cell type changes in Alzheimer’s disease. Genome Med 5(5):48. doi:10.1186/gm452gm452
Bossers K, Wirz KT, Meerhoff GF, Essing AH, van Dongen JW, Houba P, Kruse CG, Verhaagen J et al (2010) Concerted changes in transcripts in the prefrontal cortex precede neuropathology in Alzheimer’s disease. Brain 133(Pt 12):3699–3723. doi:10.1093/brain/awq258
Avramopoulos D, Szymanski M, Wang R, Bassett S (2011) Gene expression reveals overlap between normal aging and Alzheimer’s disease genes. Neurobiol Aging 32(12):2319. doi:10.1016/j.neurobiolaging.2010.04.019, e2327-2334
Tan MG, Chua WT, Esiri MM, Smith AD, Vinters HV, Lai MK (2010) Genome wide profiling of altered gene expression in the neocortex of Alzheimer’s disease. J Neurosci Res 88(6):1157–1169. doi:10.1002/jnr.22290
Liang WS, Dunckley T, Beach TG, Grover A, Mastroeni D, Ramsey K, Caselli RJ, Kukull WA et al (2010) Neuronal gene expression in non-demented individuals with intermediate Alzheimer’s disease neuropathology. Neurobiol Aging 31(4):549–566. doi:10.1016/j.neurobiolaging.2008.05.013
Nunez-Iglesias J, Liu CC, Morgan TE, Finch CE, Zhou XJ (2010) Joint genome-wide profiling of miRNA and mRNA expression in Alzheimer’s disease cortex reveals altered miRNA regulation. PLoS One 5(2), e8898. doi:10.1371/journal.pone.0008898
Ginsberg SD, Alldred MJ, Counts SE, Cataldo AM, Neve RL, Jiang Y, Wuu J, Chao MV et al (2010) Microarray analysis of hippocampal CA1 neurons implicates early endosomal dysfunction during Alzheimer’s disease progression. Biol Psychiatry 68(10):885–893. doi:10.1016/j.biopsych.2010.05.030
Katsel P, Tan W, Haroutunian V (2009) Gain in brain immunity in the oldest-old differentiates cognitively normal from demented individuals. PLoS One 4(10), e7642. doi:10.1371/journal.pone.0007642
Bronner IF, Bochdanovits Z, Rizzu P, Kamphorst W, Ravid R, van Swieten JC, Heutink P (2009) Comprehensive mRNA expression profiling distinguishes tauopathies and identifies shared molecular pathways. PLoS One 4(8), e6826. doi:10.1371/journal.pone.0006826
Williams C, Mehrian Shai R, Wu Y, Hsu YH, Sitzer T, Spann B, McCleary C, Mo Y et al (2009) Transcriptome analysis of synaptoneurosomes identifies neuroplasticity genes overexpressed in incipient Alzheimer’s disease. PLoS One 4(3), e4936. doi:10.1371/journal.pone.0004936
Qin W, Haroutunian V, Katsel P, Cardozo CP, Ho L, Buxbaum JD, Pasinetti GM (2009) PGC-1alpha expression decreases in the Alzheimer disease brain as a function of dementia. Arch Neurol 66(3):352–361. doi:10.1001/archneurol.2008.588
Liang WS, Dunckley T, Beach TG, Grover A, Mastroeni D, Ramsey K, Caselli RJ, Kukull WA et al (2008) Altered neuronal gene expression in brain regions differentially affected by Alzheimer’s disease: a reference data set. Physiol Genomics 33(2):240–256. doi:10.1152/physiolgenomics.00242.2007
Wilmot B, McWeeney SK, Nixon RR, Montine TJ, Laut J, Harrington CA, Kaye JA, Kramer PL (2008) Translational gene mapping of cognitive decline. Neurobiol Aging 29(4):524–541. doi:10.1016/j.neurobiolaging.2006.11.008
Katsel P, Li C, Haroutunian V (2007) Gene expression alterations in the sphingolipid metabolism pathways during progression of dementia and Alzheimer’s disease: a shift toward ceramide accumulation at the earliest recognizable stages of Alzheimer’s disease? Neurochem Res 32(4–5):845–856. doi:10.1007/s11064-007-9297-x
Grunblatt E, Zander N, Bartl J, Jie L, Monoranu CM, Arzberger T, Ravid R, Roggendorf W et al (2007) Comparison analysis of gene expression patterns between sporadic Alzheimer's and Parkinson's disease. J Alzheimers Dis 12(4):291–311
Weeraratna AT, Kalehua A, Deleon I, Bertak D, Maher G, Wade MS, Lustig A, Becker KG et al (2007) Alterations in immunological and neurological gene expression patterns in Alzheimer’s disease tissues. Exp Cell Res 313(3):450–461. doi:10.1016/j.yexcr.2006.10.028
Brooks WM, Lynch PJ, Ingle CC, Hatton A, Emson PC, Faull RL, Starkey MP (2007) Gene expression profiles of metabolic enzyme transcripts in Alzheimer’s disease. Brain Res 1127(1):127–135. doi:10.1016/j.brainres.2006.09.106
Cui JG, Hill JM, Zhao Y, Lukiw WJ (2007) Expression of inflammatory genes in the primary visual cortex of late-stage Alzheimer’s disease. Neuroreport 18(2):115–119. doi:10.1097/WNR.0b013e32801198bc00001756-200701220-00003
Parachikova A, Agadjanyan MG, Cribbs DH, Blurton-Jones M, Perreau V, Rogers J, Beach TG, Cotman CW (2007) Inflammatory changes parallel the early stages of Alzheimer disease. Neurobiol Aging 28(12):1821–1833. doi:10.1016/j.neurobiolaging.2006.08.014
Emilsson L, Saetre P, Jazin E (2006) Alzheimer’s disease: mRNA expression profiles of multiple patients show alterations of genes involved with calcium signaling. Neurobiol Dis 21(3):618–625. doi:10.1016/j.nbd.2005.09.004
Dunckley T, Beach TG, Ramsey KE, Grover A, Mastroeni D, Walker DG, LaFleur BJ, Coon KD et al (2006) Gene expression correlates of neurofibrillary tangles in Alzheimer’s disease. Neurobiol Aging 27(10):1359–1371. doi:10.1016/j.neurobiolaging.2005.08.013
Small SA, Kent K, Pierce A, Leung C, Kang MS, Okada H, Honig L, Vonsattel JP et al (2005) Model-guided microarray implicates the retromer complex in Alzheimer’s disease. Ann Neurol 58(6):909–919. doi:10.1002/ana.20667
Ricciarelli R, d'Abramo C, Massone S, Marinari U, Pronzato M, Tabaton M (2004) Microarray analysis in Alzheimer’s disease and normal aging. IUBMB Life 56(6):349–354. doi:10.1080/15216540412331286002E5HKF394LYCEQBMW
Blalock EM, Geddes JW, Chen KC, Porter NM, Markesbery WR, Landfield PW (2004) Incipient Alzheimer’s disease: microarray correlation analyses reveal major transcriptional and tumor suppressor responses. Proc Natl Acad Sci U S A 101(7):2173–2178. doi:10.1073/pnas.03085121000308512100
Walker PR, Smith B, Liu QY, Famili AF, Valdes JJ, Liu Z, Lach B (2004) Data mining of gene expression changes in Alzheimer brain. Artif Intell Med 31(2):137–154. doi:10.1016/j.artmed.2004.01.008S093336570400020X
Yao PJ, Zhu M, Pyun EI, Brooks AI, Therianos S, Meyers VE, Coleman PD (2003) Defects in expression of genes related to synaptic vesicle trafficking in frontal cortex of Alzheimer’s disease. Neurobiol Dis 12(2):97–109
Colangelo V, Schurr J, Ball MJ, Pelaez RP, Bazan NG, Lukiw WJ (2002) Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling. J Neurosci Res 70(3):462–473. doi:10.1002/jnr.10351
Loring JF, Wen X, Lee JM, Seilhamer J, Somogyi R (2001) A gene expression profile of Alzheimer’s disease. DNA Cell Biol 20(11):683–695. doi:10.1089/10445490152717541
Hata R, Masumura M, Akatsu H, Li F, Fujita H, Nagai Y, Yamamoto T, Okada H et al (2001) Up-regulation of calcineurin Abeta mRNA in the Alzheimer’s disease brain: assessment by cDNA microarray. Biochem Biophys Res Commun 284(2):310–316. doi:10.1006/bbrc.2001.4968S0006-291X(01)94968-X
Ho L, Guo Y, Spielman L, Petrescu O, Haroutunian V, Purohit D, Czernik A, Yemul S et al (2001) Altered expression of a-type but not b-type synapsin isoform in the brain of patients at high risk for Alzheimer’s disease assessed by DNA microarray technique. Neurosci Lett 298(3):191–194
Ginsberg SD, Hemby SE, Lee VM, Eberwine JH, Trojanowski JQ (2000) Expression profile of transcripts in Alzheimer’s disease tangle-bearing CA1 neurons. Ann Neurol 48(1):77–87
Monoranu CM, Apfelbacher M, Grunblatt E, Puppe B, Alafuzoff I, Ferrer I, Al-Saraj S, Keyvani K et al (2009) pH measurement as quality control on human post mortem brain tissue: a study of the BrainNet Europe consortium. Neuropathol Appl Neurobiol 35(3):329–337. doi:10.1111/j.1365-2990.2008.01003a.x
Preece P, Cairns NJ (2003) Quantifying mRNA in postmortem human brain: influence of gender, age at death, postmortem interval, brain pH, agonal state and inter-lobe mRNA variance. Brain Res Mol Brain Res 118(1–2):60–71
Durrenberger PF, Fernando S, Kashefi SN, Ferrer I, Hauw JJ, Seilhean D, Smith C, Walker R et al (2010) Effects of antemortem and postmortem variables on human brain mRNA quality: a BrainNet Europe study. J Neuropathol Exp Neurol 69(1):70–81. doi:10.1097/NEN.0b013e3181c7e32f
Ross BM, Knowler JT, McCulloch J (1992) On the stability of messenger RNA and ribosomal RNA in the brains of control human subjects and patients with Alzheimer’s disease. J Neurochem 58(5):1810–1819
Gomez Ravetti M, Rosso OA, Berretta R, Moscato P (2010) Uncovering molecular biomarkers that correlate cognitive decline with the changes of hippocampus' gene expression profiles in Alzheimer’s disease. PLoS One 5(4), e10153. doi:10.1371/journal.pone.0010153
Dudbridge F, Gusnanto A (2008) Estimation of significance thresholds for genomewide association scans. Genet Epidemiol 32(3):227–234. doi:10.1002/gepi.20297
Moskvina V, Schmidt KM (2008) On multiple-testing correction in genome-wide association studies. Genet Epidemiol 32(6):567–573. doi:10.1002/gepi.20331
McCarthy MI, Abecasis GR, Cardon LR, Goldstein DB, Little J, Ioannidis JP, Hirschhorn JN (2008) Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet 9(5):356–369. doi:10.1038/nrg2344
Nelson PT, Estus S, Abner EL, Parikh I, Malik M, Neltner JH, Ighodaro E, Wang WX et al (2014) ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology. Acta Neuropathol 127(6):825–843. doi:10.1007/s00401-014-1282-2
Perez-Palma E, Bustos BI, Villaman CF, Alarcon MA, Avila ME, Ugarte GD, Reyes AE, Opazo C et al (2014) Overrepresentation of glutamate signaling in Alzheimer’s disease: network-based pathway enrichment using meta-analysis of genome-wide association studies. PLoS One 9(4):e95413. doi:10.1371/journal.pone.0095413
Cruchaga C, Kauwe JS, Harari O, Jin SC, Cai Y, Karch CM, Benitez BA, Jeng AT et al (2013) GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer’s disease. Neuron 78(2):256–268. doi:10.1016/j.neuron.2013.02.026
Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, DeStafano AL, Bis JC et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45(12):1452–1458. doi:10.1038/ng.2802
Boada M, Antunez C, Ramirez-Lorca R, Destefano AL, Gonzalez-Perez A, Gayan J, Lopez-Arrieta J, Ikram MA et al (2013) ATP5H/KCTD2 locus is associated with Alzheimer’s disease risk. Mol Psychiatry. doi:10.1038/mp.2013.86
Reitz C, Jun G, Naj A, Rajbhandary R, Vardarajan BN, Wang LS, Valladares O, Lin CF et al (2013) Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E 4, and the risk of late-onset Alzheimer disease in African Americans. JAMA 309(14):1483–1492. doi:10.1001/jama.2013.2973
Miyashita A, Koike A, Jun G, Wang LS, Takahashi S, Matsubara E, Kawarabayashi T, Shoji M et al (2013) SORL1 is genetically associated with late-onset Alzheimer’s disease in Japanese, Koreans and Caucasians. PLoS One 8(4):e58618. doi:10.1371/journal.pone.0058618 PONE-D-12-34104
Kamboh MI, Demirci FY, Wang X, Minster RL, Carrasquillo MM, Pankratz VS, Younkin SG, Saykin AJ et al (2012) Genome-wide association study of Alzheimer’s disease. Transcult Psychiatry 2, e117. doi:10.1038/tp.2012.45
Cummings AC, Jiang L, Velez Edwards DR, McCauley JL, Laux R, McFarland LL, Fuzzell D, Knebusch C et al (2012) Genome-wide association and linkage study in the Amish detects a novel candidate late-onset Alzheimer disease gene. Ann Hum Genet 76(5):342–351. doi:10.1111/j.1469-1809.2012.00721.x
Logue MW, Schu M, Vardarajan BN, Buros J, Green RC, Go RC, Griffith P, Obisesan TO et al (2011) A comprehensive genetic association study of Alzheimer disease in African Americans. Arch Neurol 68(12):1569–1579. doi:10.1001/archneurol.2011.646
Lee JH, Cheng R, Barral S, Reitz C, Medrano M, Lantigua R, Jimenez-Velazquez IZ, Rogaeva E et al (2011) Identification of novel loci for Alzheimer disease and replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals. Arch Neurol 68(3):320–328. doi:10.1001/archneurol.2010.292
Antunez C, Boada M, Gonzalez-Perez A, Gayan J, Ramirez-Lorca R, Marin J, Hernandez I, Moreno-Rey C et al (2011) The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer’s disease. Genome Med 3(5):33. doi:10.1186/gm249
Wijsman EM, Pankratz ND, Choi Y, Rothstein JH, Faber KM, Cheng R, Lee JH, Bird TD et al (2011) Genome-wide association of familial late-onset Alzheimer’s disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. PLoS Genet 7(2), e1001308. doi:10.1371/journal.pgen.1001308
Hu X, Pickering E, Liu YC, Hall S, Fournier H, Katz E, Dechairo B, John S et al (2011) Meta-analysis for genome-wide association study identifies multiple variants at the BIN1 locus associated with late-onset Alzheimer’s disease. PLoS One 6(2), e16616. doi:10.1371/journal.pone.0016616
Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, Abraham R, Hamshere ML et al (2011) Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. Nat Genet 43(5):429–435. doi:10.1038/ng.803
Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, Gallins PJ, Buxbaum JD et al (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet 43(5):436–441. doi:10.1038/ng.801
Kim S, Swaminathan S, Shen L, Risacher SL, Nho K, Foroud T, Shaw LM, Trojanowski JQ et al (2011) Genome-wide association study of CSF biomarkers Abeta1-42, t-tau, and p-tau181p in the ADNI cohort. Neurology 76(1):69–79. doi:10.1212/WNL.0b013e318204a397
Naj AC, Beecham GW, Martin ER, Gallins PJ, Powell EH, Konidari I, Whitehead PL, Cai G et al (2010) Dementia revealed: novel chromosome 6 locus for late-onset Alzheimer disease provides genetic evidence for folate-pathway abnormalities. PLoS Genet 6(9), e1001130. doi:10.1371/journal.pgen.1001130
Seshadri S, Fitzpatrick AL, Ikram MA, DeStefano AL, Gudnason V, Boada M, Bis JC, Smith AV et al (2010) Genome-wide analysis of genetic loci associated with Alzheimer disease. JAMA 303(18):1832–1840. doi:10.1001/jama.2010.574
Potkin SG, Guffanti G, Lakatos A, Turner JA, Kruggel F, Fallon JH, Saykin AJ, Orro A et al (2009) Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer’s disease. PLoS One 4(8), e6501. doi:10.1371/journal.pone.0006501
Heinzen EL, Need AC, Hayden KM, Chiba-Falek O, Roses AD, Strittmatter WJ, Burke JR, Hulette CM et al (2010) Genome-wide scan of copy number variation in late-onset Alzheimer’s disease. J Alzheimers Dis 19(1):69–77. doi:10.3233/JAD-2010-1212
Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, Combarros O, Zelenika D et al (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease. Nat Genet 41(10):1094–1099. doi:10.1038/ng.439
Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V et al (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease. Nat Genet 41:1088–1093. doi:10.1038/ng.440
Carrasquillo MM, Zou F, Pankratz VS, Wilcox SL, Ma L, Walker LP, Younkin SG, Younkin CS et al (2009) Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer’s disease. Nat Genet 41(2):192–198. doi:10.1038/ng.305
Feulner TM, Laws SM, Friedrich P, Wagenpfeil S, Wurst SH, Riehle C, Kuhn KA, Krawczak M et al (2010) Examination of the current top candidate genes for AD in a genome-wide association study. Mol Psychiatry 15(7):756–766. doi:10.1038/mp.2008.141
Poduslo SE, Huang R, Huang J, Smith S (2009) Genome screen of late-onset Alzheimer's extended pedigrees identifies TRPC4AP by haplotype analysis. Am J Med Genet B Neuropsychiatr Genet 150B(1):50–55. doi:10.1002/ajmg.b.30767
Beecham GW, Martin ER, Li YJ, Slifer MA, Gilbert JR, Haines JL, Pericak-Vance MA (2009) Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. Am J Hum Genet 84(1):35–43. doi:10.1016/j.ajhg.2008.12.008
Bertram L, Lange C, Mullin K, Parkinson M, Hsiao M, Hogan MF, Schjeide BM, Hooli B et al (2008) Genome-wide association analysis reveals putative Alzheimer’s disease susceptibility loci in addition to APOE. Am J Hum Genet 83(5):623–632. doi:10.1016/j.ajhg.2008.10.008
Abraham R, Moskvina V, Sims R, Hollingworth P, Morgan A, Georgieva L, Dowzell K, Cichon S et al (2008) A genome-wide association study for late-onset Alzheimer’s disease using DNA pooling. BMC Med Genomics 1:44. doi:10.1186/1755-8794-1-44
Li H, Wetten S, Li L, St Jean PL, Upmanyu R, Surh L, Hosford D, Barnes MR et al (2008) Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch Neurol 65(1):45–53. doi:10.1001/archneurol.2007.3
Webster JA, Myers AJ, Pearson JV, Craig DW, Hu-Lince D, Coon KD, Zismann VL, Beach T et al (2008) Sorl1 as an Alzheimer’s disease predisposition gene? Neurodegener Dis 5(2):60–64. doi:10.1159/000110789
Reiman EM, Webster JA, Myers AJ, Hardy J, Dunckley T, Zismann VL, Joshipura KD, Pearson JV et al (2007) GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers. Neuron 54(5):713–720. doi:10.1016/j.neuron.2007.05.022
Coon KD, Myers AJ, Craig DW, Webster JA, Pearson JV, Lince DH, Zismann VL, Beach TG et al (2007) A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer’s disease. J Clin Psychiatry 68(4):613–618
Grupe A, Abraham R, Li Y, Rowland C, Hollingworth P, Morgan A, Jehu L, Segurado R et al (2007) Evidence for novel susceptibility genes for late-onset Alzheimer’s disease from a genome-wide association study of putative functional variants. Hum Mol Genet 16(8):865–873. doi:10.1093/hmg/ddm031
Bettens K, Sleegers K, Van Broeckhoven C (2013) Genetic insights in Alzheimer’s disease. Lancet Neurol 12(1):92–104. doi:10.1016/S1474-4422(12)70259-4
Jun G, Ibrahim-Verbaas CA, Vronskaya M, Lambert JC, Chung J, Naj AC, Kunkle BW, Wang LS et al (2015) A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry. doi:10.1038/mp.2015.23
Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C et al (2013) TREM2 variants in Alzheimer’s disease. N Engl J Med 368(2):117–127. doi:10.1056/NEJMoa1211851
Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J et al (2013) Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368(2):107–116. doi:10.1056/NEJMoa1211103
Benitez BA, Jin SC, Guerreiro R, Graham R, Lord J, Harold D, Sims R, Lambert JC et al (2014) Missense variant in TREML2 protects against Alzheimer’s disease. Neurobiol Aging 35(6):1510. doi:10.1016/j.neurobiolaging.2013.12.010, e1519-1526
Cruchaga C, Karch CM, Jin SC, Benitez BA, Cai Y, Guerreiro R, Harari O, Norton J et al (2014) Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease. Nature 505(7484):550–554. doi:10.1038/nature12825
Wetzel-Smith MK, Hunkapiller J, Bhangale TR, Srinivasan K, Maloney JA, Atwal JK, Sa SM, Yaylaoglu MB et al (2014) A rare mutation in UNC5C predisposes to late-onset Alzheimer’s disease and increases neuronal cell death. Nat Med 20(12):1452–1457. doi:10.1038/nm.3736
Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P et al (2012) A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488(7409):96–99. doi:10.1038/nature11283
Medway CW, Abdul-Hay S, Mims T, Ma L, Bisceglio G, Zou F, Pankratz S, Sando SB et al (2014) ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease. Mol Neurodegener 9:11. doi:10.1186/1750-1326-9-11
Klose RJ, Bird AP (2006) Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31(2):89–97. doi:10.1016/j.tibs.2005.12.008
Jurkowska RZ, Jurkowski TP, Jeltsch A (2011) Structure and function of mammalian DNA methyltransferases. Chembiochem 12(2):206–222. doi:10.1002/cbic.201000195
Bandyopadhyay D, Medrano EE (2003) The emerging role of epigenetics in cellular and organismal aging. Exp Gerontol 38(11–12):1299–1307
Jaenisch R, Bird A (2003) Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33(Suppl):245–254. doi:10.1038/ng1089ng1089
Londin E, Loher P, Telonis AG, Quann K, Clark P, Jing Y, Hatzimichael E, Kirino Y et al (2015) Analysis of 13 cell types reveals evidence for the expression of numerous novel primate- and tissue-specific microRNAs. Proc Natl Acad Sci U S A 112(10):E1106–E1115. doi:10.1073/pnas.1420955112
Ketelaar ME, Hofstra EM, Hayden MR (2012) What monozygotic twins discordant for phenotype illustrate about mechanisms influencing genetic forms of neurodegeneration. Clin Genet 81(4):325–333. doi:10.1111/j.1399-0004.2011.01795.x
Poulsen P, Esteller M, Vaag A, Fraga MF (2007) The epigenetic basis of twin discordance in age-related diseases. Pediatr Res 61(5 Pt 2):38R–42R. doi:10.1203/pdr.0b013e31803c7b98
Lunnon K, Mill J (2013) Epigenetic studies in Alzheimer’s disease: current findings, caveats, and considerations for future studies. Am J Med Genet B Neuropsychiatr Genet 162B(8):789–799. doi:10.1002/ajmg.b.32201
Mill J (2011) Toward an integrated genetic and epigenetic approach to Alzheimer’s disease. Neurobiol Aging 32(7):1188–1191. doi:10.1016/j.neurobiolaging.2010.10.021
Chouliaras L, Rutten BP, Kenis G, Peerbooms O, Visser PJ, Verhey F, van Os J, Steinbusch HW et al (2010) Epigenetic regulation in the pathophysiology of Alzheimer’s disease. Prog Neurobiol 90(4):498–510. doi:10.1016/j.pneurobio.2010.01.002
Mastroeni D, Grover A, Delvaux E, Whiteside C, Coleman PD, Rogers J (2011) Epigenetic mechanisms in Alzheimer’s disease. Neurobiol Aging 32(7):1161–1180. doi:10.1016/j.neurobiolaging.2010.08.017
Bennett DA, Yu L, Yang J, Srivastava GP, Aubin C, De Jager PL (2015) Epigenomics of Alzheimer’s disease. Transl Res 165(1):200–220. doi:10.1016/j.trsl.2014.05.006
Bakulski KM, Dolinoy DC, Sartor MA, Paulson HL, Konen JR, Lieberman AP, Albin RL, Hu H et al (2012) Genome-wide DNA methylation differences between late-onset Alzheimer’s disease and cognitively normal controls in human frontal cortex. J Alzheimers Dis 29(3):571–588. doi:10.3233/JAD-2012-111223
De Jager PL, Srivastava G, Lunnon K, Burgess J, Schalkwyk LC, Yu L, Eaton ML, Keenan BT et al (2014) Alzheimer’s disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nat Neurosci 17(9):1156–1163. doi:10.1038/nn.3786
Chouliaras L, Mastroeni D, Delvaux E, Grover A, Kenis G, Hof PR, Steinbusch HW, Coleman PD et al (2013) Consistent decrease in global DNA methylation and hydroxymethylation in the hippocampus of Alzheimer’s disease patients. Neurobiol Aging 34(9):2091–2099. doi:10.1016/j.neurobiolaging.2013.02.021
Mastroeni D, McKee A, Grover A, Rogers J, Coleman PD (2009) Epigenetic differences in cortical neurons from a pair of monozygotic twins discordant for Alzheimer’s disease. PLoS One 4(8), e6617. doi:10.1371/journal.pone.0006617
Mastroeni D, Grover A, Delvaux E, Whiteside C, Coleman PD, Rogers J (2010) Epigenetic changes in Alzheimer’s disease: decrements in DNA methylation. Neurobiol Aging 31(12):2025–2037. doi:10.1016/j.neurobiolaging.2008.12.005
Bradley-Whitman MA, Lovell MA (2013) Epigenetic changes in the progression of Alzheimer’s disease. Mech Ageing Dev 134(10):486–495. doi:10.1016/j.mad.2013.08.005
Coppieters N, Dieriks BV, Lill C, Faull RL, Curtis MA, Dragunow M (2014) Global changes in DNA methylation and hydroxymethylation in Alzheimer’s disease human brain. Neurobiol Aging 35(6):1334–1344. doi:10.1016/j.neurobiolaging.2013.11.031
Lashley T, Gami P, Valizadeh N, Li A, Revesz T, Balazs R (2015) Alterations in global DNA methylation and hydroxymethylation are not detected in Alzheimer’s disease. Neuropathol Appl Neurobiol 41(4):497–506. doi:10.1111/nan.12183
Di Francesco A, Arosio B, Falconi A, Micioni Di Bonaventura MV, Karimi M, Mari D, Casati M, Maccarrone M et al (2015) Global changes in DNA methylation in Alzheimer’s disease peripheral blood mononuclear cells. Brain Behav Immun 45:139–144. doi:10.1016/j.bbi.2014.11.002
Lunnon K, Smith R, Hannon E, De Jager PL, Srivastava G, Volta M, Troakes C, Al-Sarraj S et al (2014) Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer’s disease. Nat Neurosci 17(9):1164–1170. doi:10.1038/nn.3782
Van den Hove DL, Kompotis K, Lardenoije R, Kenis G, Mill J, Steinbusch HW, Lesch KP, Fitzsimons CP et al (2014) Epigenetically regulated microRNAs in Alzheimer’s disease. Neurobiol Aging 35(4):731–745. doi:10.1016/j.neurobiolaging.2013.10.082
Zhang K, Schrag M, Crofton A, Trivedi R, Vinters H, Kirsch W (2012) Targeted proteomics for quantification of histone acetylation in Alzheimer’s disease. Proteomics 12(8):1261–1268. doi:10.1002/pmic.201200010
Tan L, Yu JT, Tan MS, Liu QY, Wang HF, Zhang W, Jiang T (2014) Genome-wide serum microRNA expression profiling identifies serum biomarkers for Alzheimer’s disease. J Alzheimers Dis 40(4):1017–1027. doi:10.3233/JAD-132144
Ho Y, Gruhler A, Heilbut A, Bader GD, Moore L, Adams SL, Millar A, Taylor P et al (2002) Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry. Nature 415(6868):180–183. doi:10.1038/415180a415180a
Gavin AC, Bosche M, Krause R, Grandi P, Marzioch M, Bauer A, Schultz J, Rick JM et al (2002) Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415(6868):141–147. doi:10.1038/415141a415141a
Ito T, Chiba T, Ozawa R, Yoshida M, Hattori M, Sakaki Y (2001) A comprehensive two-hybrid analysis to explore the yeast protein interactome. Proc Natl Acad Sci U S A 98(8):4569–4574. doi:10.1073/pnas.061034498061034498
Uetz P, Giot L, Cagney G, Mansfield TA, Judson RS, Knight JR, Lockshon D, Narayan V et al (2000) A comprehensive analysis of protein-protein interactions in Saccharomyces cerevisiae. Nature 403(6770):623–627. doi:10.1038/35001009
Liu ZP, Wang Y, Zhang XS, Chen L (2010) Identifying dysfunctional crosstalk of pathways in various regions of Alzheimer’s disease brains. BMC Syst Biol 4(Suppl 2):S11. doi:10.1186/1752-0509-4-S2-S11
Liu ZP, Wang Y, Zhang XS, Xia W, Chen L (2011) Detecting and analyzing differentially activated pathways in brain regions of Alzheimer’s disease patients. Mol Biosyst 7(5):1441–1452. doi:10.1039/c0mb00325e
Liang D, Han G, Feng X, Sun J, Duan Y, Lei H (2012) Concerted perturbation observed in a hub network in Alzheimer’s disease. PLoS One 7(7), e40498. doi:10.1371/journal.pone.0040498PONE-D-11-13418
Hallock P, Thomas MA (2012) Integrating the Alzheimer’s disease proteome and transcriptome: a comprehensive network model of a complex disease. OMICS 16(1–2):37–49. doi:10.1089/omi.2011.0054
Keshava Prasad TS, Goel R, Kandasamy K, Keerthikumar S, Kumar S, Mathivanan S, Telikicherla D, Raju R et al (2009) Human Protein Reference Database—2009 update. Nucleic Acids Res 37(Database issue):D767–D772. doi:10.1093/nar/gkn892
Goni J, Esteban FJ, de Mendizabal NV, Sepulcre J, Ardanza-Trevijano S, Agirrezabal I, Villoslada P (2008) A computational analysis of protein-protein interaction networks in neurodegenerative diseases. BMC Syst Biol 2:52. doi:10.1186/1752-0509-2-52
Chen JY, Shen C, Sivachenko AY (2006) Mining Alzheimer disease relevant proteins from integrated protein interactome data. In: Pacific Symposium on Biocomputing11. pp 367–378
Kikuchi M, Ogishima S, Miyamoto T, Miyashita A, Kuwano R, Nakaya J, Tanaka H (2013) Identification of unstable network modules reveals disease modules associated with the progression of Alzheimer’s disease. PLoS One 8(11), e76162. doi:10.1371/journal.pone.0076162PONE-D-13-31714
Rosvall M, Bergstrom CT (2008) Maps of random walks on complex networks reveal community structure. Proc Natl Acad Sci U S A 105(4):1118–1123. doi:10.1073/pnas.0706851105
Regan K, Wang K, Doughty E, Li H, Li J, Lee Y, Kann MG, Lussier YA (2012) Translating Mendelian and complex inheritance of Alzheimer’s disease genes for predicting unique personal genome variants. J Am Med Inform Assoc 19(2):306–316. doi:10.1136/amiajnl-2011-000656
Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, Zhang C, Xie T et al (2013) Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 153(3):707–720. doi:10.1016/j.cell.2013.03.030
Talwar P, Silla Y, Grover S, Gupta M, Agarwal R, Kushwaha S, Kukreti R (2014) Genomic convergence and network analysis approach to identify candidate genes in Alzheimer’s disease. BMC Genomics 15:199. doi:10.1186/1471-2164-15-199
McDermott JE, Costa M, Janszen D, Singhal M, Tilton SC (2010) Separating the drivers from the driven: integrative network and pathway approaches aid identification of disease biomarkers from high-throughput data. Dis Markers 28(4):253–266. doi:10.3233/DMA-2010-0695
Sieberts SK, Schadt EE (2007) Moving toward a system genetics view of disease. Mamm Genome 18(6–7):389–401. doi:10.1007/s00335-007-9040-6
Schadt EE (2006) Novel integrative genomics strategies to identify genes for complex traits. Anim Genet 37(Suppl 1):18–23. doi:10.1111/j.1365-2052.2006.01473.x
Acknowledgments
We thank the Director, Dr. Rajesh Gokhale, Institute of Genomics and Integrative Biology (CSIR) and Dr. Mitali Mukerji (IGIB) for their motivation and unconditional support. Financial support from the Council of Scientific and Industrial Research (CSIR) (BSC0123) is duly acknowledged. PT acknowledges CSIR, Government of India for providing fellowship and CR acknowledges UGC, Government of India for providing fellowship. We thank the anonymous reviewers for their helpful suggestions for improving the manuscript.
Conflict of Interest
The authors declare that they have no competing interests.
Author’s Contribution
PT performed literature mining and data interpretation, conceptualized, and wrote the manuscript. SK, RA, CR, SG, and VT have contributed by helping in improving the manuscript. RK has conceived and supervised the study. All the authors read and approved the final manuscript.
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Talwar, P., Sinha, J., Grover, S. et al. Dissecting Complex and Multifactorial Nature of Alzheimer’s Disease Pathogenesis: a Clinical, Genomic, and Systems Biology Perspective. Mol Neurobiol 53, 4833–4864 (2016). https://doi.org/10.1007/s12035-015-9390-0
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DOI: https://doi.org/10.1007/s12035-015-9390-0