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Involvement of ApoE4 in dementia with Lewy bodies in the prodromal and demented stages: evaluation of the Strasbourg cohort

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Abstract

ApoE4 as a risk factor for dementia with Lewy bodies (DLB) is still an issue. We sought to determine the involvement of ApoE4 according to different clinical parameters in our cohort of patients from Strasbourg, France. ApoE genotyping was performed on the AlphaLewyMA cohort. In this cohort, 197 patients were genotyped: 105 DLB patients, 37 Alzheimer’s disease (AD) patients, 29 patients with AD/DLB comorbidity, and 26 control subjects (CS). The groups of patients were also classified according to the stage of evolution of the disease: prodromal or demented. We analyzed other parameters in relation to ApoE4 status, such as years of education (YOE) and Alzheimer CSF biomarkers. We observed a higher proportion of ApoE4 carriers in the AD (51.4%) and AD/DLB (72.4%) groups compared to the DLB (25.7%) and CS (11.5%) groups (p < 0.0001). We found a correlation between age at disease onset and YOE in the AD group (p = 0.039) but not in the DLB group (p = 0.056). Interestingly, in the DLB group, the subgroup of patients with high YOE (≥ 11) had significantly more patients with ApoE4 than the subgroup with low YOE (< 11). AD biomarkers did not seem to be impacted by the presence of ApoE4, except for Aβ42: DLB ApoE4-positive demented patients showed a more marked Aβ42 decrease. ApoE4 does not appear to be a risk factor for “pure” DLB patients. These results suggest a strong link between ApoE4 and amyloidopathy and consequently with AD. Trial registration: AlphaLewyMa, Identifier: NCT01876459, date of registration: June 12, 2013.

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Data availability

All data generated or analyzed during this study are included in this published article.

Abbreviations

AD :

Alzheimer’s disease

AD-d :

AD demented

CS :

Control subjects

CSF :

Cerebrospinal fluid

DLB :

Dementia with Lewy bodies

DLB-d :

DLB demented

FCSRT :

Free and Cued Selective Reminding Test

MMSE :

Mini Mental State Examination

Pro-AD :

Prodromal AD

Pro-DLB :

Prodromal DLB

RBD :

Rapid eye movement sleep behavior disorder

YOE :

Years of education

t-Tau :

Total Tau

References

  1. Kemp J, Philippi N, Phillipps C, Demuynck C, Albasser T, Martin-Hunyadi C, et al. Cognitive profile in prodromal dementia with Lewy bodies. Alzheimers Res Ther. 2017;9(1):19.

    Article  PubMed  PubMed Central  Google Scholar 

  2. McKeith IG, Ferman TJ, Thomas AJ, Blanc F, Boeve BF, Fujishiro H, et al. Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology. 2020;94(17):743–55.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Donaghy PC, McKeith IG. The clinical characteristics of dementia with Lewy bodies and a consideration of prodromal diagnosis. Alzheimers Res Ther. 2014;6(4):46.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M. Alpha-synuclein in Lewy bodies. Nature. 1997;388(6645):839–40.

    Article  CAS  PubMed  Google Scholar 

  5. Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S, et al. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat Genet. 2019;51(3):404–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wightman DP, Jansen IE, Savage JE, Shadrin AA, Bahrami S, Holland D, et al. A genome-wide association study with 1,126,563 individuals identifies new risk loci for Alzheimer’s disease. Nat Genet. 2021;53(9):1276–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jansen IE, van der Lee SJ, Gomez-Fonseca D, de Rojas I, Dalmasso MC, Grenier-Boley B, et al. Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers. Acta Neuropathol. 2022;144(5):821–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Outeiro TF, Koss DJ, Erskine D, Walker L, Kurzawa-Akanbi M, Burn D, et al. Dementia with Lewy bodies: an update and outlook. Mol Neurodegener. 2019;14(1):5.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Chia R, Sabir MS, Bandres-Ciga S, Saez-Atienzar S, Reynolds RH, Gustavsson E, et al. Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture. Nat Genet. 2021;53(3):294–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Guerreiro R, Ross OA, Kun-Rodrigues C, Hernandez DG, Orme T, Eicher JD, et al. Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study. Lancet Neurol. 2018;17(1):64–74.

    Article  PubMed  Google Scholar 

  11. Bras J, Guerreiro R, Darwent L, Parkkinen L, Ansorge O, Escott-Price V, et al. Genetic analysis implicates APOE, SNCA and suggests lysosomal dysfunction in the etiology of dementia with Lewy bodies. Hum Mol Genet. 2014;23(23):6139–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron. 2009;63(3):287–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Liu S, Breitbart A, Sun Y, Mehta PD, Boutajangout A, Scholtzova H, et al. Blocking the apolipoprotein E/amyloid beta interaction in triple transgenic mice ameliorates Alzheimer’s disease related amyloid beta and tau pathology. J Neurochem. 2014;128(4):577–91.

    Article  CAS  PubMed  Google Scholar 

  14. Tsuang D, Leverenz JB, Lopez OL, Hamilton RL, Bennett DA, Schneider JA, et al. APOE epsilon4 increases risk for dementia in pure synucleinopathies. JAMA Neurol. 2013;70(2):223–8.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Dickson DW, Heckman MG, Murray ME, Soto AI, Walton RL, Diehl NN, et al. APOE epsilon4 is associated with severity of Lewy body pathology independent of Alzheimer pathology. Neurology. 2018;91(12):e1182–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhao N, Attrebi ON, Ren Y, Qiao W, Sonustun B, Martens YA, et al. APOE4 exacerbates alpha-synuclein pathology and related toxicity independent of amyloid. Sci Transl Med. 2020;12(529)

  17. Rongve A, Witoelar A, Ruiz A, Athanasiu L, Abdelnour C, Clarimon J, et al. GBA and APOE epsilon4 associate with sporadic dementia with Lewy bodies in European genome wide association study. Sci Rep. 2019;9(1):7013.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Prokopenko I, Miyakawa G, Zheng B, Heikkinen J, Petrova Quayle D, Udeh-Momoh C, et al. Alzheimer’s disease pathology explains association between dementia with Lewy bodies and APOE-epsilon4/TOMM40 long poly-T repeat allele variants. Alzheimers Dement (N Y). 2019;5:814–24.

    Article  PubMed  Google Scholar 

  19. Schaffert J, LoBue C, White CL 3rd, Wilmoth K, Didehbani N, Lacritz L, et al. Risk factors for earlier dementia onset in autopsy-confirmed Alzheimer’s disease, mixed Alzheimer’s with Lewy bodies, and pure Lewy body disease. Alzheimers Dement. 2020;16(3):524–30.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Raunio A, Kaivola K, Tuimala J, Kero M, Oinas M, Polvikoski T, et al. Lewy-related pathology exhibits two anatomically and genetically distinct progression patterns: a population-based study of Finns aged 85. Acta Neuropathol. 2019;138(5):771–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kaivola K, Shah Z, Chia R, International LBDGC, Scholz SW. Genetic evaluation of dementia with Lewy bodies implicates distinct disease subgroups. Brain. 2022;145(5):1757–62

  22. Pillai JA, Bena J, Bonner-Jackson A, Leverenz JB. Impact of APOE epsilon4 genotype on initial cognitive symptoms differs for Alzheimer’s and Lewy body neuropathology. Alzheimers Res Ther. 2021;13(1):31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Chen KL, Sun YM, Zhou Y, Zhao QH, Ding D, Guo QH. Associations between APOE polymorphisms and seven diseases with cognitive impairment including Alzheimer’s disease, frontotemporal dementia, and dementia with Lewy bodies in southeast China. Psychiatr Genet. 2016;26(3):124–31.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Berge G, Sando SB, Rongve A, Aarsland D, White LR. Apolipoprotein E epsilon2 genotype delays onset of dementia with Lewy bodies in a Norwegian cohort. J Neurol Neurosurg Psychiatry. 2014;85(11):1227–31.

    Article  PubMed  Google Scholar 

  25. Boot BP, Orr CF, Ahlskog JE, Ferman TJ, Roberts R, Pankratz VS, et al. Risk factors for dementia with Lewy bodies: a case-control study. Neurology. 2013;81(9):833–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nelson PT, Jicha GA, Kryscio RJ, Abner EL, Schmitt FA, Cooper G, et al. Low sensitivity in clinical diagnoses of dementia with Lewy bodies. J Neurol. 2010;257(3):359–66.

    Article  PubMed  Google Scholar 

  27. Ballard C, Ziabreva I, Perry R, Larsen JP, O’Brien J, McKeith I, et al. Differences in neuropathologic characteristics across the Lewy body dementia spectrum. Neurology. 2006;67(11):1931–4.

    Article  CAS  PubMed  Google Scholar 

  28. Bousiges O, Philippi N, Lavaux T, Perret-Liaudet A, Lachmann I, Schaeffer-Agalede C, et al. Differential diagnostic value of total alpha-synuclein assay in the cerebrospinal fluid between Alzheimer’s disease and dementia with Lewy bodies from the prodromal stage. Alzheimers Res Ther. 2020;12(1):120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bousiges O, Cretin B, Lavaux T, Philippi N, Jung B, Hezard S, et al. Diagnostic value of cerebrospinal fluid biomarkers (Phospho-Tau181, total-Tau, Abeta42, and Abeta40) in prodromal stage of alzheimer’s disease and dementia with Lewy bodies. J Alzheimers Dis. 2016;51(4):1069–83.

    Article  CAS  PubMed  Google Scholar 

  30. McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, et al. Diagnosis and management of dementia with Lewy bodies: fourth consensus report of the DLB Consortium. Neurology. 2017;89(1):88–100.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Ferman TJ, Smith GE, Boeve BF, Ivnik RJ, Petersen RC, Knopman D, et al. DLB fluctuations: specific features that reliably differentiate DLB from AD and normal aging. Neurology. 2004;62(2):181–7.

    Article  CAS  PubMed  Google Scholar 

  32. Fenelon G, Soulas T, Zenasni F, de Langavant LC. The changing face of Parkinson’s disease-associated psychosis: a cross-sectional study based on the new NINDS-NIMH criteria. Mov Disord. 2010;25(6):763–6.

    Article  PubMed  Google Scholar 

  33. Gjerstad MD, Boeve B, Wentzel-Larsen T, Aarsland D, Larsen JP. Occurrence and clinical correlates of REM sleep behaviour disorder in patients with Parkinson’s disease over time. J Neurol Neurosurg Psychiatry. 2008;79(4):387–91.

    Article  CAS  PubMed  Google Scholar 

  34. Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):270–9.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Dubois B, Feldman HH, Jacova C, Dekosky ST, Barberger-Gateau P, Cummings J, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol. 2007;6(8):734–46.

    Article  PubMed  Google Scholar 

  36. McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7(3):263–9.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 1990;31(3):545–8.

    Article  CAS  PubMed  Google Scholar 

  38. Bousiges O, Bombois S, Schraen S, Wallon D, Quillard MM, Gabelle A, et al. Cerebrospinal fluid Alzheimer biomarkers can be useful for discriminating dementia with Lewy bodies from Alzheimer’s disease at the prodromal stage. J Neurol Neurosurg Psychiatry. 2018;89(5):467–75.

    Article  PubMed  Google Scholar 

  39. van Steenoven I, van der Flier WM, Scheltens P, Teunissen CE, Lemstra AW. Amyloid-beta peptides in cerebrospinal fluid of patients with dementia with Lewy bodies. Alzheimers Res Ther. 2019;11(1):83.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Robinson JL, Lee EB, Xie SX, Rennert L, Suh E, Bredenberg C, et al. Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated. Brain. 2018;141(7):2181–93.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Chatterjee A, Hirsch-Reinshagen V, Moussavi SA, Ducharme B, Mackenzie IR, Hsiung GR. Clinico-pathological comparison of patients with autopsy-confirmed Alzheimer’s disease, dementia with Lewy bodies, and mixed pathology. Alzheimers Dement (Amst). 2021;13(1):e12189.

    Article  PubMed  Google Scholar 

  42. Peuralinna T, Myllykangas L, Oinas M, Nalls MA, Keage HA, Isoviita VM, et al. Genome-wide association study of neocortical Lewy-related pathology. Ann Clin Transl Neurol. 2015;2(9):920–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Stern Y. Cognitive reserve in ageing and Alzheimer’s disease. Lancet Neurol. 2012;11(11):1006–12.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Larsson SC, Traylor M, Malik R, Dichgans M, Burgess S, Markus HS, et al. Modifiable pathways in Alzheimer’s disease: Mendelian randomisation analysis. BMJ. 2017;359:j5375.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Parra KL, Alexander GE, Raichlen DA, Klimentidis YC, Furlong MA. Exposure to air pollution and risk of incident dementia in the UK Biobank. Environ Res. 2022;209:112895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Gharbi-Meliani A, Dugravot A, Sabia S, Regy M, Fayosse A, Schnitzler A, et al. The association of APOE epsilon4 with cognitive function over the adult life course and incidence of dementia: 20 years follow-up of the Whitehall II study. Alzheimers Res Ther. 2021;13(1):5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Alexander DM, Williams LM, Gatt JM, Dobson-Stone C, Kuan SA, Todd EG, et al. The contribution of apolipoprotein E alleles on cognitive performance and dynamic neural activity over six decades. Biol Psychol. 2007;75(3):229–38.

    Article  CAS  PubMed  Google Scholar 

  48. Mondadori CRA, de Quervain DJF, Buchmann A, Mustovic H, Wollmer MA, Schmidt CF, et al. Better memory and neural efficiency in young apolipoprotein E epsilon 4 carriers. Cereb Cortex. 2007;17(8):1934–47.

    Article  PubMed  Google Scholar 

  49. Yu VWY, Lin CH, Chen SP, Hong CJ, Tsai SJ. Intelligence and event-related potentials for young female human volunteer apolipoprotein E epsilon 4 and non-epsilon 4 carriers. Neurosci Lett. 2000;294(3):179–81.

    Article  CAS  PubMed  Google Scholar 

  50. Wright RO, Hu H, Silverman EK, Tsaih SW, Schwartz J, Bellinger D, et al. Apolipoprotein E genotype predicts 24-month Bayley scales infant development score. Pediatr Res. 2003;54(6):819–25.

    Article  CAS  PubMed  Google Scholar 

  51. Marchant NL, King SL, Tabet N, Rusted JM. Positive effects of cholinergic stimulation favor young APOE epsilon 4 carriers. Neuropsychopharmacol. 2010;35(5):1090–6.

    Article  CAS  Google Scholar 

  52. Tuminello ER, Han SD. The apolipoprotein e antagonistic pleiotropy hypothesis: review and recommendations. Int J Alzheimers Dis. 2011;2011:726197.

    PubMed  PubMed Central  Google Scholar 

  53. Mendes A, Noblet V, Mondino M, de Sousa PL, Manji S, Archenault A, et al. Association of cerebral microbleeds with cerebrospinal fluid Alzheimer-biomarkers and clinical symptoms in early dementia with Lewy bodies. Int J Geriatr Psychiatry. 2021;36(6):851–7.

    Article  PubMed  Google Scholar 

  54. Philippi N, Noblet V, Hamdaoui M, Soulier D, Botzung A, Ehrhard E, et al. The insula, a grey matter of tastes: a volumetric MRI study in dementia with Lewy bodies. Alzheimers Res Ther. 2020;12(1):79.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Abdelnour C, Ferreira D, van de Beek M, Cedres N, Oppedal K, Cavallin L, et al. Parsing heterogeneity within dementia with Lewy bodies using clustering of biological, clinical, and demographic data. Alzheimers Res Ther. 2022;14(1):14.

    Article  PubMed  PubMed Central  Google Scholar 

  56. O’Dowd S, Schumacher J, Burn DJ, Bonanni L, Onofrj M, Thomas A, et al. Fluctuating cognition in the Lewy body dementias. Brain. 2019;142(11):3338–50.

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank Nick Barton for the help in translation.

Funding

This work was funded by PHRC Interégional.

Author information

Authors and Affiliations

  1. ICube Laboratory UMR 7357 and FMTS (Fédération de Médecine Translationnelle de Strasbourg), IMIS Team and IMAGeS Team, University of Strasbourg and CNRS, Strasbourg, France

    Olivier Bousiges, Benjamin Cretin, Anne Botzung, Nathalie Philippi & Frédéric Blanc

  2. Laboratory of Biochemistry and Molecular Biology, University Hospital of Strasbourg, Strasbourg, France

    Olivier Bousiges

  3. CM2R (Research and Resources Memory Center), Geriatrics Department, Geriatric Day Hospital, Neurogeriatric Service, University Hospital of Strasbourg, Strasbourg, France

    Benjamin Cretin, Candice Muller, Anne Botzung, Lea Sanna, Catherine Demuynck & Frédéric Blanc

  4. CM2R, Neuropsychology Unit, Head and Neck Department, Neurology Department, University of Strasbourg, Strasbourg, France

    Pierre Anthony & Nathalie Philippi

  5. CM2R, Geriatrics Department and Neurology Department, Colmar General Hospital, Colmar, France

    Pierre Anthony

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  1. Olivier Bousiges
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  2. Benjamin Cretin
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  3. Candice Muller
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Contributions

OB and FB: study concept and design, analysis of the results, and drafting the manuscript. OB: ApoE genotyping and statistical analyses, analyses of biological measurements, and contribution to data interpretation and revision of the manuscript for important intellectual content. AB, LS, and FB: study protocol design. NP, PA, CD, CM, BC, and FB: clinical work, organization of lumbar punctures, diagnosis confirmation, and contribution to data interpretation and revision of the manuscript for important intellectual content.

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Correspondence to Olivier Bousiges.

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Bousiges, O., Cretin, B., Muller, C. et al. Involvement of ApoE4 in dementia with Lewy bodies in the prodromal and demented stages: evaluation of the Strasbourg cohort. GeroScience 46, 1527–1542 (2024). https://doi.org/10.1007/s11357-023-00883-6

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