Aquaporin-4 as an early cerebrospinal fluid biomarker of Alzheimer's disease

ImportanceAquaporin-4 (AQP4) plays a critical role in the glymphatic system, responsible for clearing brain solutes like A{beta} peptides. Exploring AQP4 as an Alzheimers disease (AD) biomarker might aid in the understanding of AD neuropathology and monitor the effects of novel drug candidates on the glymphatic system. ObjectiveTo determine the potential of CSF AQP4 as an early stage AD biomarker using a newly established immunoassay. DesignA 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. SettingMulticenter study: Ulm University Hospital (discovery), University of Perugia (validation cohort I), University Hospital of Torino (validation cohort II). ParticipantsDiscovery 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. ExposuresCSF AQP4 Main Outcome (s) and Measure (s)AQP4 CSF biomarker detection ResultsA 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 RelevanceThree 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 POINTSO_ST_ABSQuestionC_ST_ABSIs cerebrospinal fluid (CSF) aquaporin-4 (AQP4) an early Alzheimers disease (AD) biomarker? FindingsIn 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. MeaningCSF AQP4 is altered in early stages of AD and might be a fluid biomarker for blood brain barrier damage.