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

Alzheimer disease associated variants in SORL1 accelerate dementia development in Parkinson disease.

Author information

1
The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway; Centre for Organelle Research, University of Stavanger, Stavanger, Norway. Electronic address: jodi.maple.grodem@sus.no.
2
The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway. Electronic address: janete.chung@uis.no.
3
The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway; Centre for Organelle Research, University of Stavanger, Stavanger, Norway. Electronic address: kristin.a.lunde@uis.no.
4
Department of Neurology, Haukeland University Hospital, Bergen, Norway; Institute for Clinical Medicine, University of Bergen, Bergen, Norway. Electronic address: charalampos.tzoulis@uib.no.
5
Department of Neurology, Haukeland University Hospital, Bergen, Norway; Institute for Clinical Medicine, University of Bergen, Bergen, Norway. Electronic address: ole-bjorn.tysnes@helse-bergen.no.
6
The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway; Department of Neurology, Stavanger University Hospital, Stavanger, Norway. Electronic address: kenn.freddy.pedersen@sus.no.
7
The Norwegian Centre for Movement Disorders, Stavanger University Hospital, Stavanger, Norway; Department of Neurology, Stavanger University Hospital, Stavanger, Norway; Department of Mathematics and Natural Sciences, University of Stavanger, Stavanger, Norway. Electronic address: guido.werner.alves@sus.no.

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

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