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Research paper
APOE4 predicts amyloid-β in cortical brain biopsy but not idiopathic normal pressure hydrocephalus
  1. Okko T Pyykkö1,
  2. Seppo Helisalmi2,
  3. Anne M Koivisto2,3,
  4. Juhani A A Mölsä1,
  5. Jaana Rummukainen4,
  6. Ossi Nerg3,
  7. Irina Alafuzoff4,5,
  8. Sakari Savolainen1,
  9. Hilkka Soininen2,3,
  10. Juha E Jääskeläinen1,
  11. Jaakko Rinne1,
  12. Ville Leinonen1,
  13. Mikko Hiltunen2
  1. 1Neurosurgery of NeuroCenter, Kuopio University Hospital, Kuopio, Finland
  2. 2Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
  3. 3Neurology of NeuroCenter, Kuopio University Hospital, Kuopio, Finland
  4. 4Department of Pathology, Kuopio University Hospital, Kuopio, Finland
  5. 5Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden
  1. Correspondence to Dr O T Pyykkö, Neurosurgery of NeuroCentre, Kuopio University Hospital, PO Box 1777, 70211 Kuopio, Finland; okko.pyykko{at}


Objective To investigate the association of apolipoprotein E (APOE) genotype, especially the APOE4 allele, to (1) idiopathic normal pressure hydrocephalus (iNPH) and (2) amyloid-β (Aβ) plaques in cortical brain biopsies of presumed NPH patients with and without a final clinical diagnosis of Alzheimer's disease (AD).

Methods 202 patients with presumed NPH were evaluated by intraventricular pressure monitoring and frontal cortical biopsy immunostained against Aβ (134 semiquantified by Aβ plaques/mm2). The 202 patients and 687 cognitively healthy individuals were genotyped for APOE. The final clinical diagnoses in a median follow-up of 3.9 years were: 113 iNPH (94 shunt responsive, 16 shunt non-responsive, three not shunted); 36 AD (12 mixed iNPH + AD); 53 others.

Results The APOE genotypes distributed similarly in the 94 shunt responsive and 16 non-responsive iNPH patients and healthy controls. In multivariate analysis, the APOE4 allele correlated independently with Aβ plaques in the cortical biopsies (OR 8.7, 95% CI 3.6 to 20, p<0.001). The APOE4 allele in presumed NPH predicted later AD as follows: sensitivity 61%; specificity 77%; positive predictive value 37%; negative predictive value 90%.

Conclusion In presumed NPH patients, APOE4 associates independently with the presence of Aβ plaques in the frontal cortical biopsy. APOE4 is not a risk factor for iNPH and does not predict the response to shunt. Our data further support the view that the iNPH syndrome is a distinct dementing disease.

Trial registration number Kuopio NPH Registry (

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  • Funding The study was supported by research grants from the Kuopio University Hospital EVO Fund (5252614, 5772708), the Finnish Medical Foundation, the Health Research Council of the Academy of Finland, the Emil Aaltonen Foundation, the Sigrid Juselius Foundation and the strategic funding of the University of Eastern Finland.

  • Competing interests None.

  • Ethics approval The study was approved by the Kuopio University Hospital Research Ethics Committee, the Finnish National Supervisory Authority for Welfare and Health, and the Finnish Ministry of Social Affairs and Health.

  • Provenance and peer review Not commissioned; externally peer reviewed.