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. 2017 May 26;3(3):348-359.
doi: 10.1016/j.trci.2017.05.001. eCollection 2017 Sep.

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

Kevin G Burfeind  1 , Charles F Murchison  2 , Shawn K Westaway  2 , Matthew J Simon  1 , Deniz Erten-Lyons  2 , Jeffrey A Kaye  2 , Joseph F Quinn  2 , Jeffrey J Iliff  1   3
Affiliations

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

Kevin G Burfeind et al. Alzheimers Dement (N Y). .

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.

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Figures

Fig. 1
Fig. 1
Plots of individual data points and annualized rate of change for rs3875089 carriers and noncarriers. Graphs (A-E) show the score recorded for all five functional and cognitive test for every individual visit (after AD diagnosis) in all of the studies. From these data points, slopes are calculated for rs3875089 carriers (both homozygous and heterozygous carriers of the minor allele) and noncarriers (shown in the table). Abbreviations: CDR SoB, Clinical Dementia Rating Sum of Boxes; MMSE, Mini–Mental State Examination.
Fig. 2
Fig. 2
Plots of individual data points and annualized rate of change for rs3763043 carriers and noncarriers. Graphs (A-E) show the score recorded for all five functional and cognitive test for every individual visit (after AD diagnosis) in all of the studies. From these data points, slopes are calculated for rs763043 carriers (both homozygous and heterozygous carriers of the minor allele) and noncarriers (shown in the table). Abbreviations: CDR SoB, Clinical Dementia Rating Sum of Boxes; MMSE, Mini–Mental State Examination.
Fig. 3
Fig. 3
Schematic of AQP4 gene and AQP4 protein perivascular localization in the brain. (A) AQP4 consists of five exons (exons 0–4, shown as solid colored rectangles) and can be translated into two different isoforms. The AQP4-M1 isoform consists of exons 0–4 and is 323 amino acids long. The AQP4-M23 isoform consists of exons 1–4 and is 301 amino acids long. When the APQ4 gene is translated into the AQP4-M23 isoform, the subsequent protein aggregates into crystalline arrays that localize to astrocyte endfeet that ensheathe the cerebral vasculature. AQP4 SNPs rs3875089 and rs3763040 are located in the putative promoter of exon 1, which is the first exon of the AQP4-M23 isoform. The other SNPs are located in either the 3′ untranslated region (UTR) (rs335929 and rs3763043) or in the 3′ intronic region. (B) Immunohistochemistry for AQP4 in human cerebral cortex tissue section. AQP4 (labeled in red) is expressed on astrocyte endfeet that ensheathe cerebral blood vessels, including capillaries (B1) and large vessels (B2). Abbreviations: AQP4, aquaporin-4; SNP, single-nucleotide polymorphism.
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