Aquaporin-4 polymorphisms predict amyloid burden and clinical outcome in the Alzheimer's disease spectrum

Chandra, Avinash; Farrell, Chloë; Wilson, Heather; Dervenoulas, George; Natale, Edoardo Rosario de; Politis, Marios

doi:10.1016/j.neurobiolaging.2020.06.007

Cited by 46 publications

(34 citation statements)

References 41 publications

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“…The association between AQP4 and interstitial waste clearance was further validated by a postmortem study of aging human brains, which revealed a link between reduced perivascular localization of AQP4 and Aβ deposition (Zeppenfeld et al, 2017 ). In addition, Single Nucleotide Polymorphisms (SNPs) of the AQP4 gene were associated with brain Aβ uptake on PET and the rate of cognitive decline in the spectrum of Alzheimer’s disease (AD; Burfeind et al, 2017 ; Chandra et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Aquaporin-4 Polymorphisms Are Associated With Cognitive Performance in Parkinson’s Disease

Fang

Dai

Jin

et al. 2022

Front. Aging Neurosci.

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ObjectiveAquaporin-4 (AQP4) facilitates a sleep-enhanced interstitial brain waste clearance system. This study was conducted to determine the clinical implication of AQP4 polymorphisms in Parkinson’s disease (PD).MethodsThree-hundred and eighty-two patients with PD and 180 healthy controls with a mean follow-up time of 66.1 months from the Parkinson’s Progression Marker Initiative study were analyzed. We examined whether AQP4 SNPs were associated with an altered rate of motor or cognitive decline using linear mixed model and Cox regression. We then investigated whether AQP4 SNPs were associated with Aβ burden as measured by 18F Florbetapir standard uptake values. Furthermore, we examined if AQP4 SNPs moderated the association between REM sleep behavior disorder (RBD) and CSF biomarkers.ResultsIn patients with PD, AQP4 rs162009 (AA/AG vs. GG) was associated with slower dementia conversion, better performance in letter-number sequencing and symbol digit modalities, lower Aβ deposition in the putamen, anterior cingulum, and frontotemporal areas. In the subgroup of high RBD screening questionnaire score, rs162009 AA/AG had a higher CSF Aβ42 level. rs162009 AA/AG also had better performance in semantic fluency in healthy controls. Besides, rs68006382 (GG/GA vs. AA) was associated with faster progression to mild cognitive impairment, worse performance in letter-number sequencing, semantic fluency, and symbol digit modalities in patients with PD.InterpretationGenetic variations of AQP4 and subsequent alterations of glymphatic efficacy might contribute to an altered rate of cognitive decline in PD. AQP4 rs162009 is likely a novel genetic prognostic marker of glymphatic function and cognitive decline in PD.

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Section: Introductionmentioning

confidence: 99%

Aquaporin-4 Polymorphisms Are Associated With Cognitive Performance in Parkinson’s Disease

Fang

Dai

Jin

et al. 2022

Front. Aging Neurosci.

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“…Alternatively, the redistribution of aquaporin-4 could be part of the mechanistic actions underlying glymphatic dysfunction. Recently, genetic variants of aquaporin-4 have been associated with sleep disturbances, amyloid-β burden and clinical conversion from MCI to AD [308][309][310]. While the precise role and interactions of aquaporin-4 with the glymphatic system have not been fully elucidated, these findings further support the hypothesis that dysfunction of the glymphatic system could play a pivotal role in neurodegeneration and disease pathogenesis.…”

Section: Dysfunction Of the Glymphatic Systemmentioning

confidence: 91%

Novel PET Biomarkers to Disentangle Molecular Pathways across Age-Related Neurodegenerative Diseases

Wilson

Politis

Rabiner

et al. 2020

Cells

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There is a need to disentangle the etiological puzzle of age-related neurodegenerative diseases, whose clinical phenotypes arise from known, and as yet unknown, pathways that can act distinctly or in concert. Enhanced sub-phenotyping and the identification of in vivo biomarker-driven signature profiles could improve the stratification of patients into clinical trials and, potentially, help to drive the treatment landscape towards the precision medicine paradigm. The rapidly growing field of neuroimaging offers valuable tools to investigate disease pathophysiology and molecular pathways in humans, with the potential to capture the whole disease course starting from preclinical stages. Positron emission tomography (PET) combines the advantages of a versatile imaging technique with the ability to quantify, to nanomolar sensitivity, molecular targets in vivo. This review will discuss current research and available imaging biomarkers evaluating dysregulation of the main molecular pathways across age-related neurodegenerative diseases. The molecular pathways focused on in this review involve mitochondrial dysfunction and energy dysregulation; neuroinflammation; protein misfolding; aggregation and the concepts of pathobiology, synaptic dysfunction, neurotransmitter dysregulation and dysfunction of the glymphatic system. The use of PET imaging to dissect these molecular pathways and the potential to aid sub-phenotyping will be discussed, with a focus on novel PET biomarkers.

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“…After identifying APOE 4 as a genetic risk factor for AD, CLU (also known as APOJ ), CR1 , PICAM , ABCA 7, and CD 33 were identified [ 50 , 51 , 52 ]. Astrocytic water channel aquaporin-4 (AQP4) plays a pivotal role in the glymphatic system, and AQP 4 variants were associated with Aβ burden and an increased risk of AD [ 53 , 54 ]. Several association studies on genetic variations of low-density lipoprotein receptor-related protein 1 ( LRP1 ) suggested that LRP1 variants may not influence AD risk [ 55 ] but were associated with the lipid levels [ 56 ].…”

Section: Multifactorial Pathobiology In Admentioning

confidence: 99%

Waste Clearance in the Brain and Neuroinflammation: A Novel Perspective on Biomarker and Drug Target Discovery in Alzheimer’s Disease

Uchida

2022

Cells

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Alzheimer’s disease (AD) is a multifactorial disease with a heterogeneous etiology. The pathology of Alzheimer’s disease is characterized by amyloid-beta and hyperphosphorylated tau, which are necessary for disease progression. Many clinical trials on disease-modifying drugs for AD have failed to indicate their clinical benefits. Recent advances in fundamental research have indicated that neuroinflammation plays an important pathological role in AD. Damage- and pathogen-associated molecular patterns in the brain induce neuroinflammation and inflammasome activation, causing caspase-1-dependent glial and neuronal cell death. These waste products in the brain are eliminated by the glymphatic system via perivascular spaces, the blood-brain barrier, and the blood–cerebrospinal fluid barrier. Age-related vascular dysfunction is associated with an impairment of clearance and barrier functions, leading to neuroinflammation. The proteins involved in waste clearance in the brain and peripheral circulation may be potential biomarkers and drug targets in the early stages of cognitive impairment. This short review focuses on waste clearance dysfunction in AD pathobiology and discusses the improvement of waste clearance as an early intervention in prodromal AD and preclinical stages of dementia.

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Aquaporin-4 polymorphisms predict amyloid burden and clinical outcome in the Alzheimer's disease spectrum

Cited by 46 publications

References 41 publications

Aquaporin-4 Polymorphisms Are Associated With Cognitive Performance in Parkinson’s Disease

Aquaporin-4 Polymorphisms Are Associated With Cognitive Performance in Parkinson’s Disease

Novel PET Biomarkers to Disentangle Molecular Pathways across Age-Related Neurodegenerative Diseases

Waste Clearance in the Brain and Neuroinflammation: A Novel Perspective on Biomarker and Drug Target Discovery in Alzheimer’s Disease

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