Genetic Factors Influencing the Development and Treatment of Cognitive Impairment and Psychosis in Parkinson’s Disease

  • Santiago Perez-LloretEmail author
  • Viviana Bernath
  • Francisco J. Barrantes


Parkinson’s disease (PD) is a neurodegenerative disease in which both genetic and environmental factors play significant roles. In addition to increasing the risk of developing PD, gene mutations might also influence the phenotypical characteristics of the disease, including the development of cognitive impairment and psychosis. For instance, mutations of the GBA gene, which encodes the enzyme γ-glucocerebrosidase, have been related to cognitive impairment or dementia and visual hallucinations. Interest in the APOE gene, which encodes the apolipoprotein E, stems from the finding of increased Alzheimer’s disease risk in carriers of APOE ε4 alleles. In a cohort of 390 PD patients, APOE ε4 allele carriers showed significantly increased cognitive decline during the 2-year follow-up period. Mutations of the LRRK2 gene, which encodes the leucine-rich repeat kinase 2, have been related to a lower risk of cognitive impairment and dementia and lower scores for apathy and hallucinations. PD patients with mutations in the BDNF, COMT, PARP4, and MTCL1 genes showed increased risk of cognitive impairment, dementia, and visual hallucinations, but these results have not been replicated yet. Hallucinations have also been related to mutations in the cholecystokinin CCK gene. These findings suggest that gene mutations may be important determinants of cognitive impairment and psychosis in PD and highlight promising targets for new therapeutic approaches.


Parkinson’s disease Genetics Gene mutations Cognitive impairment Hallucinations Neuropsychiatric symptoms 


  1. 1.
    Pringsheim T, Jette N, Frolkis A, et al. The prevalence of Parkinson’s disease: a systematic review and meta-analysis. Mov Disord. 2014;29:1583–90.CrossRefGoogle Scholar
  2. 2.
    Chaudhuri KR, Schapira AH. Non-motor symptoms of Parkinson’s disease: dopaminergic pathophysiology and treatment. Lancet Neurol. 2009;8:464–74.CrossRefGoogle Scholar
  3. 3.
    Hornykiewicz O. Dopamine (3-hydroxytyramine) and brain function. Pharmacol Rev. 1966;18:925–64.PubMedGoogle Scholar
  4. 4.
    Fahn S. The history of dopamine and levodopa in the treatment of Parkinson’s disease. Mov Disord. 2008;23(Suppl 3):S497–508.CrossRefGoogle Scholar
  5. 5.
    Soto C. Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci. 2003;4:49–60.CrossRefGoogle Scholar
  6. 6.
    Poewe W, Gauthier S, Aarsland D, et al. Diagnosis and management of Parkinson’s disease dementia. Int J Clin Pract. 2008;62:1581–7.CrossRefGoogle Scholar
  7. 7.
    Aarsland D, Marsh L, Schrag A. Neuropsychiatric symptoms in Parkinson’s disease. Mov Disord. 2009;24:2175–86.CrossRefGoogle Scholar
  8. 8.
    Buter TC, Van Den Hout A, Matthews FE, et al. Dementia and survival in Parkinson disease: a 12-year population study. Neurology. 2008;70:1017–22.CrossRefGoogle Scholar
  9. 9.
    Akbar U, Friedman JH. Recognition and treatment of neuropsychiatric disturbances in Parkinson’s disease. Expert Rev Neurother. 2015;15:1053–65.CrossRefGoogle Scholar
  10. 10.
    Factor SA, Feustel PJ, Friedman JH, et al. Longitudinal outcome of Parkinson’s disease patients with psychosis. Neurology. 2003;60:1756–61.CrossRefGoogle Scholar
  11. 11.
    Lill CM. Genetics of Parkinson’s disease. Mol Cell Probes. 2016;30:386–96.CrossRefGoogle Scholar
  12. 12.
    Klein C, Westenberger A. Genetics of Parkinson’s disease. Cold Spring Harb Perspect Med. 2012;2:a008888.CrossRefGoogle Scholar
  13. 13.
    Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science. 1997;276:2045–7.CrossRefGoogle Scholar
  14. 14.
    Bekris LM, Mata IF, Zabetian CP. The genetics of Parkinson disease. J Geriatr Psychiatry Neurol. 2010;23:228–42.CrossRefGoogle Scholar
  15. 15.
    Marras C, Lang A, Van De Warrenburg BP, et al. Nomenclature of genetic movement disorders: recommendations of the international Parkinson and movement disorder society task force. Mov Disord. 2016;31:436–57.CrossRefGoogle Scholar
  16. 16.
    Spillantini MG, Schmidt ML, Lee VM, et al. Alpha-synuclein in Lewy bodies. Nature. 1997;388:839–40.CrossRefGoogle Scholar
  17. 17.
    Bendor JT, Logan TP, Edwards RH. The function of alpha-synuclein. Neuron. 2013;79:1044–66.CrossRefGoogle Scholar
  18. 18.
    Brettschneider J, Del Tredici K, Lee VM, et al. Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat Rev Neurosci. 2015;16:109–20.CrossRefGoogle Scholar
  19. 19.
    Walsh DM, Selkoe DJ. A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration. Nat Rev Neurosci. 2016;17:251–60.CrossRefGoogle Scholar
  20. 20.
    Paisan-Ruiz C, Jain S, Evans EW, et al. Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s disease. Neuron. 2004;44:595–600.CrossRefGoogle Scholar
  21. 21.
    Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron. 2004;44:601–7.CrossRefGoogle Scholar
  22. 22.
    Healy DG, Falchi M, O’sullivan SS, et al. Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson’s disease: a case-control study. Lancet Neurol. 2008;7:583–90.CrossRefGoogle Scholar
  23. 23.
    Ross OA, Soto-Ortolaza AI, Heckman MG, et al. Association of LRRK2 exonic variants with susceptibility to Parkinson’s disease: a case-control study. Lancet Neurol. 2011;10:898–908.CrossRefGoogle Scholar
  24. 24.
    Webber PJ, West AB. LRRK2 in Parkinson’s disease: function in cells and neurodegeneration. FEBS J. 2009;276:6436–44.CrossRefGoogle Scholar
  25. 25.
    Nalls MA, Pankratz N, Lill CM, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet. 2014;46:989–93.CrossRefGoogle Scholar
  26. 26.
    Goker-Alpan O, Schiffmann R, Lamarca ME, et al. Parkinsonism among Gaucher disease carriers. J Med Genet. 2004;41:937–40.CrossRefGoogle Scholar
  27. 27.
    Sidransky E, Nalls MA, Aasly JO, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med. 2009;361:1651–61.CrossRefGoogle Scholar
  28. 28.
    Nalls MA, Escott-Price V, Williams NM, et al. Genetic risk and age in Parkinson’s disease: continuum not stratum. Mov Disord. 2015;30:850–4.CrossRefGoogle Scholar
  29. 29.
    Pihlstrom L, Morset KR, Grimstad E, et al. A cumulative genetic risk score predicts progression in Parkinson’s disease. Mov Disord. 2016;31:487–90.CrossRefGoogle Scholar
  30. 30.
    Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297:353–6.CrossRefGoogle Scholar
  31. 31.
    Mawuenyega KG, Sigurdson W, Ovod V, et al. Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science. 2010;330:1774.CrossRefGoogle Scholar
  32. 32.
    Siderowf A, Xie SX, Hurtig H, et al. CSF amyloid {beta} 1-42 predicts cognitive decline in Parkinson disease. Neurology. 2010;75:1055–61.CrossRefGoogle Scholar
  33. 33.
    Deleidi M, Maetzler W. Protein clearance mechanisms of alpha-synuclein and amyloid-Beta in lewy body disorders. Int J Alzheimers Dis. 2012;2012:391438.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Brockmann K, Lerche S, Dilger SS, et al. SNPs in Abeta clearance proteins: lower CSF Abeta1-42 levels and earlier onset of dementia in PD. Neurology. 2017;89:2335–40.CrossRefGoogle Scholar
  35. 35.
    Garai K, Verghese PB, Baban B, et al. The binding of apolipoprotein E to oligomers and fibrils of amyloid-beta alters the kinetics of amyloid aggregation. Biochemistry. 2014;53:6323–31.CrossRefGoogle Scholar
  36. 36.
    Deane R, Sagare A, Hamm K, et al. apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain. J Clin Invest. 2008;118:4002–13.CrossRefGoogle Scholar
  37. 37.
    Tsuang D, Leverenz JB, Lopez OL, et al. APOE epsilon4 increases risk for dementia in pure synucleinopathies. JAMA Neurol. 2013;70:223–8.CrossRefGoogle Scholar
  38. 38.
    Schrag A, Siddiqui UF, Anastasiou Z, et al. Clinical variables and biomarkers in prediction of cognitive impairment in patients with newly diagnosed Parkinson’s disease: a cohort study. Lancet Neurol. 2017;16:66–75.CrossRefGoogle Scholar
  39. 39.
    Mata IF, Leverenz JB, Weintraub D, et al. APOE, MAPT, and SNCA genes and cognitive performance in Parkinson disease. JAMA Neurol. 2014;71:1405–12.CrossRefGoogle Scholar
  40. 40.
    Factor SA, Steenland NK, Higgins DS, et al. Disease-related and genetic correlates of psychotic symptoms in Parkinson’s disease. Mov Disord. 2011;26:2190–5.CrossRefGoogle Scholar
  41. 41.
    Goetz CG, Burke PF, Leurgans S, et al. Genetic variation analysis in Parkinson disease patients with and without hallucinations: case-control study. Arch Neurol. 2001;58:209–13.CrossRefGoogle Scholar
  42. 42.
    Kachergus J, Mata IF, Hulihan M, et al. Identification of a novel LRRK2 mutation linked to autosomal dominant parkinsonism: evidence of a common founder across European populations. Am J Hum Genet. 2005;76:672–80.CrossRefGoogle Scholar
  43. 43.
    Thaler A, Ash E, Gan-Or Z, et al. The LRRK2 G2019S mutation as the cause of Parkinson’s disease in Ashkenazi Jews. J Neural Transm (Vienna). 2009;116:1473–82.CrossRefGoogle Scholar
  44. 44.
    Mirelman A, Heman T, Yasinovsky K, et al. Fall risk and gait in Parkinson’s disease: the role of the LRRK2 G2019S mutation. Mov Disord. 2013;28:1683–90.CrossRefGoogle Scholar
  45. 45.
    Srivatsal S, Cholerton B, Leverenz JB, et al. Cognitive profile of LRRK2-related Parkinson’s disease. Mov Disord. 2015;30:728–33.CrossRefGoogle Scholar
  46. 46.
    Kalia LV, Lang AE, Hazrati LN, et al. Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA Neurol. 2015;72:100–5.CrossRefGoogle Scholar
  47. 47.
    Somme JH, Molano Salazar A, Gonzalez A, et al. Cognitive and behavioral symptoms in Parkinson’s disease patients with the G2019S and R1441G mutations of the LRRK2 gene. Parkinsonism Relat Disord. 2015;21:494–9.CrossRefGoogle Scholar
  48. 48.
    Neumann J, Bras J, Deas E, et al. Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease. Brain. 2009;132:1783–94.CrossRefGoogle Scholar
  49. 49.
    Goker-Alpan O, Lopez G, Vithayathil J, et al. The spectrum of parkinsonian manifestations associated with glucocerebrosidase mutations. Arch Neurol. 2008;65:1353–7.CrossRefGoogle Scholar
  50. 50.
    Seto-Salvia N, Pagonabarraga J, Houlden H, et al. Glucocerebrosidase mutations confer a greater risk of dementia during Parkinson’s disease course. Mov Disord. 2012;27:393–9.CrossRefGoogle Scholar
  51. 51.
    Brockmann K, Srulijes K, Hauser AK, et al. GBA-associated PD presents with nonmotor characteristics. Neurology. 2011;77:276–80.CrossRefGoogle Scholar
  52. 52.
    Oeda T, Umemura A, Mori Y, et al. Impact of glucocerebrosidase mutations on motor and nonmotor complications in Parkinson’s disease. Neurobiol Aging. 2015;36:3306–13.CrossRefGoogle Scholar
  53. 53.
    Mata IF, Leverenz JB, Weintraub D, et al. GBA variants are associated with a distinct pattern of cognitive deficits in Parkinson’s disease. Mov Disord. 2016;31:95–102.CrossRefGoogle Scholar
  54. 54.
    Davis MY, Johnson CO, Leverenz JB, et al. Association of GBA mutations and the E326K polymorphism with motor and cognitive progression in Parkinson disease. JAMA Neurol. 2016;73:1217–24.CrossRefGoogle Scholar
  55. 55.
    Jesus S, Huertas I, Bernal-Bernal I, et al. GBA variants influence motor and non-motor features of Parkinson’s disease. PLoS One. 2016;11:e0167749.CrossRefGoogle Scholar
  56. 56.
    Cilia R, Tunesi S, Marotta G, et al. Survival and dementia in GBA-associated Parkinson’s disease: the mutation matters. Ann Neurol. 2016;80:662–73.CrossRefGoogle Scholar
  57. 57.
    Mata IF, Johnson CO, Leverenz JB, et al. Large-scale exploratory genetic analysis of cognitive impairment in Parkinson’s disease. Neurobiol Aging. 2017;56:211 e211–7.CrossRefGoogle Scholar
  58. 58.
    Caspell-Garcia C, Simuni T, Tosun-Turgut D, et al. Multiple modality biomarker prediction of cognitive impairment in prospectively followed de novo Parkinson disease. PLoS One. 2017;12:e0175674.CrossRefGoogle Scholar
  59. 59.
    Fujii C, Harada S, Ohkoshi N, et al. Association between polymorphism of the cholecystokinin gene and idiopathic Parkinson’s disease. Clin Genet. 1999;56:394–9.CrossRefGoogle Scholar
  60. 60.
    Wang J, Si YM, Liu ZL, et al. Cholecystokinin, cholecystokinin-A receptor and cholecystokinin-B receptor gene polymorphisms in Parkinson’s disease. Pharmacogenetics. 2003;13:365–9.CrossRefGoogle Scholar
  61. 61.
    Goldman JG, Goetz CG, Berry-Kravis E, et al. Genetic polymorphisms in Parkinson disease subjects with and without hallucinations: an analysis of the cholecystokinin system. Arch Neurol. 2004;61:1280–4.PubMedGoogle Scholar
  62. 62.
    Lautner R, Insel PS, Skillback T, et al. Preclinical effects of APOE epsilon4 on cerebrospinal fluid Abeta42 concentrations. Alzheimers Res Ther. 2017;9:87.CrossRefGoogle Scholar
  63. 63.
    Emre M, Aarsland D, Brown R, et al. Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Mov Disord. 2007;22:1689–707; quiz 1837.CrossRefGoogle Scholar
  64. 64.
    Zahodne LB, Fernandez HH. Pathophysiology and treatment of psychosis in Parkinson’s disease: a review. Drugs Aging. 2008;25:665–82.CrossRefGoogle Scholar
  65. 65.
    Moore SF, Barker RA. Predictors of Parkinson’s disease dementia: towards targeted therapies for a heterogeneous disease. Parkinsonism Relat Disord. 2014;20(Suppl 1):S104–7.CrossRefGoogle Scholar
  66. 66.
    Goedert M. NEURODEGENERATION. Alzheimer’s and Parkinson’s diseases: the prion concept in relation to assembled Abeta, tau, and alpha-synuclein. Science. 2015;349:1255555.CrossRefGoogle Scholar
  67. 67.
    Lerche S, Schulte C, Srulijes K, et al. Cognitive impairment in Glucocerebrosidase (GBA)-associated PD: not primarily associated with cerebrospinal fluid Abeta and Tau profiles. Mov Disord. 2017;32:1780–3.CrossRefGoogle Scholar
  68. 68.
    Jindal H, Bhatt B, Sk S, et al. Alzheimer disease immunotherapeutics: then and now. Hum Vaccin Immunother. 2014;10:2741–3.CrossRefGoogle Scholar
  69. 69.
    Schliebs R. Basal forebrain cholinergic dysfunction in Alzheimer’s disease – interrelationship with beta-amyloid, inflammation and neurotrophin signaling. Neurochem Res. 2005;30:895–908.CrossRefGoogle Scholar
  70. 70.
    Perez-Lloret S, Barrantes FJ. Deficits in cholinergic neurotransmission and their clinical correlates in Parkinson’s disease. NPJ Park Dis. 2016;2:16001–12.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Santiago Perez-Lloret
    • 1
    Email author
  • Viviana Bernath
    • 2
  • Francisco J. Barrantes
    • 3
  1. 1.Institute of Cardiology Research, National Scientific and Technological Research Council-University of Buenos Aires, (CONICET-ININCA)Buenos AiresArgentina
  2. 2.Genda Genetics and Molecular Biology LaboratoryBuenos AiresArgentina
  3. 3.Laboratory of Molecular Neurobiology, Biomedical Research Institute, UCA-CONICET, Faculty of Medical SciencesBuenos AiresArgentina

Personalised recommendations