ABCA1‐Mediated Cholesterol Efflux Capacity to Cerebrospinal Fluid Is Reduced in Patients With Mild Cognitive Impairment and Alzheimer's Disease

Abstract

BackgroundAnimal and human studies indicate that ABCA1‐mediated cholesterol transport is important in Alzheimer's disease (AD). We hypothesized that the efficiency of cerebrospinal fluid (CSF) to facilitate ABCA1‐mediated cholesterol efflux would be reduced in participants with mild cognitive impairment (MCI) or AD compared with cognitively healthy participants.Methods and ResultsCSF was collected from a cross‐sectional study of cognitively healthy participants (n=47) and participants with MCI (n=35) or probable AD (n=26).The capacity of CSF to mediate cholesterol transport was assessed using a BHK cell line that can be induced to express the ABCA1 transporter. ABCA1‐mediated cholesterol efflux capacity was 30% less in participants with MCI or AD compared with cognitively healthy participants (P<0.001 for both). Cholesterol efflux capacity correlated with CSF cholesterol content (r=0.37, P<0.001). CSF phosphatidylcholine decreased in participants with MCI and AD compared with cognitively healthy participants (9% less in MCI and 27% less in AD compared with cognitively healthy participants, P=0.01) and correlated with CSF efflux capacity (r=0.3, P=0.001). CSF sphingomyelin also correlated with the efflux capacity (r=0.24, P=0.02). Concentrations of CSF apoA‐I and apoE did not significantly correlate with measures of efflux capacity.ConclusionsIn people with MCI and AD, the capacity of CSF to facilitate ABCA1‐mediated cholesterol efflux is impaired. This lesser cholesterol efflux in MCI supports a pathophysiological role for ABCA1‐mediated cholesterol transport in early neurodegeneration.

Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease

“…Deletion of ABCA1 gene increases amyloid β accumulation, whereas its overexpression prevents amyloid β aggregation in amyloid mouse models [6]. In support of the previous cell-based and animal studies, cerebrospinal fluid (CSF) from patients with mild cognitive impairment and Alzheimer's disease showed 30% less efficiency in the ABCA1-mediated cholesterol efflux, compared with cognitively normal participants [7 ▪ ]. Although earlier human genetic analyses provided inconsistent results [4], a recent large-scale study involving more than 92 000 individuals clearly indicated that a well established loss-of-function mutation Asp1800His (N1800H) in ABCA1, is strongly associated with a higher risk of Alzheimer's disease [8 ▪▪ ].…”

Revealing a Novel Landscape of the Association Between Blood Lipid Levels and Alzheimer's Disease: A Meta-Analysis of a Case-Control Study

“…After reviewing the full article, 357 articles were excluded, since 232 were reviews, 35 were cross-sectional studies, 22 were reporting incomplete data, 18 were cohort studies, 15 involved subjects whose mean age was under 60, 15 were animal trials, 10 were inaccessible, 8 were twin studies, and 2 had participants using statins. After excluding the above papers, 27 articles ( Table 1) were eligible for inclusion in this meta-analysis (de Bustos et al, 2000;Wada, 2000;Hoshino et al, 2002;Schonknecht et al, 2002;Borroni et al, 2003;Teunissen et al, 2003;Watanabe et al, 2004;Cankurtaran et al, 2005;Yamamoto et al, 2005;Raygani et al, 2006;Ban et al, 2009;Cascalheira et al, 2009;Kolsch et al, 2010; Zengi et al, 2011; Popp et al, 2012Popp et al, , 2013Singh et al, 2012;Xiao et al, 2012;Alam et al, 2014;Chang et al, 2014;Zhao et al, 2014;Li et al, 2015bLi et al, , 2017Yassine et al, 2016;Zheng et al, 2016;Kouzuki et al, 2018;Chen et al, 2019). One Flow diagram of the literature selection is provided in Figure 1.…”

Apolipoproteins and their subspecies in human cerebrospinal fluid and plasma

“…The role of apoA‐I in the brain is not well known. A recent cross‐sectional study in cognitively healthy participants and participants with mild cognitive impairment or Alzheimer's disease found no correlation between CSF cholesterol efflux capacity and CSF apoA‐I concentrations, suggesting a role of apoA‐I beyond cholesterol efflux [23].…”