Correlation Of Renal Function With Cognitive Function And Cerebrospinal Fluid Alzheimer’s Disease Biomarker Levels

Background and objective:Alzheimer’s disease(AD)is the most common type of dementia in the old.The imbalance of overproduction and impaired clearance ofβ-amyloid(Aβ)leads to excessive aggregation of Aβin the brain,which contributes to neurological damage and ultimately AD dementia based on the Aβcascade hypothesis.Among them,99%of patients are sporadic AD,which is caused by impaired clearance of Aβin the brain.Previous studies showed that about 40%of intracerebral Aβis cleared by peripheral organ and tissues,and the kidneys were found to be involved in Aβclearance in AD mouse model.These results suggest that it is worth to explore the impact of renal dysfunction on Aβclearance and the development of AD.AD is an aging-related disease.In addition to being involved in Aβclearance,the kidney also secretes the anti-aging protein Klotho.Therefore,Klotho secretion in the kidney may also affect the development of AD and needs to be explored.The current study analyzed the correlation between renal function and cognitive function in individuals with unilateral nephrectomy,and explored the correlation between renal function and Cerebrospinal fluid(CSF)AD biomarker levels,in which was further investigated whether plasma Klotho is involved.Materials and methods1.Study of the association between renal function with cognitive function and CSF AD biomarker levels(1)To investigate the impact of renal function on cognitive function,a cross-sectional observational study was conducted.56 individuals who had undergone unilateral nephrectomy and 54 normal individuals with two intact kidneys were recruited.Cognitive function and clinical characteristics were assessed.Fasting venous blood samples were collected to detect estimated glomerular filtration rate(e GFR).(2)To investigate the effect of renal function on CSF AD biomarker levels,we enrolled33 Pi B-PET-positive AD patients and 33 Aβ-negative age-and sex-matched cognitively normal(CN)controls from Chongqing Ageing&Dementia Study(CADS)cohort.CSF and fasting venous blood samples were collected.Levels of e GFR,CSF Aβ,tau and neurofilament light chain(NFL)protein were measured.2.Study on the role of plasma Klotho in the correlation between renal function and CSF AD biomarker levels.In the present cross-sectional,the study population was the same as the subjects included in the CADS cohort described above.The levels of plasma Klotho were measured.Mediation analysis was conducted to determine whether and the extent to which the kidney-brain crosstalk was mediated by plasma Klotho.Results1.Study of the association between renal function with cognitive function and CSF AD biomarker levels(1)We found that individuals with a single kidney(SK)have lower e GFR levels compared to those with two kidneys(TK)(SK:70.09?11.58 ml/min/1.73 m~2;TK:99.29?12.44 ml/min/1.73 m~2;p<0.001).And SK have lower scores on MMSE(SK:26.29?3.83;TK:27.81?1.76;p=0.009)and Mo CA scales(SK:18.71?5.71;TK:22.00?4.05;p=0.004).(2)The e GFR was positively correlated with MMSE(r=0.246,p=0.010)and Mo CA scores(r=0.274,p=0.004).The age was negatively correlated with MMSE scores(r=-0.248,p=0.009),Mo CA scores(r=-0.304,p=0.001)and e GFR levels(r=-0.308,p=0.001).(3)The e GFR was positively associated with Aβ42(r=0.419,p=0.003),Aβ40 levels(r=0.322,p=0.024)in CSF and negatively associated with CSF T-tau levels(r=-0.360,p=0.015).2.Study on the role of plasma Klotho in the correlation between renal function and CSF AD biomarker levels.(1)We found higher plasma Klotho(AD:846.42?564.103 pg/m L;CN:575.46?394.468pg/m L;p=0.033)and lower e GFR levels(AD:116.0?22.23 ml/min/1.73 m~2;CN:149.7?31.05 ml/min/1.73 m~2;p<0.001)in AD patients compared with CN.(2)Plasma Klotho levels were negatively correlated with the e GFR(r=-0.432,p=0.001).(3)Plasma Klotho levels were negatively correlated with CSF Aβ42(r=-0.341,p=0.013).(4)Mediation analysis showed that plasma Klotho mediated 24.96%of the association between the e GFR and CSF Aβ42(all p<0.05).ConclusionsReduced renal function is associated with cognitive impairment and may impact brain Aβmetabolism via the kidney-brain crosstalk,in which the plasma Klotho may be involved as a mediator.