CoChat
Sign Up
Cited by 163Functional Brain Connectivity StudiesDementia and Cognitive Impairment ResearchNeural dynamics and brain function

Resting-State Network Disruption and APOE Genotype in Alzheimer's Disease: A lagged Functional Connectivity Study

Open access
Canuet, Leonides, Tellado, Ivan, Couceiro, Veronica, Fraile, Carmen, Fernandez-Novoa, Lucia, Ishii, Ryouhei, Takeda, Masatoshi, Cacabelos, Ramon·2012·PLoS ONE
DOI 10.1371/journal.pone.0046289PMC PMC3457973
Open this paper in CoChat — free accountOpen PDF

Abstract

BACKGROUND: The apolipoprotein E epsilon 4 (APOE-4) is associated with a genetic vulnerability to Alzheimer's disease (AD) and with AD-related abnormalities in cortical rhythms. However, it is unclear whether APOE-4 is linked to a specific pattern of intrinsic functional disintegration of the brain after the development of the disease or during its different stages. This study aimed at identifying spatial patterns and effects of APOE genotype on resting-state oscillations and functional connectivity in patients with AD, using a physiological connectivity index called "lagged phase synchronization". METHODOLOGY/PRINCIPAL FINDINGS: Resting EEG was recorded during awake, eyes-closed state in 125 patients with AD and 60 elderly controls. Source current density and functional connectivity were determined using eLORETA. Patients with AD exhibited reduced parieto-occipital alpha oscillations compared with controls, and those carrying the APOE-4 allele had reduced alpha activity in the left inferior parietal and temporo-occipital cortex relative to noncarriers. There was a decreased alpha2 connectivity pattern in AD, involving the left temporal and bilateral parietal cortex. Several brain regions exhibited increased lagged phase synchronization in low frequencies, specifically in the theta band, across and within hemispheres, where temporal lobe connections were particularly compromised. Areas with abnormal theta connectivity correlated with cognitive scores. In patients with early AD, we found an APOE-4-related decrease in interhemispheric alpha connectivity in frontal and parieto-temporal regions. CONCLUSIONS/SIGNIFICANCE: In addition to regional cortical dysfunction, as indicated by abnormal alpha oscillations, there are patterns of functional network disruption affecting theta and alpha bands in AD that associate with the level of cognitive disturbance or with the APOE genotype. These functional patterns of nonlinear connectivity may potentially represent neurophysiological or phenotypic markers of AD, and aid in early detection of the disorder.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0046289

Cites

7 of 7 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • The results compare well with growing evidence of early functional impairments in humans at risk of developing Alzheimer's disease, such as mid-life APOE4 carriers or asymptomatic elderly with amyloid deposition, and corroborate the reported absence of a correlation between amyloid plaques and functional connectivity in humans.

    “The results compare well with growing evidence of early functional impairments in humans at risk of developing Alzheimer's disease, such as mid-life APO␧4 carriers (Sheline et al., 2010a;Canuet et al., 2012) or asymptomatic elderly with amyloid deposition (Hedden et al., 2009;Sperling et al., 2009;Sheline et al., 2010b), and corroborate the reported absence of a correlation between amyloid plaques”

    From Early Alterations in Functional Connectivity and White Matter Structure in a Transgenic Mouse Model of Cerebral Amyloidosis (2014) · cites this paper as Canuet et al., 2012

    Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 72

  1. [1]Wenk L (2003) Neuropathologic changes in Alzheimer's disease. J Clin Psychiatry 64 Suppl 9: 7– 10. 12934968
  2. [2]Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J (2004) The importance of neuritic plaques and tangles to the development and evolution of AD. Neurology 62: 1984– 1989. 15184601
  3. [3]Cacabelos R (2003) The application of functional genomics to Alzheimer's disease. Pharmacogenomics 4: 597– 621. 12943467
  4. [4]Cacabelos R, Fernandez-Novoa L, Lombardi V, Kubota Y, Takeda M (2005) Molecular genetics of Alzheimer's disease and aging. Methods Find Exp Clin Pharmacol 27 Suppl A: 1– 573. 16470248
  5. [6]Roses AD, Saunders AM, Alberts MA, Strittmatter WJ, Schmechel D, et al (1995) Apolipoprotein E E4 allele and risk of dementia. JAMA 273: 374– 375. 7823377
  6. [7]Takeda M, Martínez R, Kudo T, Tanaka T, Okochi M, et al (2010) Apolipoprotein E and central nervous system disorders: reviews of clinical findings. Psychiatry Clin Neurosci 64: 592– 607. 21105952
  7. [8]Bigler ED, Lowry CM, Anderson CV, Johnson SC, Terry J, et al (2000) Dementia, quantitative neuroimaging, and apolipoprotein E genotype. AJNR Am J Neuroradiol 21: 1857– 1868. 11110538 PMC7974277
  8. [9]Li TQ, Wahlund LO (2011) The search for neuroimaging biomarkers of Alzheimer's disease with advanced MRI techniques. Acta Radiol 52: 211– 222. 21498351
  9. [10]Allen G, Barnard H, McColl R, Hester AL, Fields JA, et al (2007) Reduced hippocampal functional connectivity in Alzheimer disease. Arch Neurol 64: 1482– 1487. 17923631
  10. [11]Liu Y, Wang K, Yu C, He Y, Zhou Y, et al (2008) Regional homogeneity, functional connectivity and imaging markers of Alzheimer's disease: a review of resting-state fMRI studies. Neuropsychologia 46: 1648– 1656. 18346763
  11. [12]Pievani M, de Haan W, Wu T, Seeley WW, Frisoni GB (2011) Functional network disruption in the degenerative dementias. Lancet Neurol 10: 829– 843. 21778116 PMC3219874
  12. [13]Rytsar R, Fornari E, Frackowiak RS, Ghika JA, Knyazeva MG (2011) Inhibition in early Alzheimer's disease: an fMRI-based study of effective connectivity. Neuroimage 57: 1131– 1139. 21616155
  13. [14]Sorg C, Riedl V, Perneczky R, Kurz A, Wohlschläger AM (2009) Impact of Alzheimer's disease on the functional connectivity of spontaneous brain activity. Curr Alzheimer Res 6: 541– 553. 19747154
  14. [15]Wang K, Liang M, Wang L, Tian L, Zhang X, et al (2007) Altered functional connectivity in early Alzheimer's disease: a resting-state fMRI study. Hum Brain Mapp 28: 967– 978. 17133390 PMC6871392
  15. [16]Zhang HY, Wang SJ, Xing J, Liu B, Ma ZL, et al (2009) Detection of PCC functional connectivity characteristics in resting-state fMRI in mild Alzheimer's disease. Behav Brain Res 197: 103– 108. 18786570
  16. [17]Adler G, Brassen S, Jajcevic A (2003) EEG coherence in Alzheimer's dementia. J Neural Transm 110: 1051– 1058. 12928837
  17. [18]Sankari Z, Adeli H, Adeli A (2011) Intrahemispheric, interhemispheric, and distal EEG coherence in Alzheimer's disease. Clin Neurophysiol 122: 897– 906. 21056936
  18. [19]Stam CJ, Montez T, Jones BF, Rombouts SA, van der Made Y, et al (2005) Disturbed fluctuations of resting state EEG synchronization in Alzheimer's disease. Clin Neurophysiol 116: 708– 715. 15721085
  19. [20]Alonso JF, Poza J, Mañanas MA, Romero S, Fernández A, et al (2011) MEG connectivity analysis in patients with Alzheimer's disease using cross mutual information and spectral coherence. Ann Biomed Eng 39: 524– 536. 20824340
  20. [21]Kramer G, van der Flier WM, de Langen C, Blankenstein MA, Scheltens P, et al (2008) EEG functional connectivity and ApoE genotype in Alzheimer's disease and controls. Clin Neurophysiol 119: 2727– 2732. 18848805
  21. [22]Stam CJ, Jones BF, Manshanden I, van Cappellen van Walsum AM, Montez T, et al (2006) Magnetoencephalographic evaluation of resting-state functional connectivity in Alzheimer's disease. Neuroimage 32: 1335– 1344. 16815039
  22. [23]Canuet L, Ishii R, Pascual-Marqui RD, Iwase M, Kurimoto R, et al (2011) Resting-state EEG source localization and functional connectivity in schizophrenia-like psychosis of epilepsy. PLoS One 6: e27863. 22125634 PMC3220705
  23. [24]Pascual-Marqui RD, Lehmann D, Koukkou M, Kochi K, Anderer P, et al (2011) Assessing interactions in the brain with exact low-resolution electromagnetic tomography. Philos Transact A Math Phys Eng Sci 369: 3768– 3784. 21893527
  24. [25]Schoffelen JM, Gross J (2009) Source connectivity analysis with MEG and EEG. Hum Brain Mapp 30: 1857– 1865. 19235884 PMC6870611
  25. [26]Bozzali M, Padovani A, Caltagirone C, Borroni B (2011) Regional grey matter loss and brain disconnection across Alzheimer disease evolution. Curr Med Chem 18: 2452– 2458. 21568913
  26. [27]Damoiseaux JS, Smith SM, Witter MP, Sanz-Arigita EJ, Barkhof F, et al (2009) White matter tract integrity in aging and Alzheimer's disease. Hum Brain Mapp 30: 1051– 1059. 18412132 PMC6870688
  27. [28]Lo CY, Wang PN, Chou KH, Wang J, He Y, et al (2010) Diffusion tensor tractography reveals abnormal topological organization in structural cortical networks in Alzheimer's disease. J Neurosci 30: 16876– 16885. 21159959 PMC6634928
  28. [29]Brown JA, Terashima KH, Burggren AC, Ercoli LM, Miller KJ, et al (2011) Brain network local interconnectivity loss in aging APOE-4 allele carriers. Proc Natl Acad Sci U S A 108: 20760– 20765. 22106308 PMC3251140
  29. [30]Filippini N, MacIntosh BJ, Hough MG, Goodwin GM, Frisoni GB, et al (2009a) Distinct patterns of brain activity in young carriers of the APOE-epsilon4 allele. Proc Natl Acad Sci U S A 106: 7209– 7214. 19357304 PMC2678478
  30. [31]Filippini N, Ebmeier KP, MacIntosh BJ, Trachtenberg AJ, Frisoni GB, et al (2011) Differential effects of the APOE genotype on brain function across the lifespan. Neuroimage 54: 602– 610. 20705142
  31. [33]Babiloni C, Benussi L, Binetti G, Cassetta E, Dal Forno G, et al (2006a) Apolipoprotein E and alpha brain rhythms in mild cognitive impairment: a multicentric electroencephalogram study. Ann Neurol 59: 323– 234. 16358334
  32. [34]de Waal H, Stam CJ, Blankenstein MA, Pijnenburg YA, Scheltens P, et al (2011) EEG abnormalities in early and late onset Alzheimer's disease: understanding heterogeneity. J Neurol Neurosurg Psychiatry 82: 67– 71. 20935323
  33. [35]Jelic V, Julin P, Shigeta M, Nordberg A, Lannfelt L, et al (1997) Apolipoprotein E epsilon4 allele decreases functional connectivity in Alzheimer's disease as measured by EEG coherence. J Neurol Neurosurg Psychiatry 63: 59– 65. 9221969 PMC2169641
  34. [36]Gour N, Ranjeva JP, Ceccaldi M, Confort-Gouny S, Barbeau E, et al (2011) Basal functional connectivity within the anterior temporal network is associated with performance on declarative memory tasks. Neuroimage 58: 687– 697. 21722740
  35. [38]Jelles B, Scheltens P, van der Flier WM, Jonkman EJ, da Silva FH, et al (2008) Global dynamical analysis of the EEG in Alzheimer's disease: frequency-specific changes of functional interactions. Clin Neurophysiol 119: 837– 841. 18258479
  36. [39]Jeong J (2004) EEG dynamics in patients with Alzheimer's disease. Clin Neurophysiol 115: 1490– 1505. 15203050
  37. [40]Hlinka J, Palus M, Vejmelka M, Mantini D, Corbetta M (2011) Functional connectivity in resting-state fMRI: is linear correlation sufficient? Neuroimage 54: 2218– 2225. 20800096 PMC4139498
  38. [41]Stam CJ, Nolte G, Daffertshofer A (2007) Phase lag index: assessment of functional connectivity from multichannel EEG and MEG with diminished bias from common sources. Hum Brain Mapp 28: 1178– 1193. 17266107 PMC6871367
  39. [42]Nolte G, Bai O, Wheaton L, Mari Z, Vorbach S, et al (2004) Identifying true brain interaction from EEG data using the imaginary part of coherency. Clin Neurophysiol 115: 2292– 2307. 15351371
  40. [43]McKhann G, Drachman D, Folstein M, Katzman R, Price D, et al (1984) Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34: 939– 944. 6610841
  41. [45]Folstein M, Folstein SE, McHugh PR (1975) “Mini-Mental State” a Practical Method for Grading the Cognitive State of Patients for the Clinician. J Psychiatr Res 12: 189– 198. 1202204
  42. [46]Reisberg B, Jamil IA, Khan S, Monteiro I, Torossian C, et al.. (2011) Staging dementia. In: Abou-Saleh M, Katona C, Kumar A, eds. Principles and practice of geriatric psychiatry 3rd Ed. London: John Wiley & Sons, Ltd. pp 162–169.
  43. [47]Pascual-Marqui RD, Michel CM, Lehmann D (1994) Low resolution electromagnetic tomography: A new method for localizing electrical activity in the brain. Int J Psychophysiol 18: 49– 65. 7876038
  44. [48]Pascual-Marqui RD (2002) Standardized low-resolution brain electromagnetic tomography (sLORETA): Technical details. Methods Find Exp Clin Pharmacol 24 Suppl D: 5– 12. 12575463
  45. [49]Mazziotta J, Toga A, Evans A, Fox P, Lancaster J, et al (2001) A probabilistic atlas and reference system for the human brain: International Consortium for Brain Mapping (ICBM). Philos Trans R Soc Lond B Biol Sci 356: 1293– 1322. 11545704 PMC1088516
  46. [50]Mulert C, Jäger L, Schmitt R, Bussfeld P, Pogarell O, et al (2004) Integration of fMRI and simultaneous EEG: towards a comprehensive understanding of localization and time-course of brain activity in target detection. Neuroimage 22: 83– 94. 15109999
  47. [51]Vitacco D, Brandeis D, Pascual-Marqui R, Martin E (2002) Correspondence of event-related potential tomography and functional magnetic resonance imaging during language processing. Hum Brain Mapp 17: 4– 12. 12203683 PMC6872086
  48. [52]Worrell GA, Lagerlund TD, Sharbrough FW, Brinkmann BH, Busacker NE (2000) Localization of the Epileptic Focus by Low-Resolution Electromagnetic Tomography in Patients with a Lesion Demonstrated by MRI. Brain Topogr 12: 273– 282. 10912735
  49. [53]Dierks T, Jelic V, Pascual-Marqui RD, Wahlund LO, Julin P, et al (2000) Spatial pattern of cerebral glucose metabolism (PET) correlates with localization of intracerebral EEG-generators in Alzheimer's disease. Clin Neurophysiol 111: 1817– 1824. 11018498
  50. [54]Zumsteg D, Friedman A, Wieser HG, Wennberg RA (2006) Propagation of interictal discharges in temporal lobe epilepsy: correlation of spatiotemporal mapping with intracranial foramen ovale electrode recordings. Clin Neurophysiol 117: 2615– 2626. 17029950
  51. [55]Pascual-Marqui RD (2007) Instantaneous and lagged measurements of linear and nonlinear dependence between groups of multivariate time series: frequency decomposition. arXiv:0711.1455 [stat.ME], November-09. Arxiv website. Available: http://arxiv.org/abs/0711.1455. Accessed 2011 June 29. · arXiv
  52. [57]Holmes AP, Blair RC, Watson JD, Ford I (1996) Nonparametric analysis of statistic images from functional mapping experiments. J Cereb Blood Flow Metab 16: 7– 22. 8530558
  53. [59]Pascual-Marqui RD, Lehmann D, Koenig T, Kochi K, Merlo MC, et al (1999) Low resolution brain electromagnetic tomography (LORETA) functional imaging in acute, neuroleptic-naive, first-episode, productive schizophrenia. Psychiatry Res 90: 169– 179. 10466736
  54. [60]Anderer P, Pascual-Marqui RD, Semlitsch HV, Saletu B (1998) Electrical sources of P300 event-related brain potentials revealed by low resolution electromagnetic tomography: Effects of normal aging. Neuropsychobiology 37: 20– 27. 9438268
  55. [61]Canuet L, Ishii R, Iwase M, Ikezawa K, Kurimoto R, et al (2010) Working memory abnormalities in chronic interictal epileptic psychosis and schizophrenia revealed by magnetoencephalography. Epilepsy Behav 17: 109– 119. 20004619
  56. [62]Ikezawa K, Ishii R, Iwase M, Kurimoto R, Canuet L, et al (2011) Decreased alpha event-related synchronization in the left posterior temporal cortex in schizophrenia: a magnetoencephalography-beamformer study. Neurosci Res 71: 235– 243. 21801762
  57. [63]Ishii R, Canuet L, Kurimoto R, Ikezawa K, Aoki Y, et al (2010) Frontal shift of posterior alpha activity is correlated with cognitive impairment in early Alzheimer's disease: a magnetoencephalography-beamformer study. Psychogeriatrics 10: 138– 143. 20860569
  58. [64]Kurimoto R, Ishii R, Canuet L, Ikezawa K, Azechi M, et al (2008) Event-related synchronization of alpha activity in early Alzheimer's disease and mild cognitive impairment: an MEG study combining beamformer and group comparison. Neurosci Lett 443: 86– 89. 18634854
  59. [65]Babiloni C, Binetti G, Cassetta E, Dal Forno G, Del Percio C, et al (2006b) Sources of cortical rhythms change as a function of cognitive impairment in pathological aging: a multicenter study. Clin Neurophysiol 117: 252– 268. 16377238
  60. [66]Cacabelos R (1996) Diagnosis of Alzheimer's disease: defining genetic profiles (genotype vs phenotype). Acta Neurol Scand Suppl 165: 72– 84. 8740992
  61. [67]Matsuda H (2001) Cerebral blood flow and metabolic abnormalities in Alzheimer's disease. Ann Nucl Med 15: 85– 92. 11448080
  62. [68]Meltzer CC, Zubieta JK, Brandt J, Tune LE, Mayberg HS, et al (1996) Regional hypometabolism in Alzheimer's disease as measured by positron emission tomography after correction for effects of partial volume averaging. Neurology 47: 454– 461. 8757020
  63. [69]Sperling RA, Dickerson BC, Pihlajamaki M, Vannini P, LaViolette PS, et al (2010) Functional alterations in memory networks in early Alzheimer's disease. Neuromolecular Med 2: 27– 43. PMC3036844 20069392
  64. [72]Bajo R, Maestú F, Nevado A, Sancho M, Gutiérrez R, et al (2010) Functional connectivity in mild cognitive impairment during a memory task: implications for the disconnection hypothesis. J Alzheimers Dis 22: 183– 193. 20847450
  65. [73]Maestú F, Yubero R, Moratti S, Campo P, Gil-Gregorio P, et al (2011) Brain activity patterns in stable and progressive mild cognitive impairment during working memory as evidenced by magnetoencephalography. J Clin Neurophysiol 28: 202– 209. 21399524
  66. [74]Ishii R, Shinosaki K, Ukai S, Inouye T, Ishihara T, et al (1999) Medial prefrontal cortex generates frontal midline theta rhythm. Neuroreport 10: 675– 679. 10208529
  67. [76]Lee SH, Park YM, Kim DW, Im CH (2010) Global synchronization index as a biological correlate of cognitive decline in Alzheimer's disease. Neurosci Res 66: 333– 339. 20025913
  68. [77]Park YM, Che HJ, Im CH, Jung HT, Bae SM, et al (2008) Decreased EEG synchronization and its correlation with symptom severity in Alzheimer's disease. Neurosci Res 62: 112– 117. 18672010
  69. [78]Filippini N, Zarei M, Beckmann CF, Galluzzi S, Borsci G, et al (2009) Regional atrophy of transcallosal prefrontal connections in cognitively normal APOE epsilon4 carriers. J Magn Reson Imaging 29: 1021– 1026. 19388128
  70. [79]Trachtenberg AJ, Filippini N, Ebmeier KP, Smith SM, Karpe F, et al (2012) The effects of APOE on the functional architecture of the resting brain. Neuroimage 59: 565– 572. 21851856
  71. [80]Sheline YI, Morris JC, Snyder AZ, Price JL, Yan Z, et al (2010) APOE-4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aβ42. J Neurosci 30: 17035– 17040. 21159973 PMC3023180
  72. [81]Thatcher RW, North DM, Biver CJ (2012) Diffusion spectral imaging modules correlate with EEG LORETA neuroimaging modules. Hum Brain Mapp 33: 1062– 1075. 21567657 PMC6869865

Cited by

Sorted by citations

Authors
Canuet, L., Tellado, I., Couceiro, V., Fraile, C., Fernandez-Novoa, L., Ishii, R., Takeda, M., & Cacabelos, R.
Affiliations
  • EuroEspes Biomedical Research Center (ES)
  • The University of Osaka (JP)
Corresponding author
Canuet, Leonides
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-09-25
Volume
7
Issue
9
Pages
e46289
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0046289
PMC
PMC3457973
OpenAlex
W1996031356
Cited by
163
References
7
Citations by year
2026: 10 · 2025: 13 · 2024: 10 · 2023: 12 · 2022: 11 · 2021: 12 · 2020: 20 · 2019: 14 · 2018: 13 · 2017: 13 · 2016: 6 · 2015: 9 · 2014: 16 · 2013: 4
FWCI
4.75
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
Japan Society for the Promotion of Science (21591516)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
Keywords
Alzheimer's disease, APOE ε4, resting-state functional connectivity, alpha oscillations, theta oscillations, EEG source localization, eLORETA, interhemispheric connectivity, cognitive impairment, early diagnosis biomarkers
MeSH terms
Aged, Alzheimer Disease, Apolipoproteins E, Brain, Electroencephalography, Female, Genotype, Humans, Male, Parietal Lobe, Apolipoprotein E4

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review