A prospective study on blood Aβ levels and the cognitive function of patients with hemodialysis: a potential therapeutic strategy for Alzheimer’s disease

Abstract

To obtain the proof of concept of a novel therapy for Alzheimer's disease (AD), we conducted two prospective studies with hemodialysis patients who had amyloid β protein (Aβ) removed from their blood three times a week. One major pathological change in the brain associated with AD is Aβ deposition, mainly 40 amino acids Aβ1-40 and 42 amino acids Aβ1-42. Impaired Aβ clearance is proposed to be one cause of increased Aβ in the AD brain. Thus, we hypothesized that an extracorporeal removal system of Aβ from the blood may remove brain Aβ and be a useful therapeutic strategy for AD. In the first prospective study, plasma Aβ levels and the cognitive function of 30 hemodialysis patients (65-76 years old) were evaluated at baseline as well as 18 or 36 months after. Although plasma Aβ1-40 levels either decreased or remained unchanged, levels of Aβ1-42 either remained unchanged or increased at the second time point. Mini-Mental State Examination scores of most subjects increased or were maintained at the second time point. Aβ1-40 influx into the blood correlated with MMSE at the second time point. In the second prospective study, five patients (51-84 years old) with renal failure were evaluated before and after the initiation of hemodialysis. Plasma Aβ levels decreased, while cognitive function improved after initiating blood Aβ removal. Therefore, long-term hemodialysis, which effectively removes blood Aβ, might alter Aβ influx and help maintain cognitive function.

Estimated Glomerular Filtration Rate is not Associated with Alzheimer’s Disease in a Northern Ireland Cohort

“…Other case-control studies of similar size have also reported lower eGFR in AD cases compared to controls [32,33] providing some support for the hypothesis that reduced renal function contributes to impaired Aβ clearance and increased cerebral deposition [13][14][15][16][17][18]34]. Our current findings support data from the Cardiovascular Health Cognition Study in 3,349 individuals, where an association with serum creatinine and vascular dementia was identified but not in those with AD [35].…”

“…Amyloid-β (Aβ) is the hallmark constituent of AD plaques and renal clearance has been proposed as a mechanism that aids the removal of cerebral Aβ [13]. An imbalance between the processes of production and clearance leads to Aβ accumulation and AD development and has become a therapeutic target of diseasemodifying agents [14].…”

<p>Removal of Aβ Oligomers from the Blood: A Potential Therapeutic System for Alzheimer’s Disease</p>

“…24 Additionally, cognitive function was maintained or improved slightly in a prospective study of 30 hemodialysis patients. 20 We also reported that a lower risk of dementia correlated with a longer duration of hemodialysis in a study that included more than 200,000 hemodialysis patients in Japan. 25 Other groups have shown that removing Aβs from peripheral circulation may be useful therapy for AD patients.…”

“…8,17 In an earlier study, we found that E-BARS carried out on human subjects and that targeted whole blood with HexDC or dialyzers resulted in clearance of Aβ monomers Aβ 1-40 and Aβ 1-42 . 8,15,17,18,20 Most interesting, the extent of Aβ monomer clearance during a single four-hour session of hemodialysis matched the total Aβ monomer load in the brain. 21…”

“…17,18 Hemodialyzers remove blood Aβ mainly via adsorption. 16,19 Interestingly, a substantial influx of Aβ was from peripheral tissues into the blood was observed during hemodialysis; 17,18,20 the total amount of Aβ influx during one 4-hr session of hemodialysis was comparable to the total amount of Aβ present in the brain. 21 Furthermore, our histopathological study revealed significantly diminished accumulation of Aβ in the brains of patients undergoing hemodialysis as compared to agematched control subjects who were not undergoing hemodialysis.…”