Rare Genetic Variant in SORL1 May Increase Penetrance of Alzheimer's Disease in a Family with Several Generations of APOE-ɛ4 Homozygosity

J Alzheimers Dis. 2017;56(1):63-74. doi: 10.3233/JAD-160091.


Background: The major genetic risk factor for late onset Alzheimer's disease (AD) is the APOE-ɛ4 allele. However, APOE-ɛ4 homozygosity is not fully penetrant, suggesting co-occurrence of additional genetic variants.

Objective: To identify genetic factors that, next to APOE-ɛ4 homozygosity, contribute to the development of AD.

Methods: We identified a family with nine AD patients spanning four generations, with an inheritance pattern suggestive of autosomal dominant AD, with no variants in PSEN1, PSEN2, or APP. We collected DNA from four affected and seven unaffected family members and performed exome sequencing on DNA from three affected and one unaffected family members.

Results: All affected family members were homozygous for the APOE-ɛ4 allele. Statistical analysis revealed that AD onset in this family was significantly earlier than could be expected based on APOE genotype and gender. Next to APOE-ɛ4 homozygosity, we found that all four affected family members carried a rare variant in the VPS10 domain of the SORL1 gene, associated with AβPP processing and AD risk. Furthermore, three of four affected family members carried a rare variant in the TSHZ3 gene, also associated with AβPP processing. Affected family members presented between 61 and 74 years, with variable presence of microbleeds/cerebral amyloid angiopathy and electroencephalographic abnormalities.

Conclusion: We hypothesize that next to APOE-ɛ4 homozygosity, impaired SORL1 protein function, and possibly impaired TSHZ3 function, further disturbed Aβ processing. The convergence of these genetic factors over several generations might clarify the increased AD penetrance and the autosomal dominant-like inheritance pattern of AD as observed in this family.

Keywords: APOE; Alzheimer’s disease; SORL1; genetics; penetrance.

MeSH terms

  • Aged
  • Alzheimer Disease / genetics*
  • Amyloid beta-Protein Precursor / genetics
  • Apolipoprotein E4 / genetics*
  • Family Health*
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Male
  • Middle Aged
  • Mutation / genetics*
  • Nociceptin Receptor
  • Presenilin-1 / genetics
  • Presenilin-2 / genetics
  • Receptors, Opioid / genetics*


  • Amyloid beta-Protein Precursor
  • Apolipoprotein E4
  • Homeodomain Proteins
  • PSEN1 protein, human
  • PSEN2 protein, human
  • Presenilin-1
  • Presenilin-2
  • Receptors, Opioid
  • TSHZ3 protein, human
  • Nociceptin Receptor
  • OPRL1 protein, human