Chronic kidney disease as a natural model of accelerated cognitive ageing: mechanisms and novel therapeutic directions"

Abstract Cognitive impairment is common in chronic kidney disease (CKD), affecting approximately 40% of patients and increasing sharply as kidney function declines. CKD accelerates many pathophysiological mechanisms shared with brain ageing, with implications for, rather than any equivalence to, the neurodegenerative diseases associated with dementia, notably Alzheimer’s disease and Lewy body dementia. Furthermore, CKD introduces distinct injuries that further amplify these pathways. The convergent mechanisms include cerebral small vessel disease, chronic neuroinflammation, blood-brain barrier (BBB) disruption, accumulation of neurotoxic uraemic solutes, gut-brain-kidney axis dysbiosis, and impaired glymphatic clearance; superimposed on these, haemodialysis imposes repeated episodes of acute cerebral haemodynamic stress. Recent evidence also highlights the kidney’s failure to clear circulating aggregation-prone proteins, such as amyloid-β and α-synuclein. Because these processes develop earlier and progress more rapidly in CKD than in the general ageing population, they effectively create a ‘time-compressed’ version of age-related cognitive decline. In this review, we propose reconceptualising CKD as a prevalent clinical model of accelerated cognitive decline. We examine converging evidence from epidemiology, neuroimaging, and molecular studies to support this hypothesis. Finally, we discuss how emerging therapies—ranging from targeted adsorbents and Klotho replacement to microbiome modulation and preventive immunology—are testable hypotheses in CKD, with possible relevance for dementia in the wider ageing population.