The effects of noncoding aquaporin-4 single-nucleotide polymorphisms on cognition and functional progression of Alzheimer's disease

Kevin G. Burfeind, Charles F. Murchison, Shawn Westaway, Matthew J. Simon, Deniz Erten-Lyons, Jeffrey Kaye, Joseph Quinn, Jeffrey Iliff

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Introduction The glymphatic system is a brain-wide perivascular network that facilitates clearance of proteins, including amyloid β, from the brain interstitium through the perivascular exchange of cerebrospinal fluid and interstitial fluid. The astrocytic water channel aquaporin-4 (AQP4) is required for glymphatic system function, and impairment of glymphatic function in the aging brain is associated with altered AQP4 expression and localization. In human cortical tissue, alterations in AQP4 expression and localization are associated with Alzheimer's disease (AD) status and pathology. Although this suggests a potential role for AQP4 in the development or progression of AD, the relationship between of naturally occurring variants in the human AQP4 gene and cognitive function has not yet been evaluated. Methods Using data from several longitudinal aging cohorts, we investigated the association between five AQP4 single-nucleotide polymorphisms (SNPs) and the rate of cognitive decline in participants with a diagnosis of AD. Results None of the five SNPs were associated with different rates of AD diagnosis, age of dementia onset in trial subjects. No association between AQP4 SNPs with histological measures of AD pathology, including Braak stage or neuritic plaque density was observed. However, AQP4 SNPs were associated with altered rates of cognitive decline after AD diagnosis, with two SNPS (rs9951307 and rs3875089) associated with slower cognitive decline and two (rs3763040 and rs3763043) associated with more rapid cognitive decline after AD diagnosis. Discussion These results provide the first evidence that variations in the AQP4 gene, whose gene product AQP4 is vital for glymphatic pathway function, may modulate the progression of cognitive decline in AD.

Original languageEnglish (US)
Pages (from-to)348-359
Number of pages12
JournalAlzheimer's and Dementia: Translational Research and Clinical Interventions
Volume3
Issue number3
DOIs
StatePublished - Sep 1 2017

Fingerprint

Aquaporin 4
Cognition
Single Nucleotide Polymorphism
Alzheimer Disease
Brain
Pathology
Genes
Amyloidogenic Proteins
Aquaporins
Extracellular Fluid
Amyloid Plaques
Age of Onset
Cerebrospinal Fluid
Dementia
Cognitive Dysfunction

Keywords

  • Alzheimer's disease
  • Amyloid β
  • Aquaporin-4
  • Cognitive decline
  • Cohort study
  • Genetics
  • Glymphatic system

ASJC Scopus subject areas

  • Clinical Neurology
  • Psychiatry and Mental health

Cite this

@article{e8c4461cd6d644f6bf220cc570ecd19e,
title = "The effects of noncoding aquaporin-4 single-nucleotide polymorphisms on cognition and functional progression of Alzheimer's disease",
abstract = "Introduction The glymphatic system is a brain-wide perivascular network that facilitates clearance of proteins, including amyloid β, from the brain interstitium through the perivascular exchange of cerebrospinal fluid and interstitial fluid. The astrocytic water channel aquaporin-4 (AQP4) is required for glymphatic system function, and impairment of glymphatic function in the aging brain is associated with altered AQP4 expression and localization. In human cortical tissue, alterations in AQP4 expression and localization are associated with Alzheimer's disease (AD) status and pathology. Although this suggests a potential role for AQP4 in the development or progression of AD, the relationship between of naturally occurring variants in the human AQP4 gene and cognitive function has not yet been evaluated. Methods Using data from several longitudinal aging cohorts, we investigated the association between five AQP4 single-nucleotide polymorphisms (SNPs) and the rate of cognitive decline in participants with a diagnosis of AD. Results None of the five SNPs were associated with different rates of AD diagnosis, age of dementia onset in trial subjects. No association between AQP4 SNPs with histological measures of AD pathology, including Braak stage or neuritic plaque density was observed. However, AQP4 SNPs were associated with altered rates of cognitive decline after AD diagnosis, with two SNPS (rs9951307 and rs3875089) associated with slower cognitive decline and two (rs3763040 and rs3763043) associated with more rapid cognitive decline after AD diagnosis. Discussion These results provide the first evidence that variations in the AQP4 gene, whose gene product AQP4 is vital for glymphatic pathway function, may modulate the progression of cognitive decline in AD.",
keywords = "Alzheimer's disease, Amyloid β, Aquaporin-4, Cognitive decline, Cohort study, Genetics, Glymphatic system",
author = "Burfeind, {Kevin G.} and Murchison, {Charles F.} and Shawn Westaway and Simon, {Matthew J.} and Deniz Erten-Lyons and Jeffrey Kaye and Joseph Quinn and Jeffrey Iliff",
year = "2017",
month = "9",
day = "1",
doi = "10.1016/j.trci.2017.05.001",
language = "English (US)",
volume = "3",
pages = "348--359",
journal = "Alzheimer's and Dementia: Translational Research and Clinical Interventions",
issn = "2352-8737",
publisher = "Elsevier Inc.",
number = "3",

}

TY - JOUR

T1 - The effects of noncoding aquaporin-4 single-nucleotide polymorphisms on cognition and functional progression of Alzheimer's disease

AU - Burfeind, Kevin G.

AU - Murchison, Charles F.

AU - Westaway, Shawn

AU - Simon, Matthew J.

AU - Erten-Lyons, Deniz

AU - Kaye, Jeffrey

AU - Quinn, Joseph

AU - Iliff, Jeffrey

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Introduction The glymphatic system is a brain-wide perivascular network that facilitates clearance of proteins, including amyloid β, from the brain interstitium through the perivascular exchange of cerebrospinal fluid and interstitial fluid. The astrocytic water channel aquaporin-4 (AQP4) is required for glymphatic system function, and impairment of glymphatic function in the aging brain is associated with altered AQP4 expression and localization. In human cortical tissue, alterations in AQP4 expression and localization are associated with Alzheimer's disease (AD) status and pathology. Although this suggests a potential role for AQP4 in the development or progression of AD, the relationship between of naturally occurring variants in the human AQP4 gene and cognitive function has not yet been evaluated. Methods Using data from several longitudinal aging cohorts, we investigated the association between five AQP4 single-nucleotide polymorphisms (SNPs) and the rate of cognitive decline in participants with a diagnosis of AD. Results None of the five SNPs were associated with different rates of AD diagnosis, age of dementia onset in trial subjects. No association between AQP4 SNPs with histological measures of AD pathology, including Braak stage or neuritic plaque density was observed. However, AQP4 SNPs were associated with altered rates of cognitive decline after AD diagnosis, with two SNPS (rs9951307 and rs3875089) associated with slower cognitive decline and two (rs3763040 and rs3763043) associated with more rapid cognitive decline after AD diagnosis. Discussion These results provide the first evidence that variations in the AQP4 gene, whose gene product AQP4 is vital for glymphatic pathway function, may modulate the progression of cognitive decline in AD.

AB - Introduction The glymphatic system is a brain-wide perivascular network that facilitates clearance of proteins, including amyloid β, from the brain interstitium through the perivascular exchange of cerebrospinal fluid and interstitial fluid. The astrocytic water channel aquaporin-4 (AQP4) is required for glymphatic system function, and impairment of glymphatic function in the aging brain is associated with altered AQP4 expression and localization. In human cortical tissue, alterations in AQP4 expression and localization are associated with Alzheimer's disease (AD) status and pathology. Although this suggests a potential role for AQP4 in the development or progression of AD, the relationship between of naturally occurring variants in the human AQP4 gene and cognitive function has not yet been evaluated. Methods Using data from several longitudinal aging cohorts, we investigated the association between five AQP4 single-nucleotide polymorphisms (SNPs) and the rate of cognitive decline in participants with a diagnosis of AD. Results None of the five SNPs were associated with different rates of AD diagnosis, age of dementia onset in trial subjects. No association between AQP4 SNPs with histological measures of AD pathology, including Braak stage or neuritic plaque density was observed. However, AQP4 SNPs were associated with altered rates of cognitive decline after AD diagnosis, with two SNPS (rs9951307 and rs3875089) associated with slower cognitive decline and two (rs3763040 and rs3763043) associated with more rapid cognitive decline after AD diagnosis. Discussion These results provide the first evidence that variations in the AQP4 gene, whose gene product AQP4 is vital for glymphatic pathway function, may modulate the progression of cognitive decline in AD.

KW - Alzheimer's disease

KW - Amyloid β

KW - Aquaporin-4

KW - Cognitive decline

KW - Cohort study

KW - Genetics

KW - Glymphatic system

UR - http://www.scopus.com/inward/record.url?scp=85020675319&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020675319&partnerID=8YFLogxK

U2 - 10.1016/j.trci.2017.05.001

DO - 10.1016/j.trci.2017.05.001

M3 - Article

VL - 3

SP - 348

EP - 359

JO - Alzheimer's and Dementia: Translational Research and Clinical Interventions

JF - Alzheimer's and Dementia: Translational Research and Clinical Interventions

SN - 2352-8737

IS - 3

ER -