The Role of Dialysis in the Pathogenesis and Treatment of Dementia

Dearbhla M. Kelly

Disclosures

Nephrol Dial Transplant. 2019;34(7):1080-1083. 

In This Article

Amyloid-beta Clearance

One of the major pathological changes in the brain associated with AD is Aβ deposition, mainly 40 amino acids Aβ1–40 and 42 amino acids Aβ1–42. Kidney function is likely to be involved in peripheral Aβ clearance.[27] Serum Aβ levels measured in 47 CKD patients and 43 healthy controls were significantly higher in CKD patients than in healthy controls, whereas 31 of CKD patients receiving PD had lower levels comparable to those of healthy subjects. The reason for the highly elevated Aβ concentrations in renal failure patients without dialysis is unclear. The excretion of Aβs into the urine was estimated at <1% of the circulating pool under normal conditions although proteinuria may increase urinary excretion.[28]

Impaired Aβ clearance is proposed to contribute to Aβ deposition in the AD brain.[29] Thus, it has been postulated that an extracorporeal clearance of Aβ from the blood may remove brain Aβ and be a useful therapeutic strategy for AD. A prospective study of 30 HD patients demonstrated that plasma Aβ40 levels decreased or remained unchanged, whereas Aβ42 levels were unchanged or significantly increased at 18 months follow-up.[30] Mini-Mental State Examination scores of most subjects increased or were maintained at the second time point with the exception of those with extensive cerebral white matter changes. This suggests that cognitive impairment resulting from cerebrovascular disease was not improved by HD.

In a similar study of cognitively impaired HD patients, the overall clearance rates of plasma Aβ42 and Aβ40 were 28% and 35%, respectively, with predominant reduction during the initial 2 h of HD. Aβ42 but not Aβ40 baseline levels were significantly associated with Montreal Cognitive Assessment (MoCA) test results.[31] The authors argue that by inducing 'peripheral Aβ sink', HD may be considered as an anti-amyloid treatment strategy. As HD serves as 'peripheral Aβ sink', repetitive removal of plasma amyloid might also stimulate Aβ efflux from the brain, a possible explanation of the significant positive association between Aβ42 plasma levels and dialysis salvage. The rapid reduction of Aβ concentrations in the blood may act as a trigger for enhancing the excretion of Aβ from the brain, resulting in cognitive improvement.

Recent research has also investigated the peripheral clearance of Aβ by PD in an attempt to reduce the amyloid plaque burden in the brain.[32] Plasma Aβ levels before and immediately after PD in 30 patients with newly diagnosed CKD and in APP/PS1 mice (a standard animal model of AD) were measured. APP/PS1 mice underwent PD once a day for 1 month from 6 months of age (prevention study) or 9 months of age (treatment study). In both cases, plasma Aβ40 and Aβ42 levels were significantly reduced after dialysis. In the animal model, PD resulted in a decrease in Aβ levels in the brain interstitial fluid with reduced plaque deposition. The dialysis-treated mice showed reduced levels of hyperphosphorylated tau in the brain, indicating attenuated neurodegeneration along with decreased inflammation and increased microglial phagocytosis of Aβ in the brain. Their cognitive performance was also improved.

However, since amyloid deposition precedes the clinical onset of AD, it is not clear that improving the clearance of Aβ will improve cognitive function or prevent cognitive decline. The removal of Aβ plaques does not influence elimination of NFTs after NFTs have been established in the brain.[33] The presence of Aβ is associated with a decrease in cognitive performance; however, the quantitative level of Aβ inconsistently predicts the amount of cognitive decline.[34] It is suggested that other contributors, such as the hyperphosphorylation of tau, are the functional cause of degeneration after the initial onset of AD.[9] Indeed, meta-analysis of cognitive decline in preclinical AD finds tauopathy more impactful than Aβ.[35]

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