Aquaporin-4 as an early cerebrospinal fluid biomarker of Alzheimer’s disease
Authors: de San José Nerea Gómez , Halbgebauer Steffen , Steinacker Petra , Anderl-Straub Sarah , Rumeileh Samir Abu , Barba Lorenzo , Oeckl Patrick , Bellomo Giovanni , Gaetani Lorenzo , Toja Andrea , Mravinacová Sára , Bergström Sofia , Månberg Anna , Grassini Alberto , Rainero Innocenzo , Nilsson Peter , Parnetti Lucilla , Otto Markus 
Published: June 2024

Importance

Aquaporin-4 (AQP4) plays a critical role in the glymphatic system, responsible for clearing brain solutes like Aβ peptides. Exploring AQP4 as an Alzheimer’s disease (AD) biomarker might aid in the understanding of AD neuropathology and monitor the effects of novel drug candidates on the glymphatic system.

Objective

To determine the potential of CSF AQP4 as an early stage AD biomarker using a newly established immunoassay.

Design

A discovery cohort (n = 157) (2010-2022), composed by AD patients, other neurodegenerative conditions and controls (CON), was used to assess the diagnostic performance of CSF AQP4. Subsequently, AQP4 concentration across the clinical AD spectrum was analyzed in two independent validation cohorts (n = 176) (2016-2023). Stratified randomization based on diagnosis and blinded analyses were performed.

Setting

Multicenter study: Ulm University Hospital (discovery), University of Perugia (validation cohort I), University Hospital of Torino (validation cohort II).

Participants

Discovery cohort: 38 CON, 40 AD, 21 primary progressive aphasia, 20 behavioural variant frontotemporal dementia, 17 amyotrophic lateral sclerosis (ALS), and 21 Lewy body disease (LBD). Validation cohorts: 55 CON, 14 preclinical AD, 51 AD with mild cognitive impairment (AD-MCI), 39 AD dementia (ADD) and 17 mild cognitive impairment with non-AD pathology (non-AD MCI). The discovery cohort was selected through random sampling, while validation cohort I and II followed a consecutive sampling method.

Exposures

CSF AQP4

Main Outcome (s) and Measure (s)

AQP4 CSF biomarker detection

Results

A total of 333 participants were included in this study. In the discovery cohort, the median (IQR) age was 69 (61-75) years and 46.5% of the cohort were women. CSF AQP4 concentration was increased in AD patients compared to CON (p < 0.001), ALS (p = 0.015), and LBD (p = 0.012) patients. CSF AQP4 in AD patients were further analyzed in validation cohort I (median (IQR) age, 74 (71-77) years; 62.0% women), and II (median (IQR) age, 71 (65-75) years; 58.5% women). When analyzing the different stages of the AD continuum in validation cohort I, AD-MCI (p = 0.011) and ADD (p = 0.002) patients had significantly higher AQP4 concentrations than CON. Similar results were obtained in cohort II, where AQP4 levels were higher in AD-MCI (p < 0.001) and ADD (p = 0.028) patients compared to controls. The AQP4 accuracy (area under the receiver operating characteristic curve [AUC]) to distinguish AD patients from CON was 0.81 (95% CI: 0.71 to 0.90, p <0.001) in the discovery cohort, 0.70 (95% CI: 0.60 to 0.81, p<0.001) in validation cohort I and 0.82 (95% CI 0.71 to 0.94, p <0.001) in II. Moreover, patients with AD-MCI could be distinguished from non-AD MCI with an AUC of 0.79 (95% CI: 0.65 to 0.93, p = 0.002).

Conclusions and Relevance

Three independent cohorts consistently showed elevated AQP4 levels in AD (including AD-MCI and ADD) compared to CON and other neurodegenerative conditions, suggesting specificity to AD pathology. These findings contribute to understanding AD neuropathology and propose AQP4 as a potential early biomarker of AD. Further investigations are needed to proof AQP4 as a fluid blood brain barrier damage marker.

KEY POINTS

Question

Is cerebrospinal fluid (CSF) aquaporin-4 (AQP4) an early Alzheimer’s disease (AD) biomarker?

Findings

In this cross-sectional study of 333 participants from 3 different cohorts, the CSF concentration of AQP4 was significantly increased in patients with AD, both with mild cognitive impairment (MCI) and dementia, when compared to controls (CON) and other neurodegenerative conditions.

Meaning

CSF AQP4 is altered in early stages of AD and might be a fluid biomarker for blood brain barrier damage.