Alzheimer Disease Associated Variants in SORL1 Accelerate Dementia Development in Parkinson Disease

Neurosci Lett. 2018 May 1;674:123-126. doi: 10.1016/j.neulet.2018.03.036. Epub 2018 Mar 19.

Abstract

Objective: Dementia in Parkinson disease (PD) is a common occurrence, and shows a marked overlap at a clinical and pathological level with Alzheimer's disease (AD), suggesting they share underlying disease mechanisms. Genetic variants in SORL1 have been identified in patients with AD, but a possible role in other dementias is unknown. The aim of this study was to investigate whether common polymorphisms in SORL1 affect the risk of developing dementia in a population-based cohort of patients with incident PD.

Methods: One common, nonsynonymous SORL1 variant (rs2298813; A528T) was identified in whole exome sequencing data from 185 patients with PD from the Norwegian ParkWest study, who had been followed up to the 7-year visit after diagnosis. A528T was tested for association with PD risk, the development of dementia, and in a subset of patients (n = 103) for associations with established AD cerebrospinal fluid (CSF) biomarkers measured at the time of PD diagnosis.

Results: We found an association of A528T carrier status with increased risk of developing PD dementia (HR 2.31; 95% CI 1.09-4.90; p = 0.03) compared to non-carriers. Additionally, A528T carrier status was associated with a reduced ratio of CSF β-amyloid 42 to p-Tau (p = 0.014) but no alterations in absolute AD marker levels (all p > 0.05) at the time of PD diagnosis.

Conclusion: Our results show the first association of the AD risk factor SORL1 with incident dementia in PD, providing new evidence that AD related disease mechanisms may contribute to dementia in a subset of patients with PD. Finding support for a shared etiology for AD and PD dementia provides new directions for research into treatments for these diseases.

Keywords: Alzheimer’s disease; Dementia; Genetic association; Parkinson’s disease; SORL1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alzheimer Disease / cerebrospinal fluid
  • Alzheimer Disease / genetics*
  • Amyloid beta-Peptides / cerebrospinal fluid
  • Dementia / cerebrospinal fluid
  • Dementia / complications
  • Dementia / genetics*
  • Disease Progression
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • LDL-Receptor Related Proteins / genetics*
  • Male
  • Membrane Transport Proteins / genetics*
  • Middle Aged
  • Parkinson Disease / cerebrospinal fluid
  • Parkinson Disease / complications
  • Parkinson Disease / genetics*
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Whole Exome Sequencing
  • tau Proteins / cerebrospinal fluid

Substances

  • Amyloid beta-Peptides
  • LDL-Receptor Related Proteins
  • MAPT protein, human
  • Membrane Transport Proteins
  • SORL1 protein, human
  • tau Proteins